AVBS2001 INTRODUCTORY VETERINARY PATHOGENESIS

FORMULAE

True positives
Sensitivity =
True positives+ false negatives
True negatives
Specificity =
True negatives+ false positives
true positives
PPV =
true positive+false positives
truenegatives
NPV =
true negatives +false negatives
( sensitivity)( prevalence)
PPV =
( sensitivity )( prevalence )+(1specificity)(1 prevalence )

LEARNING OBJECTIVES

Describer the pathogenesis of disease in terms of the basic interactions

between the host, agents of disease and the environment
Apply understanding of the host-pathogen-environment interaction to propose
potential ways that environmental changes (natural or in husbandry) might
increase or decrease the susceptibility of the host to disease
Explain the basic pathological processes, which are host responses that
manifest as disease
o Degeneration and necrosis
o Immunity, inflammation and repair
o Circulatory disturbances
o Disorders of growth
o Tissue deposits and pigments
Students should be able to
o Describe what each of these processes involves
o Relate them to the changes that take place in tissues
o Recognise and methodically describe and, on an elementary level,
interpret these changes in histological sections
Describe the range of agents of disease (such as genetics, physical (e.g. heat,
trauma) and chemical agents (e.g. nutrients, toxins and drugs) and infectious
agents
o Describe the basic structure, morphology and behaviour of infectious
agents of disease (including bacteria, viruses, fungi, protozoa and
metazoan), and
o Explain the general mechanisms by which they cause disease
Evaluate the usefulness of cytology, histopathology, practical microbiological
and parasitological techniques and immunology-based tests in disease
investigations in both diagnostic work and research and be able to select
appropriate specimens for these techniques
Cell injury
 o Define cell injury
o Distinguish reversible vs irreversible cell injury
o Characteristics of apoptosis
o Characteristics of necrosis
o Central role membrane function/dysfunction
o Importance of free radicals in damaging membranes
o Morphology of cell injury apoptosis and non-apoptotic cell injury
o Morphology of necrosis
Inflammation
o Explain the concepts of tradeoff, clinical disease, subclinical disease,
elimination, colonisation, latency, repair (fibrosis/regeneration)
o Describe the overall immune system and explain how our
understanding of the immune system has evolved
o Describe the physical and chemical components of the innate immune
system: physical boundaries, complement, chemokines, vascular
changes, oedema
o Explain how these elements interact to eliminate pathogens and/or
damage the host
o Describe morphological changes in tissues associated with these
responses
o Understand the basic general principles of inflammation and how they
might manifest in animals
o Describe the vascular events that occur in inflammation including
haemodynamic changes, permeability changes, and the event
involving leucocytes. Included in this should be a basic understanding
of how the biochemical mediators of inflammation fit into the overall
inflammatory process
o Explain how these elements interact to eliminate pathogens and/or
damage the host
o Explain how elements of the innate response interact with the adaptive
response
o Describe morphological changes in tissues associated with these
responses
Know the main inflammatory cells in the body, be able to identify
them in tissues; understand their functions and under what
circumstances they will characterise a particular inflammatory
response
o Understand the fundamental basis of tissue repair and factors that may
inhibit or delay repair
Disorders of growth
o Understand the concepts of controlled and uncontrolled disorders of
growth
o Be familiar with the commonly-used terms in disorders of growth
o Have a sound understanding of the role of viral agents and physical
agents in the aetiopathogenesis in neoplasia and be able to give
relevant examples
o Understand and be able to describe the 3 key factors critical in the
development of congenital defects, giving specific examples to
illustrate their effect
Apply an understanding of the critical developmental time points
in embryonal and foetal development
 o Understand congenital defects can manifest as anatomic anomalies or
biochemical defects and be able to give examples of each of these
Host-pathogen interactions
o Recognise aspects of host-pathogen interaction and place them in
context with HPE interactions
o Explain the important of HP interactions in the manifestation of disease
outcomes (exposure, colonisation, subclinical disease, clinical disease),
and in managing health/disease
o Explains some of the evolutionary forces that shape host-pathogen
interactions
Epidemiology
o Identify and disconnect the HPE factors that are relevant in the triad to
know how to control and prevent disease
Immune-based testing
o Understand the interpretation and utility of different types of diagnostic
tests
Virology
o Describe the basic structure of a virus and discuss how this differs from
bacteria and fungi
o Explain the differences between non-enveloped and enveloped viruses
and DNA viruses and RNA viruses with respect to their different
properties, using examples discussed in lectures
o Discuss how mutation in the viral genome can later the host range and
virulence
o Using influenza viruses as the classic example, describe the difference
between antigenic shift and antigenic drift and its implication the
outbreak of disease
o Describe the types of virus-cell interactions that occur using examples
of viral diseases that have this type of interaction
o Discuss the mechanisms by which viruses can cause cell damage by
describing their effects on individual cell morphology and ow it
influences the epidemiology of disease and the type of disease seen
o Explain the meaning of the terms cytopathic effects (CPE),
haemadsorption, syncytia formation, viral interference, inclusion bodies
o Explain the difference between lytic and non-lytic viral infections
o List and describe the types of virus-cell interactions giving examples of
viruses that have this type of interaction
o Explain the difference between persistent and non-persistent viral
infection with regard to the pathogenesis of cellular and organ damage
o List and describe the possible effects of viral infections on cell
morphology
o Discuss the mechanisms of the terms cytopathic effects,
haemadsorption, syncytia formation, viral interference, inclusion bodies
o Use the information provided in the immunology section of this course
to explain what interferons are
o Outline the different routes by which viruses gain entry to the body,
giving examples of viruses that use this route and discuss the host
defence mechanisms that viruses must overcome at each of these sites
of entry
o Explain what is meant by viral tropism
 o Using examples, discuss how viruses spread throughout the body after
entry
o Explain the possible outcomes of viral infection of the foetus
o Outline the basic mechanisms by which viruses may lead to the
production of disease in the animal, giving specific viral examples of
each
o Discuss, using examples, how some viruses predispose to secondary
infections with other agents of disease
o Give examples of viral disease of animals complicated by bacterial
infection or autoimmunity
o Explain the terms persistent, latent, chronic, slow
o Discuss the mechanisms by which retroviruses induce oncogenesis
o Discuss the mechanism by which DNA viruses induce oncogenesis
o Explain th3e methods of diagnosing viral disease that include the
detection of virus, viral antigens, viral nucleic acid, or antibody against
the virus, with the method used dependent on the particular virus in
question
o Explain what is meant by the term serology
o Describe the basic principles of ELISA, PCR, immunohistochemistry,
immunofluorescence as methods of detecting viral infections, using
examples of how they are used in clinical practice

Objectives:

Understand parasitosis as a form of symbiosis

Understand and correctly apply the descriptive terminology for kinds of parasites and types of hosts
Understand factors behind the degree of harm
Explain the reasons whys under natural condition parasites rarely cause disease
Explain the reasons why parasites cause disease at farms as well as our homes

Classification of diseases according to:

Agent of disease
Manifestation of the disease (pathology)
o Degeneration and necrosis
o Immunity, inflammation and repair
o Circulatory disturbances
o Disorders of growth
o Tissue deposits and pigments
Effect on the host
Host response
Environment (e.g. frostbite, compromise of skin barrier due to moisture)

Factors in the HPE interaction:

Host
o Behavioural defences
o Innate immunity
Barrier defences
Non-specific chemical defences (free radicals, HCl of the stomach)
Non-specific cellular defences
o Adaptive immunity
Antigen presentation
Th1 dominated pathways of cell-m,ediated immunity
Th2 dominmated pathways of antibody-mediated immunity
o Host response
o Population density high density allows enough new nave subjects (children) to infect in order to
maintain the pathogen population
 Agent of disease
o Virulence
o Physical/chemical features
o Genetic mutations/inheritance
Environment

->Clinical signs and lesions are caused by more or less of a combination of the effects of the agent and the host
response to it

Disease can affect:

The environment
The host
The pathogen
o Host-pathogen co-evolution response challenges pathogen to change/evolve in order to survive.
Depends on
HP equilibrium
Virulence of organism
Hosts immune system
o Evolution of pathogen-host pathogen increases chance of survival of species, causing both to
form an evolutionary unit e.g. white-tail caribou parasite kills competitors but only causes minor
disease in them
o Evolution of pathogen genes equal rate across all
Non-synonymous advantageous in surface domains
Non-synonymous disadvantageous in internal domains
o Increase of resistance to host by transfer among/between species

Sheep:

High moisture in pasture causes growth of toxic fungus (Pithomyces chartarum which produces
sporidesmin)
Sheep are hungry
Chlorophyll and chlorophyll breakdown
Treatment
o Remove affected sheep from sunlight
o Prevent more toxin ingestion
o Supportive therapy
Prevention
o Avoid pasture conditions that promote build-up of dead plant material
o Remove sheep from risky pastures
o Spore counts in pastures

Chlamydia pecorum in koalas:

Pre-disposing factors of environment

o Fragementation
o wAter table
o fire regimes
o Regrowth
o Livstock
o Hunting
o Translocations
Factors of host
o Host response to infection
Behavioural defences
Innate immunity
Adaptive immunity
o Nutrition
o Toxins
o Territorial stress
o Genetic changes
o Co-infection (KoRV)
Pathogen factors
o Concomitant infection with other pathogen
o Antigenic variability
o Strategies to evade host
Pathological processes
o Conjunctivitis
o Proliferative lesion in conjunctivae secondary to inflammation
 o Exudative inflammation in urogenital tract

Equilibrium between resistance and disease:

Imperfect equilibrium survival of pathogen,

without causing clinical disease (subclinical
disease) by:
o Replicating within phagocytes
o Being sequestered in granulomas
Dynamic equilibrium
o Organisms that optimise transmission
rate will persist longer
o If morbidity reduced, then can inhabit the
same host for longer
o However, might prefer rapid transmission
between hosts
Solitary host species -> less
chance of transmission of
disease and higher chance of survival of species
Shorter lifespan of host -> more chance of breeding before dying
Adaption most common interaction
o Of adherence molecules to receptors
o Of disease/repair cascades/pathways
o Of antigens pathogens have to multiply their antigens to increase evasion by host

Toxoplasmosis:

Permanent host: cats

Vectors: rodents
Oocysts shed in cat
Evolutionary HP interaction
o Rats with Toxoplasma in their brain.allowing Toxoplasma to infect more hosts
Less stealthy
Attracted to the smell of cats

Pathogen infection:

1. Infection comes in contact with host

2. Attachment
3. Multiplication
4. Persistence
5. Colonisation
6. Elimination

Term Definition
Disease abnormality of structure or function, or both, in a tissue, organ or whole animal, product of a
complex interaction between the host, the pathogen and the environment. Can be due to the
effect of the causative agent, or the hosts response to it
Colonisation An outcome of infection whereby a microbe exists and replicates on a host surface without
causing disease, especially in the case of mucosal surfaces, which can then progress to
invasion
Commensals Microogranisms that establish an inoffensive relationship with the host through colonisation,
and are usually present in that host
Compromise An altered state of the host that makes it susceptible to agents of disease
Exposure Potential for contact between host and pathogen, which, if realised, causes infection
Invasion An outcome of infection whereby the microbe replicates, spreads and causes subclinical or
clinical disease
Invasiveness Capacity of agents of disease to penetrate cells or tissues
Infection Direct contact between the host and infectious agent
Latency Persistence of an organism in a dormant state after invasion of the host during which disease
is not progressive
Pathology the structure and functional manifestations of disease, OR the branch of science dealing with
the essential nature of disease, especially the changes in body tissues which cause or are
caused by disease
General the study of the underlying nature of disease processes or pathological principles
pathology
Systemic the study of the peculiarities of disease affecting each body system
pathology
Pathogenesis the development of disease, including examination of the relationship between the
aetiological agent and the lesion as well as the relationship between the lesion and the
clinical signs
Pathophysiol the physiology of disordered function
ogy
Saprophyte Environmental microorganism that exists on dead or decaying organic matter
Aetiology The science dealing with the causes of disease (common usage = causes of disease)
Aetiological Pathogen/causative agent/ agent of disease involved in a specific disease event
agent
Microbiology The study of the infectious agents/pathogens including bacteria, mycoplasma, rickettsia,
viruses and prions
Mycology The study of the fungal infectious agents
Parasitology The study of the protozoan and metazoan infectious agents (usually referred to as parasites)
Pathogen Aetiological agent/agent of disease, including infectious agents, physical and chemical
agents
Pathogenic Capable of causing disease
Pathogenicit The ability of a pathogenic agent to produce disease in a host
y
Clinical sign An objective physical manifestation of a disease detected at clinical examination of an
animal
Gross The study of the changes causing or caused by disease, visible to the naked eye
pathology
Histopatholo The study of disease at the microscopic level, involving the examinations of the changes
gy caused by or causing a disease at the cellular and tissue level
Lesion A structural or functional alteration in a tissue or organ due to disease

Fields of study in disease:

Pathogenesis cause and development of disease

Morphological diagnosis morphological changes due to the disease
Pathophysiology functional sequelae of the morphologic changes

Shape of lesion:

Agents of disease:

Infectious (living organisms; not necessarily contagious)

o Bacteria
o Viruses
o Fungi
o Protozoan parasites
o Metazoan parasites
o Prions/infectious proteins
Physical
o Temperature extremes
o Radiation
o Physical trauma
Chemical agents
o Toxins, poisons, drugs
o Metabolites (or their insufficiency)
o Free radicals
Genetic factors
Idiopathic (cause uncertain)

Manifestation of disease: agents of disease dont always cause disease depends on interaction between host,
pathogen and environment

Clinical vs subclinical:
 Clinical
Pathogen present and causing damage in the tissue
at a sufficient level to cause clinical signs
Often only identifies disease once significant
damage has been done/the animal has already
become contagious
Subclinical
Pathogen present and causing damage/abnormality
in the tissue, not sufficiently to cause clinical signs
but sufficiently to be detected by laboratory tests
Allows to catch disease early in the case of
contagious diseases in a group of animal

Diagnosis Prognosis
Identification of the disease process and causative Determining the outcome of the disease on the
agent animals health

Liver anatomy

Dual blood supply

o Arterial (25%) hepatic artery, branch of celiac trunk
o Venous (75%) portal vein, coming from
1. Spleen
2. Pancreas
3. Intestines
Anatomincal structural unit: lobule
o Hexagonal
o Point where terminal branches of all incoming/coming vessels meet
o Central vein travels through centre, which carries blood to hepatic vein
o Portal triad (bile duct branches, branches of portal vein, branches of hepatic artery)
Functional structural unit: acinus
o Diamond-shaped
o Portal triads and central veins form the corners
o 3 different zones:
1. Central zone first to receive blood
2. Intermediate zone
3. Peripheral zone last to receive blood but source of bile

Blood flow within liver:

1. Branches of portal vein travel through each lobule of the liver

2. Join together to form central vein
3. Central veins join to form sublobular veins
4. Sublobular veins join to form hepatic veins
5. Hepatic veins exit the liver back to the heart

Types of tissues:

Basic Tissue type Appearance Function Location

type
Epitheliu Simple Single layer of flattened cells with disc-shaped Allows Glomeruli,
m squamous nuclei and sparse cytoplasm passage of air sacs,
materials lining of
by heart,
diffusion blood and
and lymph
filtration vessels
Less
specialise
d uses
Simple Cubelike cells with large, spherical nuclei Secretion Kidney
cuboidal and tubules
absorption

Simple Tall cells with oval nuclei, may have cilia and Absorption Digestive
columnar goblet cells , tract, some
secretion, glands,
ciliary bronchi,
action uterine
tubes

Pseudostratifi Not all cells same length, usually ciliar, goblet cells Mucus Large gland
ed ciliated secretion ducts,
columnar and upper
propulsion respiratory
tract

Stratified Several layers of flattened cells with keratinised Protects Oesophagu

squamous upper cells and a basal layer of cuboidal/columnar underlying s, vagina,
epithelium cells abrasion- urethra,
prone anus,
tissues epidermis
 Stratified Two layers of cubelike cells Protection Large duts,
cuboidal mammary
glands,
salivary
glands

Stratified Several layers of elongated cells with basal layer Protection, Male
columnar of cuboidal cells secretion urethra.
Rare in
body

Transitional Mixture of several layers of squamous (surface) Permits Ureter,

and cuboidal (basal) cells stretching bladder,
urethra
Cirrhosis: end-stage liver disease

end responses to chronic damage to liver which causes replacement of lost parenchyma with scar tissue
(fibrosis), which then constricts and cuts off blood supply
Expected pathophysiology
o Hypoprotienaemia
Circulatory disturbance oedema
o Reduced clotting factors circulatory disturbance

Hernia: externalisation of abdominal contents

Intussusception: internalisation of a segment of intestines within another section of intestines due to peristalsis

Symptom Possible cause Diagnostic test Disease

possible
Red urine Erythrocytes in urine (haematuria) Place under microscope
Haemoglobin in urine to identify RBCs
(haemobglobinuria)
Myoglobin in urine (myoglobinuria)

CELL INJURY

Cell injury: any change that results in a cells loss

of the ability to maintain homeostasis due to
exceeding its adaptive capacity to change, which
leads to morphological changes

Types
o Reversible if injurious agent
removed, cell can return to normal
function
o Irreversible even in injurious agent
removed, normal function will not
return (and cell will probably die)
Responses by cell
o Recovery
o Adaptation of homeostasis and
metabolic pathways
o Irreversible failure of homeotasis
Detection
o biochemistry testing to determine
concentration of metabolites usually inside the cell to indicate that cells have died
o detecting enzymes (including specific isomer) found in the blood/serum to determine which tissue
it comes from
Causes
o Hypoxia MOST IMPORTANT
Circulatory disturbances
O carrying capacity
Interference with respiratory chain (e.g. metabolic)
o Physical agents
Heat
Cold
Radiation
Trauma
o Chemical agents
Toxins, poisons, drugs
Metabolites
Free radicals
o Genetic factors
o Infectious agents ->inflammation
o Immune response

->Morphological changes lag behind biochemical changes, so a cell showing cell injury may already have died
Normal response to changes: once exceeded capacity, cell injury occurs

Cellular atrophy
Hypertrophy
Alteration of specific metabolic pathways

Adaptive homeostasis: adaptive response

to cell injury

Disorders of growth
o Controlled
Hypertrophy
increased size of cells
Physiological
o Hormone-induced
o Increased workload
Pathological
o Heart haemodynamic overload due to
High BP
Faulty valves
Hyperplasia increased number of cells
Physiological
o Hormonal
o Compensatory following loss of tissue
Pathological
o Excessive hormonal stimulation
o Can progress to neoplasia
Atrophy decreased size of cells
Metaplasia reversible change of one differentiated cell type to another
o Uncontrolled
Changes to epithelium
o Acquired (inflammation, trauma)
Hyperplasia
Hyperkeratosis (thickening of keratin layer)
Changes to storage

Ulceration: loss of epithelial lining

Hyperplasia Hypertrophy

Loss of cell function caused by:

Disruption of integrity of cell membranes

o Protein synthesis disruption (due to rER mb problems)
o Mb permeability disruption
o Mt respiration disruption
o Free radicals intermediates to ETC which are usually neutralised by antioxidants (se, Vit E,
superoxide dismutase, gluthatione)
Dont travel far by themselves, but cause long-distance-acting free radical chain
reactions
Formed naturally by oxidative phosphylation
Formed by the interaction with cellular components of
Ionising radiation
Toxins
Released by enzymes and neutrophils in fighting pathogens
Released by enzymes of the sER in detoxifying toxins effect more important than the
actual effect of the toxin most important liver due to high sER development
Types
Cytochrome P-450 oxidase
ROS (reactive oxygen species) from redox reactions: O 2- (superoxide), H2O2,
OH.
Causes:
Disrupts rER protein synthesis
Peroxidates mb lipids, causing the mb to rupture (lipid peroxidation)
 1. Free radicals + unsaturated lipids -> organic free radical
2. Organic free radical + O2 -> lipid hydroperoxyl radical
3. -> lipid radical + lipid peroxide
4. Lipid peroxide -> aldehyde + organic free radical
Damages protein and nucleic acids, causing genetic and metabolic problems
Disrupt mt energy production
Discrupts control of mb permeability
Lack of energy
o Na+/K+ ATP-ased pump stops working
Cell swells due to entry of Na+ and water
with it
Disruption of cardiac function due to exit of
K+
Swelling of mt, disrupting energy production
Swelling of rER, disruption protein synthesis
Anaerobic glycosis used instead -> build-up
lactic acid -> pH -> inhibits respiratory
enzymes
o Lack of synthesis
o Lack of heat production
o Lack of specialised cell function, e.g. contraction,
secretion
o Caused by:
Hypoxia
Oxygen not reaching blood, i.e. lung dysfunction
Oxygenated blood not reaching tissues (infarction, tumour, hypovolemic shock
Respiratory poisons which irreversibly bind O2 in the cell and prevents its use
Metabolic problems insufficiency of any metabolite in the aerobic respiration pathway

Progress of cell injury:

1. Switch to glycolysis and depletion of glycogen

cell injury Reversible

2. Influx of Na+ and Ca2+ and escape of K+ and Mg2+ due to failure of
Na+/K+ pump
3. Fall in intracellular pH
4. Mt swells and loses its granules
5. Chromatin starts clumping
15. Pyknosis
damage Irreversible

16. Swelling of lysosomes

17. Loss of mt enzymes and calcification

18. Permeability to large molecules (lysosome and cell mb)

necrosis

19. Release of lysosomal enzymes

20. Calcification
cell

21. Karyolysis and digestion of all cellular components

Treatment of disease:

Break the HPE interaction by

o Breaking the interaction between

Protection against cellular damage:

Cellular antioxidants
o Se + glutathione
o Vit E
o Ascorbate
o Superoxide dismutase: superoxide (O2-)-> H2O2
o Catalase: hydrogen peroxide
o Sulfydryl compounds, e.g. glutathione

Infection: contact between the aetiological agent and the host, whether or not a reaction is caused

Benefit host (e.g. gut bacteria)

Neutral effect
 Negative effect

Contagious disease: infectious disease that can be spread between animals quite easily
Infectious disease: disease caused by an infectious agent

Stages of infectious disease:

1. Exposure
2. Infection
a. By compromising primary defences
i. Vectors
ii. Inhibiting apoptosis
iii. Production of digestive enzymes
iv. Taking advantage of natural breaks (mouth, gut, etc.)
v. Taking advantage of artificial breaks
b. Avoidance of clearance using adhesion molecules
c. Impairing mucociliary escalator function
d. Due to environmental factors
i. Abrasion
ii. Trauma
iii. Maceration
3. Colonisation
a. Overcoming innate defences
i. Production of antagonists to innate pathogen-killing chemicals
ii. Circumvent phagocytosis
1. Inhibit lyososome fusion
2. Resist enzymes
3. Adaptation to cytoplasmic replication
iii. Kill phagocytes using toxins
b. Overcoming adaptive defences
i. Not having antigens to stimulate response
ii. Evasion of complement MAC due to peptidoglycan layer in mb
4. Subclinical disease
5. Clinical disease

Symptoms of cell death/cell injury:

Non-defined nuclei
Pink cytoplasm sign of lack of protein
Protein clumps

->Helicobacter can cause disease without invading tissue by placing itself in the stomach. Some strains of E.
coli as well
->All microbes can potentially become pathogens given favourable host/environmental conditions

Reversible cell injury Irreversible cell injury Cell death

Cytoplasmic vacuolation/vacuolar o Nuclear
degeneration fragmentation
Cloudy swelling (karyohexis)
Hydropic change pale, frothy o Disruption of cell
cytoplasm sign of invasion of membrane
water into cell
Fatty denegaeration,
o
Ultrastructural changes
o Loss of cell mb
specialisations (villi, cilia)

Laminitis: inflammation of the laminae, the projections of the soft tissue into the hard part of the hoof which
hold the hard part of the hoof in place and maintains the bones in place

Clamydiosis: inflammation of eyes and urogenital tract in koalas

Causes:
o Blindness
o Infertility
Host factors
o Territorial stress
o Genetic changes (MHC)
o Co-infection (KoRV)
o Nutrition
 o Toxins
Environmental factors
o Transloacations
o Fragmentation of the environment

Problems arising with immune response:

Intracellular survival of phagocytosed organisms

Circulatory disturbances

Types of circulatory disturbances:

Circula Definit Types Causes Symptoms/ Histolo Properties

tory ion effects gy
distur
bance
Oedem Excessi Localised hydrostatic due to Wet, swollen, Swollen Affects lowest
a ve Generalised impaired venous yellow extracel part of body
extrace Transudate outflow (NOT clotting fluid lular in terms of
llular (passes arterial P) oozing from space gravity
water through o Local tissue, retains filled
in the capillary thrombu shape of with
intersti endothelium s, pressure pink
tial ) tumour, point fluid
fluid Exudate abscess, scatteri
space (leaks from enlarged ng of
damaged organs, tissues
capillary) torsion
Ascites o Systemic
(transudate heart
in abdominal failure
cavity) plasma oncotic
pressure
(hypoproteinae
mia)
o Liver
disease
(impaire
d
productio
n of
plasma
proteins)
o Malnutrit
ion
o Haemorr
hage
o Protein
loss
glomerul
opathy
o Parasites
Lymphatic
physical
obstruction
o Filarial
infection
o Trauma/s
urgery
o Inflamma
tion
o Neoplasi
a
vascular
permeability (e.g.
inflammation and
histamine-like
 toxins)
[Na+]

Infarcti Lack of Haemorrhagi Occluded arterial Organs

on and oxygen c blood still supply (unlikely in with
ischae flowing to veins due to high single
mia necrotic network of alternate blood
tissue pathways) supply
Anaemic Thrombo-emoblic are very
ring of disease susceptibl
necrotic Local e to
tissue filled vasoconstriction anoxic
with Extrinsic injury
haemorrhagi compression of (brain,
ng tissue vessels kidney,
Recent Torsion causing heart)
(<12h) twisting of vessels Mesenchy
large, will mal cells
apex resist
towards are anoxic
of vascular injury
occlusion, (large
coagulative network
necrosis of arterial
(dead tissue supply) -
remains preserve
intact due to connectiv
lack of e tissue
proteolysing to allow
enzymes), regenerat
blood ion
>12h Risk by
surround by o A
zone of n
acute a
inflammatio e
n m
Old tissue i
repair and a
fibrosis o
present R
Stroke a
(liquefactiv t
e necrosis) e
cerebral
infarct o
Intestinal f
infarct due b
to torsion l
Pulmonary o
infarct due o
to CHF or d
anaemia
rather than
f
infarcts due
l
to dual blood
o
supply
w

Hypera An
emia excess
of
blood
in
arteriol
es
supplyi
ng a
tissue
 due to
arteriol
e
expans
ion
Conges Excess
tion
Thromb blood Injury to Fibrinolys
osis constit endothelial cells is
uents (trauma, degradati
formin toxaemia, on of the
ga metabolic fibrin by
solid disorders, specific
mass inflammation) enzymes
(throm usually contain (plasmin
bus) anticoagulating ) to form
forms agents, so trauma fragment
within to them exposes s which
a blood subendothelial are then
vessel collagen degraded
or Disrupted blood by liver
heart flow (external protease
which compression, s
attache excessive Organisa
s to the turbulence, lack tion and
vessel of movement, recanalis
wall thickening of ation
vessel wall) modificat
brings platelets ion of the
closer to blood
endothelium pathway
o Deep Embolis
vein m
thromb abnormal
osis body in
(DVT) the
o Aneuris circulatio
ms n
o Cardiac Infarction
anomalie
s
Hypercoagulabilit
y of blood
o Definicie
ncy of
antothr
ombin I
Haemo Contin Passive Platelet disorders: Cardiac Severity
rrhage ued diapedesis o =throm tampona depends on
escape escape of bocytopa de Locat
of blood enia comprom ion of
blood through o Thrombo ise of bleed
from intact walls pathia heart ing
the Rhexis (platelet function Rate
vessels escape function due to of
through disorder) haemope blood
rupture in a - defects ricardium loss
vessel in Death
Haemoperic secretion due to
ardium into , cerebral
the adhesion haemorr
pericardium or hage
Haemoperito aggregat Haemorr
neum ion hagic &
Haemothora Clotting disorder hypovola
x o Hereditar emic
Haemoarthr y shock
osis into deficienc Adaptati
joint spaces y of on if
 Haemoptysis clotting small
coughing factors loss of
up blood o Acquired: blood
Epistaxis o Hepatic over long
bleeding disease period of
from the (lack of time
nose coagulati Haemoly
Haematoma on factor sis
productio Loss of
extravascula n) blood
r collection o VitK cells and
of blood, antagoni plasma
usually sts protein
clotted o Warfarin ->
o Sub Vessel disorder oedema
cut o Destructi
ane on of a
ous vessel
o Sub wall
dur (neoplasi
al a,
(in toxaemia
brai , vit C
n) deficienc
Thromboem y,
boli - anoxia,
breaking off ulceratio
of thrombus, n,
which anaemia)
travels in Mechanical
the blood trauma
stream
Petechial (1-
2mm in
diameter)
due to
widespread
capillary wall
damage or
platelet
defect
Ecchymotic
(>2mm
diameter)
Linear
Haemorrhag
e serosal
and mucosal
surfaces
Haematuria
blood in
urine due to
haemorrhag
e of the
bladder
epithelium
Purpura
petechiae,
ecchymoses
and large
haemorrhag
e scattered
on body
surfaces
Haema Extrav Just
toma ascular painful
collecti if
on of subcuta
(usuall neous,
 y life
clotted threate
) blood ning if
subdur
al

o Causes
o Types
o Causes
Neoplasia
Physical
Destruction of vessel wall
Anoxia
Vit C deficiency
Ulceration
Platelet diseases thrombocytopaenia/thrombo
o Congestion too little blood removed via the venules

Resolution of haemorrhage:

Reabsorption of fluid

Ulcer: discontinuity or break in a bodily membrane that impedes the organ from continuing its normal functions

Hyperaemia: excess of blood in arterioles supplying a tissue due to vasodilation

Pathological
Physiological due to excess energy demand of the tissue/heat loss

Congestion: lack of blood in venules draining a tissue

Symptoms
o All large, very round veins full of blood
o Nearby tissues more spread apart
o Dark red (engorged with poorly oxygenated blood)
o Opening of collateral vasculature
Causes
o Venous drainage obstruction
Thrombosed vein
Bandage too tight venous flow blocked off
Torsion e.g. gastric volvulus in dogs
Tumours that compress on adjacent veins
Cirrhosis end responses to chronic damage to liver which causes replacement of lost
parenchyma with scar tissue (fibrosis), which then constricts and cuts off blood supply
Organ dilation
Gastric dilation due to animals eating too quickly and moving too fast
afterwards, causing torsion of stomach
o If animal does it regularly, causes stretching of ligaments which
mobility and chance of twisting
o Lack of acid in the stomach causes multiplication of bacteria
o Multiplication of bacteria causes excess of gas and bloating

Ulceration:

Duodenal ulcer mast cell tumour causes release of histamine, which causes HCl release by the stomach

->:Renal failure only occurs after >75% loss of tissue function

Thrombus PM clot
Friable/firm Rubbery
Attached to vessel wall Unattached
Dull and rough (arterial)/ moist and gelatinous Moist and smooth
(venous)
Grey and pink with laminations (arterial/ red +/- No laminations, separated into yellow anep
laminations
Important factors to haemorrhage:

Amount of blood loss impact ability for nut

Common diseases:

Name Type Cause Symptoms

Swine fever Pestivirus Petechial and ecchymotic
haemorrhages in the
kidney
Herpes virus Ecchymotic haemoorhage
in the kidney and
intestines
Enzootic haematuria Ingestion of bracken Haematuria, tumours
fern
Purpura haemorrhagica Strangles Urticaria
infection/vaccination Vasculitis
Immune complexes SQ oedema
depositing in vessel Haemorrhage in mucosa
walls and SQ tissues

Stringhalt (horses) Disorder of growth Neurogenic atrophy of Exaggerated flexion of

distal digital extensor hind limb when walking
nerves
Non-painful unilateral Disorder of growth Neurogenic atrophy of Sunken cheeks on one
atrophy of masticatory trigeminal node side of the face, no
muscles (dog) difficulty eating or
behaviour changes
Idiopathic masticatory Disorder of growth
myositis
Hepatic lipidosis Reversible clel injury Excess delivery of FFA Many small/large vacuoles
to liver (starvation) or Yellow tinge to liver in
reduced capacity to centrilobular pattern
synthesise
apolipoprotein
Equine pyrrolizidine Disorder of growth Hepatocellular
toxicoses hypertrophy

Apoptosis:

Induced by
o Extracellular signals
o Intracellular signals
o Physiological processes
o Pathological processes
Mediated by
o Fas ligand accepted by the Fas receptor
o TNF (tumour necrosis factor) ligand accepted by the TNF receptor
o Capsases, activated by Fas and TNF
Regulated by
o Bcl-2 proteins both anti-apoptotic and pro-apoptotic, outcome determined by balance
Roles
o Eliminating autoreactive T-cells
o Cause neurodegerenative diseases and ageing
o Remove cells damaged by
Irradiation
Hypoxia
Chemicals
Toxins
Viral infections
Neoplasia
o Embryogenesis
o Hormone-dependent involution (return of organs to their normal size)
o Maintaining proliferative cell populations
o Growth of tumours
o Death of immune cells in immune responses
o Repair of a tissue
o Cell death in low-level injurious stimuli
o Cell death in certain viral diseases
o Mechanism:
Lack of survival factors
Release of apoptotic signals
o Triggered by:
External trauma (radiation, heat)
Nutrient deprivation
Viral infection
Hypoxia
[Ca2+]
o Purpose:
To balance cell division
Because of damage and wear
In development, to create appropriate structures
o Process:`
1. Cell releases apoptotic signals
2. [Ca2+]
3. Cell surface expresses factors and proteins which initiate phagocytosis
4. Inactive protease A activated by proteolysis
5. Protease A activates protease B
6. Protease B degrade nuclear lamins and activate proteases C
7. Proteases C degrade cytosolic proteins and activates protease D, and so on
8. Proteases gradually degrade cell
9. Cell shrinks and components disappear
10. Form cell fragments (apoptotic bodies) that phagocytic cells engulf

Necrosis: cell death due to external/internal trauma cells burst to initiate inflammatory response

Detrimental to body
Disruption of cell membrane due to many signals and release of contents
Contents released prevent the digestion of dead cells by phagocytes
Many different mechanisms depending on the cause of necrosis
Basic mechanism:
o Swelling of cell
o Nucleus shrinks
o Nucleus fragments and bursts open
Macroscopic changes
o Paler (reduced blood flow)/haemorrhage
o Swollen tissue, then reduced volume
o Malacia (soft to the touch)
o Surrounding zone of inflammation
Microscopic changes
o Cytoplasmic swelling
o Eosinophilic cytoplasm (loss of ribosomes)
o Vacuolated cytoplasm
o Calcified cytoplasm (dystrophic calcification) precipitation of calcium crystals in mt then rest
of cell
o Clumped chromatin
o Pyknosis (nuclear shrinkage + basophilia)
o Karyolysis

Involution: return of an organ to its normal size

Feature Apoptosis Necrosis

Distribution Usually single cells Often contiguous
cells
Cell appearance Shrunken, convoluted Swelling
Nuclear Condensed chromatin, fragmented Lysed nucleus
morphology nucleus
Plasma mb Intact until phagocytosed Damaged, leaky
Cytoplasm Retained in apoptotic bodies Contents released
Inflammation Absent Typically present

Types of necrotic lesions: presentation may differ according to type of tissue and amount of fluid present

Liquefactive -
Caseous
Fat
Fibroid
Gangrenous
Coagulative - dead tissue remains intact due to lack of proteolysing enzymes
 Type Present Cause Type
ation of
tissu
e
Liquefact Malacia, Neutrophil-rich CNS
ion viscous, inflammatory lesions,
often hypoxic infarcts
leukocyte
-filled
liquid
mass

Coagulat Eosinophi Infarction/ischaemia

ive lic,
gelatinou
s, retains
the same
shape but
cell
contents
degraded

Caseous Liquefacti Mycobacteria/fungal/f

ve + oreign infection, e.g.
coagulati granuloma
ve (white,
friable
tissue),
granular
particles
left from
cell
digestion

Wet Liquefacti Infection of dry Lower

gangren ve gangrenous tissue limbs,
ous GI
tract
Dry Coagulati Ischaemia Lower
gangren ve limbs,
ous GI
tract

Fibrinoid Immune Immune-mediated Vesse

complexe vascular damage ls
s
(antigen
+
antibodie
s)
deposited
within
arterial
walls with
fibrin

Fat Gritty Abnormal activation Adipo

white of lipases se
flakes of tissue
Ca, Na or
Mg
deposits
on
saponifie
d mb

Postmortem autolysis: the lysis of body tissues due to the release of lysosomal enzymes following the somatic
death of the individual. Rate by T before and after death

Obscure gross and microscopic lesions

Mimic true lesions
Affect quality of specimens for histopathology and bacteriology

Effect of cell injury depends on:

Degree of damage
Extent of damage
Particular tissue affected

Pulmonary oedema:

If L side of heart affected

fluid in lung arteries, causing hydrostatic
Fluid exudated into alveoli
Proteins and mucus dissolve into fluid
Fluid froths up when breathing, filling up to the trachea, affecting O 2 absorption
Interstitium: highly-structure network of fluid tissue holding cells and structural elements into tissues,
containing

Fibres
Fibrils
Fibroblasts
ECM
o Insoluble fibrous components
Collagen
Fibronectin
Elastin
o Soluble gel component (proteoglycans)

DISORDERS OF GROWTH

Disorders of alterations in the rate of cell division and differentiation of cells within organs or tissues in
growth response to a change in cellular homeostasis caused by an agent of disease
Congenital disorders of growth (an abnormality of structure or function of a tissue) that is present at
defects birth but not necessarily detected at birth
Aplasia Failure of development
Hypoplsia failure of an organ or tissue to achieve its full size or development
Acquired disorder of growth incurred as a result of factors originating outside the organism
defect
Tumour Abnormal or proliferative mass
Neoplasm New and abnormal growth in which cell multiplication is uncontrolled and progressive
Cancer Malignant cellular tumour

Types of disorders of growth:

Acquired
o Controlled
Rate of cell division/cell size abnormal
Reversible if cause removed
Changes lie under normal cellular controls and cell adapts normally to new conditions
Types
Atrophy - organ size/cell size/cell no.
o Muscle atrophy often caused by neurogenic atrophy, or disuse, e.g.
unilateral atrophy of masticatory muscles in a dog
Hypertrophy - cell size, e.g. muscles
o Nodular hypertrophy forms a visible nodule
Hyperplasia - cell no., e.g. lymph nodes
Dysplasia proliferation with correct differentiation, but disorganisation of
tissue, in epithelial tissue
Metaplasia proliferation with incorrect differentiation, causing replacement of
one cell type with another, e.g. prostate squamous metaplasia
o Uncontrolled neoplasia genetic damage causes cells to proliferate uncontrollably (outside of
normal cellular controls) to form many non-fully differentiated clones of cells, where the number of
cells being produced exceeds the number of cells being lost
Does not revert to normal state when stimulus removed since genetic change has been
incurred
Classification according to
Behaviour
Cell of origin
Benign well-differentiated, slow-growing
Malignant poorly differentiated, invasive, fast-growing, metastatic
Steps
Oncogenesis/initiation
o Oncogenic virus
o UV radiation
Pathophysiology
Causes mutation to
Proto-oncogenes -> oncogenes
Tumour suppressor genes
 Causes disruption to
o Production of
GF
o GF receptors
o Signal
transduction
pathways
o DNA replication
o Apoptosis
Requires
Activation of growth-
promoting oncogenes
Alteration of apoptosis-
regulating genes
Inactivation of cancer-
suppressor genes
Congenital
o Aplasia
o Agenesis
o Hypoplasia

Oncogene: genes that promote autonomous cell growth

and does not require growth factors
Protooncogene: normal counterpart of an oncogene

>100 identified so far

Tumour-suppressor genes
o P53 most important
Arrests entry of cell into S phase
of cell cycle if genetic damage detected

Oncoproteins:

Types of neoplasms:

Metastatic
o Carcinoma (of epithelial cells)
o Sarcomas
Anaplastic not at all differentiation usually very malignant

Type Tissue of origin Benign Malignant Cause

Round cells Lymphoid Lymphoma Lymphosarcoma Retroviral (FeLV,
BLV), other
Spindle/mesenchy Blood vessel Haemangioma Haemangiosarcoma
mal cells endothelium
Fat Lipoma Liposarcoma
Fibroblasts Fibroma Fibrosarcoma
Bone Osteoma Osteosarcoma
Blood vessel None Haemangio-
pericytes pericytoma
Cartilage Chondroma Chondrosarcoma
Smooth muscle Leiomyoma Leiomyosarcoma
Striated muscle Rhabdomyoma Rhabdomyosarcoma
Epithelial cells Gland Adenoma Adenocarcinoma
Squamous Papilloma Squamous cell
epithelium carcinoma
Basal cells o Basal cell Basal cell caricnoma
epidermis epithelioma

Basic types of cells: that cancerous cells can revert to very malignant if cannot be identified beyond these cell
types

Type of cell Appearance Morphology Malignancy of Examples

neoplasm
Round cell Large, well-defined, Highest since Lymphocytes, plasma
basophilic nucleus already mobile cells, granulocytes,
 Round cytoplasm and in vessels monocytes,
Well-defined edges, macrophages, mast
individual cells
Epithelial cell Ovoid, dense, Intermediate
basophilic nucleus, since close to
eosinophilic vessels and only
cytoplasm lightly bound to
Closely associated neighbouring
to neighbouring cells
cells and arranged
along a basement
mb
Spindle cell Elongated, Lowest since Fibroblasts/fibrocytes,
medium-sized, encased in thick chondroblasts/chondro
well-defined, pale ECM cytes,
Eosinophilic, osteoblasts/osteocytes,
elongated myocytes
cytoplasm
Associated to
ECMs, in sheets

Round cell free cell, travels in plasma/ECF

Spindle cell cell which produces significant ECM
Epithelial cell cell which adhere very closely to their neighbours

Growth and development of neoplasms:

Aplasia of neoplasms gradual reversion to stem cell

o Stop forming structures and producing their normal products
o Produce angiogenic to induce blood vessel growth and increase growth potential
Metastasis requires ability to invade
o tissue around it
o a vessel to travel to a different tissue
o the endothelium and into the surrounding tissues
Angiogenesis development of blood vessel supply to increase ability to grow
Influenced by the tissue of origin

Requirements for metastasis:

Anaplastic: complete loss of differentiation

Pleiomorphism: having more forms

Stringhalt: in horses, exaggerated flexion of hind limb(s) due to neurogenic atrophy of distal lateral digital
extensor muscles, caused by:

Trauma
Flatweed toxicoses
Idiopathic

Difference between benign and malignant:

Characteristic Benign Malignant

Borders Well-defined Invasive (fingerlike
(circumscribed) projections)
Metastases Never Maybe
Ulceration Maybe (trauma) Often
Haemorrhage and Uncommon common
necrosis
Capsule Maybe No
Compression of Yes Yes
surrounding tissue
Fixed to/invasion of No Often
surrounding tissue
Tissue pattern Reasonable resemblance Less resemblance to
to normal normal
Pleomorphism Slight Significant
Anaplaisa Slight Significant
Mitotic rate Low High,unusual
Nuclei Uniform Pelomorphic, multiple,
large, hyperchromatic
Invasion of vessels Never Maybe

Aetiology of neoplasia: neoplasia occurs

through multiple events to occur, therefore
many agents can be implicated

Chemical factors toxins that initiate and

promote mutations
o Polycyclic aromatic HC (tobacco
smoke, cooked meat, fossil fuel
smoke)
o Nitrosamines
o Aromatic amines (in food dyes)
o Mycotoxins e.g. aflatoxin B1 in
corn and peanut plants
Physical factors - radiation
Viral
o Directly oncogenic
Viral oncogene inserts a gene that is oncogenic, obtained from another host or natural
in the virus mimics host oncoproteins (e.g. feline retrovirus, papillomavirus)
Insertional mutagenesis, e.g. avian leukosis
Hit & run mechanisms virally oncogenic/insertional mutagenesis but virus does not
continue infecting (e.g. bovine papillomaviruses)
Oncogenic retroviruses insert DNA in oncogenes
Oncogenic DNA viruses
o Indirectly oncogenic
Immunosuppression reduces ability to eliminate mutated cells
Bacteria
o Heliobacter spp gastric/hepatocellular carcinoma, gastric lymphosarcoma.
o Spirocera lupi oesophageal sarcoma
Tumour cellular allografts
o Canine transmissible venereal tumour
o Tasmanian devil facial tumour
Parasites

These cause mutations to:

Growth-promoting proto-oncogenes
o Growth factors
o Growth factor receptors
Cell-cycle regulators
Intracellular signal transducers
Growth-inhibiting tumour suppressor genes
o P53 prevents entry of cell into S phase if genetic damage present
Induces DNA repair enzymes
Induces apoptosis if DNA is irreparable
Half-life extended when activated and accumulates in the nucleus
o Bcl-2 blocks apoptosis
Apoptosis-regulating genes
DNA repair genes

By:

Alteration of gene expression

o Gene amplification
o Promotor insertion - or transcription of gene or eliminating need for an activator/repressor, or
allow gene to be expressed at a different time/tissue than usual
o Gene translocation chemical-inuduced structural change causing translocation of the promotor
Alteration of gene structure different sequence causing a mutated protein with abnormal function

Creating vaccines:

Inject a virus thats closely related

Inject a small part of a modified virus
Inject the whole inactivated virus

Types of viruses

Class Name Type Diseases Species Mechanism

 caused of infection
Bovine Hit and run
pillomavirus mechanism

Rate of growth depends on:

Mitotic rate
Proportion of cells replicating
Rate of cell death

Examples:

Transmissible neoplasms
o DFTD
Ocular squamous cell carcinoma caused by papillomavirus + UV radiation
Feline lymphosarcoma caused by
o FeLV (retrovirus) in felines
o FIV (retrovirus) in felines
o Bovine Leukaemia Virus (retrovirus) in bovine
o Herpesvirus (DNA virus) in chickens (called Mareks disease)
Feline gastric lymphoma caused by Helicobacter

Congenital disorders of growth

Examples:

Family Name Heredity Symptoms Gene Pathologic Species

affecte al process / breed
d affecte
d
X-linked DMD (Duchenne muscular X-linked Progressive Dystrop Overabunda
muscular dystrophy) recessive muscular hin nce of
dystroph wasting creatine
y Poor kinase
balance,
walking
difficulties
Limited
range of
movement
Muscle
contracture
Ptosis,
scoliosis
Inability to
walk
Polycystic kidney disease Autosoma Homozygosit Persians
l y is lethal in and
dominant utero Persian
heritabilit Cysts in Xs
y kidney, liver,
spleen
Renal failure
in middle
age
Hydrocephalus Multifacto Abnormal Excessive Chihuah
rial accumulatio CSF uas
n of CSF in production
ventricles of or impaired
brain flow and
Doming of reabsorptio
skull n
Compression Aqueductal
 of brain stenosis
Lysosom Pompes Alpha
al disease/glycogenosis glucosidase
storage deficiency
disease
Biochemi Dermatosporaxis Short /sheep,
cal stature, joint cats,
disorder laxity, cattle
bilateral hip
dislocations
at birth
Skin
hyperextensi
ble
Akabane (ah-kah-bah-nee) Virus- In 1st Infecting Cattle,
virus caused trimester -> nave sheep,
(spread hydranencep pregnant small
by haly cows ruminant
midges) 2nd -> 1st -> s
arthrogryposi 2nd
s ->damage
Final to lower
trimester -> motor
incoordinatio neurones
n, paralysis
Contracture: lack of movement due to lack of flexibility in the joints
Ptosis: drooping eyelids
Scoliosis: curving of the spine
Teratogen: environmental agent that induces physical or functional (usually biochemical) defects in developing
embryos and foetuses
teratology: study of congenital defects
Seroconversion: conversion of virus due to development of

Due to:

Genetics
o Inherited
o Spontaneous mutation
Conditions during pregnancy

Classification:

Anomaly deviation from normal

o Structural
o Functional
Malformation
o Deformation altered shape of a structure

Outcome:

Abnormal anatomy and function at birth

Abortion of foetus
Resorption of foetus

Influencing factors:

Stage of pregnancy (& embryonic dvlpt) affected

Genotype
o Inherited susceptibility to teratogens
o Susceptibility to infectious teratogens
o Other gene disorders influencing susceptibility to other gene disorder

Types:

Anatomic defect
o Fusion/fission
o Vestigeal structures
Persistence of embryonic structures, e.g. patent ductus
arteriosus (failure of vessel linking two sides of heart to close)
o Cysts fluid-filled cavities occurring in organs containing tubules/ducts
Arise in
 Kidneys
Intrahepatic branches of the bile duct
Rathkes pouch (in pituitary) - GH synthesis
o Failure of/incomplete structure development
Agenesis absence due to non-appearance of primordium in the embryo
Aplasia
Pancreatic -> fatal
Hypoplasia
Pancreatic hypoplasia -> inability to digest food due to lack of pancreatic
enzymes -> common in large breed dogs
Renal hypoplasia -> fatal if >75%
Testicular
Cerebellar (kittens) due to parvovirus, swine fever,
Laryngeal -> breathing problems
Micrencephaly small brain
o Abnormal development of a structure
Failure to canalise
Atresia failure of a structure to open, e.g. atresia ani (no anus)
Failure to separate, e.g. cyclopia failure to separate orbits in the foetus
Failure to close/fuse
Schistosoma -> cleft in abdominal midline causing extravasation of abdnominal
cavity and head to bend over to spine
Spina bifida cleft in dorsal tissues of the spine loss of function of the spinal
cord in that part of spine
Exencephaly failure of skull to fuse
Meningoencephalocoele inability of brain to fuse, causing extravasation of
meninges
Diaphragmatic hernia inability to breathe properly due to abdominal contents
in
Cheiloschisis cleft lip
Palatoschissis cleft palate, causing communication between buccal cavity and
nasal cavity inability to create negative P in mouth
Coloboma cleft in the iris of the eye
Hypospadias cleft in penis exposing the urethra
Interventricular cardiac septal defect cleft in ventricles
o Blood flows to RV
o More P in lungs -> pulmonary oedema
o Extra structures
Polydyctaly due to abnormality in splitting of fingers
Extra teeth
o Ectopic development
growth of tissue in the incorrect place
tissue/organ does not migrate properly
Cryptorchidism -testes due to migration from abdomen to scrotum, can left
some behind
Spleen
Ectopic pregnancy growth of foetus in the abdomen
Thymus due to migration from thoracic cavity to
Biochemical defect inability to synthesis adequate E or protein
o Haemophilia
o Lysosomal storage disease
deficiency of lysosomal E causing accumulation of substrate in vacuoles neuronal and
muscular tissue most susceptible
long-lived
not replaced if lost
alpha mannosidosis autosomal recessive disorder -> alpha mannosidase deficiency &
secondary neurovisceral lysosomal storage
o Dermatosporaxis
o Albinism

Importance of stage of gestation:

Significa
nce
Virus 0-30d 30- 50- 63- 76-90d 90- 104-120d 120- >173d
50d 63d 76d 104 173d
Akabane Hydroencephaly Arthrogryposis Encephalomyel
itis/ stillbirth/
abortion
 BVDV Embryon Abortion/ mummificatioin/ severe Immunotolerance Survival Survival
ic death congenital defects + retarded +
& growth/ congenital congeni
resorptio defects tal
n defects
BDV Embryon
ic death
and
resorptio
n
BVDV: Bovine Viral Diarrhoea Virus
BDV: Border Disease Virus

Causes: teratogens

Chemical agents
o Toxins
Plant teratogens, e.g. carthrogryposis -> cleft palate in cattle
Dioxin
Hg, Pb, As, Cd
o Therapeutic drugs
Chemotherapeutic agents
Corticosteroids
Tetracycline
Anthelmintics
Physical agents
o Heat
o Radiation
o Vascular occlusion
Nutritional factors
o Excess/deficiency in vit A -> neural tube and cardiac defects
o Starvation -> poor foetal growth
o Cu deficiency -> CNS hypomyelination
o I deficiency -> goitre
Infectious teratogens
o Viruses
Requirements
Cannot cause serious enough disease in mother
Cannot cause serious enough disease in foetus to cause death
Able to cross the placenta
Able to persist in specific foetal issues
Hypoplasia
Vasculitis -> vascular constriction of limb vessel, causing amputation effect
Eg., rubella, akabane, blue tongue virus, panleukopaenia, bovine viral diarrhoea, swine
fever
o Protozoa, e.g. toxoplasma gondii
o Fungi, e.g. aspergillus
o Bacteria usually cause foetal death/abortion

INFLAMMATION

Inflammation: reaction of vascularised living tissue to local cell injury, which either ends in healing or
permanent destruction of the tissue. Termed -it is

Involves both innate and adaptive immunity

Can cause more damage than the causative agent would have
o Free radicals produced by neutrophils damage mb
Does not vary much, but varies due to:
o Nature of stimulus
o Ability of host to respond
o Species variation
Many feedback loops, pathways and control mechanisms
Depends on surface mb receptor activation for leukocyte movement and identification of causative agent,
etc.
Doesnt necessarily eliminate pathogen/foreign body compromise between
o Effect of pathogen/foreign body on fertility/mortality
o Cost of elimination of pathogen
Resources
 Damage to tissue due to inflammation
Through 3 pathways:
o Kinin
o Coagulation
o Complement
Many steps in pathways allow many points at which the point can be controlled
Each factor/substance has a short half-life to ensure inflammation does not continue if all factors are not
present

Types: vary only in time course and appearance sequence of events conserved

According to time course

o Peracute rapid resolution without repair being required
o Acute innate mechanisms more important, repair required
o Subacute adaptive mechanisms more important
o Chronic adaptive mechanisms more important mixture of continuing inflammation and repair,
esp. formation of new connective tissue
Exudate
o Purulent/suppuratives
o Granulomatous
o Serous
o Ulcerative
o Fibrinous
Tissue affected
o Catarrhal MM discharge of mucus + epithelial debris
o Interstitial stroma of an organ
o Parenchymatous essential tissue of an organ
Cause
o Toxic due to toxin/poison
o Traumatic due to wound/injury
Presentation
o Pseudomembranous formation of false mb composed of fibrin, necrotic epithelium and
inflammatory leukocytes on top of MM caused by necrotising toxin, e.g. diphtheria toxin often
acute
o Ulcerative local tissue defect due to surface tissue necrosis
o Adhesive high likelihood of attachments in serous mb
o Proliferative/hyperplastic excess production of young, fibrous tissue

Classifica Type Presentati Cause Content Tissu Examples

tion on s e
accordin affect
g to ed
Exudate Purulent/ Exudate Pyogenic Neutroph Staphylococcus infection
suppurative high in bacteria ils
neutrophils (e.g.
and cellular staphyloco
debris cci)
(pus)
Creamy,
turbid
Often form
abscesses
Granulomatous Formation TB, leprosy, arcoidosis,
of syphilis
granulom
as
Usually
chronic

Serous Effusion of Mostly Serous Skin blisters

large water + mb
amounts of electrolyt
non-viscous es
serous fluid
produced
by
mesothelial
cells of
serous
 membrane
s
Ulcerative Necrotic
loss of
upper
layers of
epithelium

Fibrinous Exudate of Pseudomembranous

fibrin, e.g. colitis
in serous
cavities, in
order to
form scar
tissue

Mucopurulent Exudate Mucus

high in
mucus

Eosinophilic eosinophils
Fibrinopurulent Creamy,
cellular
exudate
containing
fibrin
Tissue Catarrhal Discharge MM
affected of mucus +
epithelial
debris
Presentati Pseudomembra Formation Necrotising MM
on nous of false toxin (e.g.
membrane diphtheria)
(fibrin,
necrotic
epithelium,
inflammato
ry
leukocytes)
on MM
Ulcer: excavation in the epithelium due to necrotic loss of upper layers of the epithelium, caused a break in skin
that fails to heal
Granuloma: dense, organised collection of macrophages which often fuse to form Langerhans giant cells, in
order to enclose foreign bodies the body is incapable of eliminating

Immunity:

Innate
o Physical barriers (epithelia, keratin in skin, mucous and cilia)
o Host chemicals (e.g. lysosymes)
o Phagocytes, e.g. neutrophils
Adaptive leukocytes and factors, e.g. cytokines
o Enhance innate immunity
o Attacks specific foreign particles

Innate vs adaptive immunity:

Characteristic Innate Adaptive

Cells can return to lymphoid No Yes
tissue

Main components:

Leukocytes
 Serum proteins (fibrin,
Platelets
Coagulation factors (vit K,
Fibrinolytic enzymes
Antibodies

Compone Nature Role Produced by Type of Activated/ Speci

nt inflamm inactivate es
ation d by variat
ion
Bradykinin Plasma- Induce Kinin system (plasma) Subacute
derived vasodilation
mediator vascular
protein permeability
Cause smooth
muscle
contraction
Stimulate pain
receptors
Stimulation of
release of
leukotriens +
prostaglandins
Serotonin Amine Vasodilation Platelets, mast cell,
permeability basophil
of venules
Bronchoconstri
ction
Stimulation of
rostaglandin
production
Tachykinin
Substance Tachykinin Stimulates Peripheral and central
P pain receptors nerves
Causes
vasodilation,
vascular
permeability
Causes
behavioural
change
associated to
inflammation
and pain in
CNS
Compleme Vasodilation
nt proteins Leukocyte
chemotaxis
Enhances
phagocytosis
C3 Compleme Cleaves to Complement system
nt protein produce C3a (macrophages, liver
and C3b endothelium)
C3a Compleme Stimulates Cleaved from C3
nt protein; histamine
anaphylo release by
toxin mast cells
Leukocyte
chemotactic
mediator
vascular
permeability
C3b Compleme Binds to Cleaved from c3
nt protein bacterial cell
walls and acts
as an opsonin,
marking it as a
target for
phagocytosis
 (opsonisation
)
C5a Compleme Stimulates Complement system
nt protein; histamine
anaphylo release by
toxin mast cells
Chemotaxis for
leukocytes
vascular
permeability
C5-C9 Compleme Forms MAC
nt protein opens hole in
the cell
Factor XII Protein Activates kinin, Liver Collagen,
fibrinolysis and platelets,
coagulation plasmin,
system exposed
basement
mb (via
conformati
onal
change)
Cytokines
stimulate
production
Membrane Compleme Inserts into Complement system
attack nt protein bacterial cell
complex walls, causing
(C5b, C6, cell lysis and
C7, C8, + death
multiple
units of
C9)
Plasmin Break down Fibrinolysis system
fibrin clots
Cleave C3
Activate Factor
XII
Thrombin Cleaves Coagulation system
fibrinogen ->
insoluble fibrin
Binds to cells
via PAR1
receptor to
trigger
chemokine
and NO
production
Fibrin (Acute Aggregates to Liver Cytokines
(fibrinogen phase form a blood stimulate
) protein, clot production
APP) Chemotaxin
C-reactive Compleme Binds bacteria Liver Cytokines
protein nt protein/ and fungi stimulate
acute Activates production
phase complement
protein
TNF Pro-
inflammat
ory
cytokines
IL1 Pro- Enhanced Macrophages
inflammat production of B-cells
ory other Dendritic cells
cytokines mediators, Neutrophils, etc.
phagocytes,
lymphocytes
Fever
Promotes
 release of APP
IL6 Pro-
inflammat
ory
cytokines
IL8 Pro- Attracts T-cells, monocytes
inflammat neutrophils, T
ory cells
cytokines
Prostaglan Eicosanoid Vasodilation, By cyclooxygenase
dins vascular pathway from arachidonic
permeability, acid
oedema,
coagulation,
thrombosis,
pain
Thrombox Eicosanoid By cyclooxygenase
anes pathway from arachidonic
acid
Leukotrien Eicosanoid Leukocyte Leukocytes
es chemotaxis Through lipoxygenase
Aggregation pathway from arachidonic
acid
adhesiveness
Lysosomal
enzyme
release
O2- generation
Histamine Vasoactive vascular Mast cells (connective
amine permeability tissues around blood
Cell- Capillary vessels)
derived dilation Basophils
mediator Promotes Platelets
contraction of
smooth muscle
cells
Anaphylaxis/all
ergic
hypersensitivit
y
C1-9 Classical
compleme
nt protein
Factor B Alternate
compleme
nt protein
Factor D Alternate
compleme
nt protein
Factor H Alternate
compleme
nt protein
Factor I Alternate
compleme
nt protein
Properdin Alternate
(P) compleme
nt protein
Haptoglobi Acute Limits free Fe
n phase
protein
Fibronectin ECM Links to
protein integrins
 PAF Causes release Platelets
(platelet- of chemical
activating mediators,
factor) activation of
neutrophils
Vasodilation
vessel
permeability
Chemotaxin
Eotaxin 1 Eosinophil
chemotaxin
RANTES Eosinophil,
monocyte and
neutrophil
chemotaxin

Mediators:

Cytokines
o Chemokines
Chemotaxis
Emigration
o Lymphokines
IL production
Attraction + activation of macrophages and lymphocytes
Stimulate B-cells to produce antibodies
o Monokines
Vasoactive amines, e.g. histamine
o vascular permeability
o Smooth muscle contraction in anaphylaxis
o Released from mast cells, basophils, platelets
Vasoactive neuropeptides, e.g. substance P
o Stimulate pain + CNS behavioural changes
o Vasodilation
o vascular permeability
o Released from peripheral nerves in
response to pain/tissue damage
APP (acute-phase proteins) plasma
proteins that change in [] of >25% during
inflammation
o Produced in liver
o Mediate inflammation
o Affect HR, BP and T
o E.g: C-reactive protein,
complement factors, fibrinogens,
haptoglobin
Eicosanoids
o Types all produced from
arachidonic acid
Thromboxanes
Prostaglandins
Leukotrienes
o Roles
Chemotaxis
Smooth muscle contraction in anaphylaxis
Vasodilation, vascular permeability
o Triggered by
Bradykinin
Cell damage
Others

Anaphylaxis: Acute allergic reaction to an antigen to which the body has become hypersensitive

Major effects of mediators:

Vasodilation Chemotaxis Vascular permeability

Prostaglandin Complement C5a Vasoactive amines, e.g histamine
Leukotrienes Leukotrienes Complement fragments
Chemokines (1L-8) Prostaglandin
 Bacterial products (LPS, Leukotrienes
peptidoglycan) Platelet activating factor
Pain Fever Tissue damage
Bradykinin Cytokines IL-1 Lysosomal contents
Substance P TNF Free radicals
PGE2 IL-6

Types of exudates:

Type Nature Occ Due to Histology

ur
in
Catarrhal Mucopurulent/m MM
ucoid in
GIT,
nas
al
cavi
ty

Serous Watery

Fibrinous With fibrin

Purulent Exudatio
n of dead
inflamma
tory cells
Fibrinopurulen Exudatio
t n of dead
inflamma
tory cells

Pseudomembr Fibrinonecrotic
anous
Haemorrhagic Bloody

Role of inflammatory response:

Contain bacterial infections

Heal wounds
Repair damaged tissue
o By regeneration of cells constituting the tissue
o By replacement of lost tissue by fibrovascular tissue -> matures to scar tissue
o Proportion of each depends on
Degree of tissue framework disruption
Capacity of tissue to regenerate
o Through factors (IL1, IL4 and TNF) and structural proteins (collagen)

Cardinal signs of inflammation:

Redness due to vasodilation

Swelling due to exudation
Pain due to irrigation of nerves by blood and extra fluid in tissue causing pressure
Heat due to vasodilation
Impaired function

Outcome of infection: by infectious agent

Immediate resolution without tissue damage

Resolution with significant tissue damage
Colonisation
Latency, e.g. within granulomas/phagocytes, e.g. mycobacterium bovis

Causative agents: cell damage and external causative agents

Chemical agents (drugs and toxins)

Physical agents
o Trauma
o Pressure
o T extreme
o Radiant E
Infectious agents
Products of injured cells
Foreign bodies
Immune responses
o Hypersensitivity
o Autoimmunity

Process of inflammation:

1. Vascular phase haemodynamic change

a. Brief constriction of vessels
b. Dilation of vessels -> hyperaemia
 c. Opening of new capillary and venular beds to accommodate extra blood
d. Congestion of veins
e. permeability of vessels -> exudation of fluid into tissue
f. Blood becomes more viscous around site of injury (due to loss of fluid)
g. Clotting starts
h. Accumulation of fluid nature is correlated to severity of inflammation
i. Transudate (low-protein) Filtration and exit of plasma through endothelium due to low-
severity inflammation
ii. Modified transudate
iii. Exudate (high-protein) exit of plasma, protein and blood cells through pores in
endothelium due to high-severity inflammation
2. Cellular stage
a. Induction
Distressed/dying cells release alarmins (HSPs, heparin sulphate, IL1a)
Sentinel cells (mast cells, granulocytes, macrophages, dendritic cells, epithelial cells)
recognise PAMPs by their TLR
Sentinel cells release pro-inflammatory cytokines (IL1, IL6, TNF), chemokines and
vasoactive molecules in response to PAMPs/alarmins
b. Emigration/diapedesis
More leukocytes pushed against vessel wall with inflammation
Endothelial cells integrate pre-formed adhesion molecules into their plasma membrane
Inflammatory mediators (endotoxins, chemokines) upregulate molecules on the surface
of endothelial cells
Histamine and porosity mediators create gaps between endothelial cells
Leukocytes roll along vessel wall
Margination leukocytes stop thanks to adhesion molecules (on leukocytes + endothelial
cells)
Pavementing many leukocytes stick to endothelium
Leukocyte migrates to endothelial cell junction once has good grip
Pass through pores in endothelium using pseudopodia to push between endothelial cells
Secrete proteases to digest basement mb
Extensive digestion of basement mb can cause microhaemorrhages
c. Chemotaxis chemokines, C5a, fibrinogen, PAF and chemokines
d. Phagocytosis
Receptors on mb surface bind to proteins on pathogens surface
Cell extends pseudopods until then reach around pathogen
Processes meet and fuse
Pathogen is invaginated
Pathogen is killed within phagosome by enzyme-dependent/-independent
mechanismseoss
Lysosome fuses with phagosome -> phagolysosome
Digestion by:
O2-dependent killing mechanism oxidative burst of O2- and H2O2 -> radicals
O2-independent killing mechanism lysozyme, lactoferrin, defensins, acid, etc.
e. Exudation
Plasma
Blood cells
Products of phagocytosis
Fibrinogen
Tissue debris
WBC degradation products
b. Mediators
i. Acute phase proteins (fibrinogen, Factor XII, C-reactive protein) released by cytokine
stimulation of the liver and travel in plasma/ECF to site of inflammation
ii. Kinin cascade activated by factor XIIa
Produces bradykinin, which induces pain, vasodilation, vascular permeability
Produces plasmin, which lyses fibrin clots and activates complement cascade
Causes release of histamine from mast cells
Activates eicosanoid production
iii. Clotting cascade activated by factor XIIa and/or tissue factor VIIa
Produces thrombin, which
o causes vasodilation
o vascular permeability
o Pro-inflammatory
Thrombin transforms fibrinogen-> fibrin
Fibrin forms a clot to trap pathogens
Stimulated by tissue damage exposing collagen/basement mb
iv. Complement cascade produces MAC (C5-9), C3a, C5a and C3b
Classical (C1-9) activated by IgM released by plasma cells upon receiving
certain PAMPs
 Alternate (factors B, D, H, I and properdin(P)) activated by
o Lysosomal enzymes released by phagocytosing leukocytes
o Microbial products released by bacterial cell wall lysis

Presentation of inflammation:

Phase Clinical Cardinal Histological Mediators Role

symptoms signs symptoms
Haemodynamic/ Hyperaemia, Reddening, Empty Dilute &
vascular oedema, swelling, spaces in flush
erythema pain, loss of tissue, cells pathogen
function more Open
separated space for
Amorphous tissue
eosinophilic regenerati
material in on
ECM
Immune
cells
infiltrating
into tissue
Necrotic
cells

Complement cascade: circulating inactive precursor proteins which can get activated by antibodies, microbial
products

1. Classical activation pathway (C1-9)

a. PAMPs stimulate plasma cells to produce IgM
b. IgM binds to antigens and activates complement system
2. Alternate activation pathway (factors B, D, H, I and properdin (P))
a. Leucocytes release lysosomal enzymes which activates complement cascade
Signs of systemic inflammation:

Presence of blood cell progenitors in the blood indicates demand for that type of cell, which exceeds the
rate at which can be produced from bone marrow -> released before mature

Immunoglob Structure (type of Foun Role Chronolo Properti Isotyp Speci

ulin heavy chain) d on gy of es es es
recruitm prese
ent nt in
IgG3 Passed in 1,2,3
colostru
m

IgD Unknown Not

Found only soluble
on nave B
cells

IgM (in cell)

IgM (soluble) B- First Ig to be

cells secreted in
response to
an antigen

IgE Mast Allergic

cells reactions,
hypersensiti
vity
IgA Muco
us mb
 Cascade Kinin Clotting Cyclooxygenase Complement
Triggered by exposure of Factor XII to
exposed collagen fibres/endothelial
basement mb
Production of vasoactive substances
Multistep process
Major product Bradykinin, Fibrin, thrombin Prostaglandins, MAC
plasmin thromboxanes

PAMP: Pathogen-associated molecular patterns, pathogenic DNA, lipopolysaccharides or other molecules found
on the surface of pathogens, which allow them to be recognised as non-self
TLR: toll-like receptor, receptors in sentinel cells that recognise PAMPs
Sentinel cells: cells which

Role of inflammation:

Role of exudation
o Dilute agent of inflammation
o Isolate agent of inflammation
o Supply area with fibrin
o Supply area with inflammatory cells (neutrophils)
o Supply area with antibodies, complement proteins, chemokines, etc.

Components of inflammation:

Fluid phase
o Chemical mediators
o Vascular events
Hyperaemia causes redness, oedema and heat
Arteriolar dilation
flow V
parts of capillary bed opened
Congestion of veins
Roles
Dilution of the pathogen
Exudate fibrin to form clots traps pathogen
Allow emigration of leucocytes
Draining fluid to lymph nodes
o Activation of systemic inflammation
o Transport of antigens to adaptive inflammation mediators
Separation of connective tissue elements to allow movement of cells and
nutrients
Cellular phase cellular components
o Margination
Capturing/tethering
Rolling thanks to selectins
o Chemotaxis
o Emigration
 Event Leukocyte receptor Epithelial receptor
Capturing/tethering L-selectin Sialyl Lewis X antigen
VLA-4 VCAM1

Triggers to inflammation:

Alarmins released from dying/distressed cells, which are received by sentinel cells
o HSP
o IL1a
PAMPs
Damage to ECM -> release of cascade-triggering factors

Sentinel cells:

Examples
o Macrophages
o Dendritic cells
o Mast cells
o Some granulocytes
o MM epithelial cells
Components
o TLRs to bind to PAMPs
o IgE only on mast cells
o Alarmins released from damaged cells to
Secrete
o Vasoactive amines
o Pro-inflammatory cytokines
o Chemokines

Antigen presentation:

M 1. Pathogen binds to lectin microreceptor

2. Internalisation into a phagosome
3. Phagosome fuses with lysosome full of proteolytic enzymes -> phagolysosome
4. Synthesesis of MHC in the ER
5. Secretion of MHC in a vesicle
6. Vesicle and former phagolysosome fuse to form special compartment
7. Some pathogenic peptides loaded onto the MHC using DM
8. Other peptides + loader separates into another vesicle
9. MHC vesicle fuses with plasma mb and MHC becomes embedded in plasma mb
10. Antigen presentation to T-cells
a. Th1-cell binds to MHC using
i. T-cell receptor which recognises the antigen
ii. CD4 molecule which recognises MHCII of macrophage
iii. LFA1 (lymphocyte functional antigen 1) on Th1 which binds to ICAM1
(Intercellular adhesion molecule) on macrophage
iv. CD2 on Th1 which binds to LFA3 on macrophage
v. CD28 on Th1 binds to CD80 on macrophage
b. Macrophage releases IL1 to
i. Activate Th1
c. Th1 releases interferon
i. Activates as yet unstimulated macrophages to produce IL2 to stimulate T-cell
replication
ii. Stimulates macrophage to digest all bacteria it comes across

B-cell 1. Antibody binds to its corresponding antigen

2. Is internalised into a vesicle
3. Fuses with lysosome containing proteolytic enzymes
4. Cleave antibody and antigen into peptides
5. rER produces MHCII and secretes as vesicle
6. Former endolysosome and MHCII vesicle meet and fuse
7. Some pathogenic peptides bind to the MHCII
8. Vesicle fuses with plasma mb and MHCII is embedded
9. Antigen presentation to Th2 cells
 a. TCR binds to antigen
b. CD4 binds to MHCII
c. LFA1 of Th2 binds to ICAM1 of B-cell
d. CD40 ligand of Th2 binds to CD40 of the B-cell
e. CD28 on Th2 (which activates B-cell) binds to CD80 of the B-cell
10. Th2 releases IL4 and IL6 to stimulate replication and differentiation into plasma cells
Any 1. Synthesis of MHCI in rER
tissue 2. Proteosomes produce peptide samples from all proteins (endogenous & exogenous) present in
cell cell
3. Peptides transported to rER and loaded onto MHCI
4. Secreted as a vesicle, which fuses with plasma mb and integrates itself into mb
5. Antigen presentation to Tc cells
a. TCR binds to antigen
b. CD8 binds to MHCI
6. Cytotoxic pathway initiated through more protein interactions and cytokine secretion
7. Perforin/granzymes released by Tc to form pores in plasma mb and kill cell

Macrophages

Mechanisms:

Of pathogen detection
o Using lectin microceptors to recognised non-specific pathogens

Influences on macrophages:

Pathogen antigens Hsp, LPS

Patho-physiological events
o Hypoxia
o Ischaemia/reperfusion
Iatrogenic events
o Mechanical ventilation
Complement proteins
Lipid mediators
Cytokines
Neuromediators
Coagulation factors
Glucose
Necrotic cells

Produces:

IL-1, 6, 12, 18
TNF
CCL
MIF
HMGB1
CXCL

Types:

According to phenotype of activated macrophages

o Classically activated activated by TNF & IFN, or TLR agonists
activity against pathogens & tumour cells
 Secrete inflammatory cytokines
Require NK cells (IFN production) & adaptive immune cells (maintain pop)
o Wound healing activated by IL-4
activity against intracellular pathogens
Promote ECM synthesis produce
Ornithine
Arginase
o Regulatory activated by glucocorticoids
Produce IL-10
Inhibit immune system response
According to the adaptive immune response that elicited the phenotype
o M-1 -> by Th1
Activated by LPS + IFN
Secrete
IL-12
Low levels of IL-10

o M-2 by Th2 often wound healing macrophages
According to morphology
o Epitheloid cells (resemble epithelial cells) macrophages that are chronically stimulated to
kill sturdy microbes
o Multinucleated giant cells (MGCs) polynuclear due to karyokinesis/fusion with other
macrophages due to sturdy microbes
o Hepatic kupffer cells in sinusoids of liver (so actually monocytes)
o Dendritic cells antigen presentation

Iatrogenic: due to medical intervention

IFN: interferon

Ty Name Function Structure Featur Prod Mat Dvlp Life No. Proper
pe es uced ure t span /uL ties
in in. dura blo
tion od
 B cells Antibody Surface markers Specifi Bone d-w h-y 1,0
(bone productio c marro 00-
marro n surface w, 4,8
w- Differenti Ab bursa 00
depen ate into of
dant stationar fabrici
cells) y plasma ous,
cells Peyer
Present s
antigens patch
to T- es
lymphocy (gut)
tes
T cells Regulatio Bone Thy
(helpe n, marro mus
r, cytotoxici w
Lymphocyte

cytoto ty
xic,
regula
tory)
Innate Neoplasia No surface Inject From Bone d 1-2w 5-15%
natura /virus- markers lethal precu marr of all
l killer infected Recognise cells toxins rsor ow, lympho
(NK) cytotoxici with no MHC I into of T lymp cytes
cell ty, early cell cells h
viral node
response s,
s thym
Recogniti us
on of
specific
antigen
Synthesis
e IL4,
IFN
Granulocytes (polymorphonuclear, PMNs)

Neutro Phagocyt Full of Bone 6-9d <1d in 1,8 Highly

phil es enzym marro blood 00- motile
bacteria e-rich w 1-2d in 77, chemot
and fungi lysoso tissues 000 axis
Multilobed (2-5)
Releases mes (to limit Sexuall
nucleus, faint
cytokines damage y
pink granules
to to host dimorp
amplify during hic
inflamma inflamm Prefer
tion ation) engulfi
Degranul ng
ation, sugar
NET over
bacteri
a
Eosino Phagocyt Bone 6-9d 8-12d 0-
phil e marro 450
parasites, w
fungi
Allergies Bilobed nucleus,
Type 1 pink-orange
hypersen granules
sitivity
Cause
histamine
release
from
mast
cells
Basop Releases Granul Bone 3-7d h-d 0-
hil histamine es marro 200
for contain w
inflamma hepari
tory Bi/tri n,
 response, lobed nucleus, histami
anti- large blue ne,
parasitic granules protein
Degranul ases
ation Recept
ors to
bind
IgE
Monocytes Differenti 2-3d m 0- Called
ate into 800 kupffe
macroph r cells
ages in the
Phagocyt liver
osis,
bactericid
Kidney-shaped
e, cell
nucleus, no
recruitme
granules
nt
Assist in
tissue
repair
Mast cells Allergic Granul Bone Withi In Found
response es marro n tiss in all
s, anti- contain w tissu ues areas
parasitic ing es of body
Release hepari Degran
histamine n, ulate
and histami due to
inflamma ne, allergic
tory protein stimulu
molecule ases, s
s cytokin Can
Recruit es regener
eosinophi IgE ate
ls recept supply
ors of
granule
s
Dendritic Process Have dendrites Withi In
cells antigen at certain dvlpt n tiss
and stages tissu ues
present it es
to T cells
Link
adaptive
and
innate
immune
systems
Some
phagocyt
osis

Stages of maturation of blood cells:

Mature cell
Band cell Neutrophil
Mast cells:

DEgranulate in response to
o Physical/chemical insult
o Activated complement proteins
Links adaptive & innate by IgE

Neutrophils:

2 pools within plasma

o Marginal pool close to wall of vessel
o Circulating pool free-flowing
Many mb-bound (neutral-staining) granules containing
enzymes and proteins:
o Proteinases for phagocytosed particles
o Proteinases for degradation of ECM
o Proteinases for enzyme activation

Macrophages:

Type of activation
o Classical become pro-inflammatory
Recruit other leukocytes by secreting
Inflammatory mediators (cytokines, chemokines, proteinases)
O2 radicals
NO
PAF
Prostaglandins
Leukotrienes
Clean up cellular debris & conserve essential nutrients (e.g. Fe)
epiSynthesise cytokines (IL1, IL6, TNF-)
o Alternative become involved in regeneration and reparation
Assist in remodelling scar tissue
Release GFs

Pathogen detection:

Class Name Type of Sentinel Properti Role E.g.

cell/molecul cell es
e
recognised
PRRs Collect MBL, SP- Circulating
ins A, SP-D
TLR Cause
release of
cytokines/
interferons
NLR Intracell Causes
ular release of
chemokine
s
Can lead to
apoptosis
if infected
RLR
 C-type Manno Terminal Macropha Cycles Cause
lectin se mannose, N- ges between phagocyto
receptor recept acetylglucosa Immature plasma sis of the
or mine, fucose dendritic mb and pathogen
cells endosom Clearance
Dermal e of
fibroblast glycoprotei
s ns from
Keratinoc circulation
ytes

Scaven Modified LDL Macropha Cause Causes

ger ges, phagocyt artheroscle
recept monocyte osis rosis (LDL
or s, Help phagocyto
platelets, remove sis-> foam
smooth foreign cells
muscle substanc attach to
cells es/ wall)
waste
Class A (SRAI, SRAII, MARCO),
material
class B (CD36)
s
TLR co-
receptor
s
NK Cell C_type
receptor lectin
s recept
or
IgG Fc
recept
or
Invariant CD1d
NK cell
receptor
s
TCR
Innate-
like
lymphoc
ytes
(ILL)
T-cell
receptor
s
Ig IgA, Ig

Scavenger receptors:

Class A
o SRAI, SRAII bind to LDLs, bacterial cell walls
o MARCO bind to LDLS, bacterial cell walls
Class B
o CD36 bind to LDL/HDL, diacylglycerol, long-chain FA of bacterial cell walls
Class C
o SRC1
Class D
o CD68
Class E
 o LOX1
Class F
o SCARF

PAMP receptors:

Type Name Structure Location Recognises Used Properties

against
Toll-like TLR5 Intramb Mb, Flagellin Bacteria 11 different
receptors monomer endosome types, 1-9 in
(TLR) all species, 10-
11 only in a
few
Some are in
endosomes &
recognise
DNA/RNA
Can also
stimulate/modi
fy immune
response
TLR4 LPS Gram-
dimer bacteria
TLR2- Peptidoglyca
TLR1 ns, LTA, LPS,
dimer zymosan
TLR2-
TLR6
dimer
TLR11 Uropathogeni
c bacteria,
prophylin
TLR10
NOD-like Cytoplasm
receptors
(NLR)

RIG-like Cytoplasm dsRNA RNA

receptors viruses
(RLR)

Cytosolic Variable Cytoplasm

DNA
sensors
(CDS)

Importance of studying inflammation:

Prevention and induction of disease

Understanding of pain and welfare
Targeting of therapeutics
Understand tests based in immunology
Understanding vaccination

Determining type of inflammation: based on the sequence of events

Identify degree of repair

 Identify type and abundance of inflammatory cells
Vascular events earlier in inflammation

Character Peracute Acute Subacute Chronic

istic
Type of Vascular events Vascular and start of Cellular, few vascular, Only cellular events, repair a
events only cellular concurrent repair major feature
Onset Min-h H-d d- 1-2 w >2w
Steps Emigration,
included phagocytosis,
exudation,
Componen Plasma proteins
ts Inhibitors/mediators of
inflammation
C-reactive protein
Coimplement
factors
Fibrinogen
Haptoglobin
Systemic Normal
responses Malaise
Fever
MR & HR
Inappetence
Severe (anaphylaxis)
Effect of histamines, kinins, leukotrienes
on smooth muscle

Transudate
Plasma being forced out into
tissues through intact vessel
Lower protein content
Exudate
Plasma leaking out into the
tissues through a leaky
Higher protein content
Yellow

Variation in inflammatory
response: generally very little
variation in sequence of events

Severity and duration

Extent (localised or
systemic)
Different parts of
inflammatory host response
are prominent with different
stimuli

Systemic lupus erythematosus:

Immune-mediated disease
Multiorgan
Autoantibodies directed
against dsDNA (humans) or
nuclear proteins (dogs)

Origin of scabs:

Clotted blood
Clotted exudate

Description of slides:

General architecture structure

 Examine constituent elements
o Structure
o Non-cellular (stroma)
Morphology
Fibrous connective tissue
Solid bone, cartilage
o Cellular
Examine non-constituent components (tissue that is not normally making up the tissue)
o Structure
o Non-cellular
o Cellular
Abnormality
o Location
o Distribution (focal , multifocal, diffuse)
o Shape
o Size relative to RBC
o Colour

Characteristic Healing Repair

Definition Restoration of structure and Physical/mechanical restoration of
function, including: damaged tissues, especially the
Blood clotting replacement of dead of damaged
Tissue mending cells in a body tissue or organ by
Scarring healthy new cells
Bone healing
Results from Circulatory disturbances Inflammation
Phases 1. Haemostasis
2. Inflammation
3. Proliferation
4. Maturation
Outcomes 1. Parenchymal
regeneration
2. Connective tissue
replacement (scarring)

Hypersensitivity:

Causes:
o Failure of tolerance
Modification of self antigens
Exposure to cryptic antigens, e.g. sperm antigens
Due to:
Normal imperfection some self-directed phagocytes are still released despite
tolerance mechanism
Genetic predisposition
o Inappropriate activation
Persistent inflammation - [cytokine]
o Non-self antigens - from
Pathogens
Allergens
Transplants/transfusions
E.g.: neospora
o Protozoa contained in cyst by Th1-dominated processes
o Progesterone inhibits Th1 and promotes Th2 during pregnancy

Type Pathways Problem Mechanis Examples

activated with ms
antibody
1 (immediate) Complement Competitive Fluid-
MAC inhibition induced
Opsonisati Inappropriate swelling
on activation
Antibody
opsonisation
through
phagocyte/Tc
 Fc receptor
2 (cytotoxic) Opsonisation
Complement
fixation by ab
attachment
3 (immune Deposition of
complex) ag-ab
complexes in
by-stander
tissue
Fixation of
complement
4 (delayed Th1/Tc- Granulamat
type) mediated ous
cytotoxicity inflammatio
n
Firm, slower
swelling

Types of T-cells:

Granulomas
o Centrally TH1 dominates
o Peripherally, Th2

Type Na Process Role MHC Locat Killing Activat Format Cytokine

of cell me involved class ion mechan ion ion needed
in ism for
differenti
ation
Helper Secrete II
cytokines restrict
that help ed
regulate B
and T cell
activity
Th1 Inflammat IL-12
ion and
tissue
injury
Th2 Repair IL-4
Th1 Secretes
7 cytokines
that act to
amplify
the acute
inflammat
ory
response
of the
innate
immune
system
Enhance
Th2
pathway
by
providing
IL-6
source

Cytoto Direct Kill target

xic killing cells by
apoptosis

Adaptive immunity:
1. Dendritic cells activated by:
a. PAMPS
b. Alarmins
c. Cytokines
2.

Tolerance: the dealing with incorrect and self-directed T cells

Types
o Central
In T-cells
1. Pre T-cell
2. Thymocytes
Prsesent MHC to antigen -> cell survives
If MHC not presented to antigen, caused to apoptose in thymus

Type Role Locatio Receptor MHC class Killing Activation

n mechanism
T helper Secrete II restricted
cells (Th) cytokines that
help an regulate
B and T cell
activity
Th1 Cell-mediated
immunity
Tc activation
Th2
Th17
Cytotoxic T Kill virus- 2ndary CD8 I restricted Binds to cell, Only by
cells (CTL, infected/aberra lymphoid perforates combination
Tc) nt cells tissues using perforin, of:
mostly hydrolytic MHC1
enzymes presentati
enter on
Degranulation IL12
(dendritic
cell)
IL2 + IFN
(Th1)
T regulatory Balance
cells (Treg) activation of
immune
response
Memory T Immune
cells memory

B lymphocytes

Types:

B1 (innate) replicate in non-lymphoid tissue, produce IgM

MHC:

Name Present on Source Presents to Recognises

MHCI All cells Peptides CD4+ Th Viruses
sampled from
cell cytoplasm
MHCII

-
Wound healing

Starts when inflammation is successful/on

its way to be successful

Steps:

1. Haemostasis immediate response

a. Primary
i. Platelet adhesion
ii. Flattening of cells
to form epithelial
cells
iii. Release of granules
(ADP, TXA2)
iv. Recruitment of
further cells
v. Vasospasm
contraction of
smooth muscle
vi. Platelet
aggregation
formation of a
haemostatic plug-
+*+
b. Secondary
i. Release of vasoconstrictive substances and tissue factors
ii. Expression of phospholipid complex in new tissue
iii. Thrombin activation
iv. Fibrin polymerisation
v. Deposition of fibrin networks for clot formation
2. Inflammation
a. Contain damage
b. Eliminate damaging stimulus
c. Removal of injured tissue-
d. Initiate deposition of ECM
i. Subendothelial collagen exposed
ii. Platelet cells attracted to damaged epithelium and
plug it
e. GFs, chemotactic factors and degradative enzymes initiate
proliferative phase
3. Proliferation starts at 4d, lasts 3-4w
a.
b. Angiogenesis
c. Fibroplasia
d. Re-epithelialisation epithelial cells try to stretch/proliferate
across wound
4. Maturation/remodelling begins at 3-4w, can last years
a. Contraction of the newly formed tissue
b. Acquisition of wound strength
c. Remodelling

Possible outcomes:

Parenchymal regeneration
Connective tissue replacement (scarring)

Balance between two outcomes influenced by:

Type of tissue
Type of cells lost
o Labile cells
o Stable cells
o Permanent cells
Amount of tissue matrix/basement mb retained
Local tissue factors
Presence of unresolved inflammatory stimuli

Influence on length of healing process:

 Extent of tissue damage
Tissue environment
o Tension and pressure on tissue
disrupts new tissue and prevents
tissue edges from being in contact
o Vascularisation and hypoxia
influences how quickly clotting
components and nutrients for new
cell growth can be provided
Intensity and duration of stimulus
Diseases that inhibit repair (diabetes,
treatment with steroids)
Foreign bodies

Type of healing:

1st intention no loss of the tissue and tissue

matrix, so more rapid to heal
2nd intention loss of tissue, tissue matrix or
vascularisation, so slower to heal

1st intention 2nd intention

Haemostatic and components more important

1. IL-2 and IL-12 influence macrophages and
activate Th2 pathway
2. Proliferative phase
3. Wound contraction
o Myofibroblasts that grow within a
wound bed have a slight contractile
capacity
o Contract slightly after colonising to
allow edges of wound to come closer
together
4. Granulation
5. Angiogenesis
o Breakdown of ECM and BM around the
tissue to allow passage of vessels
6. Fibroplasia
o Many fibroblasts align themselves
parallel to lines of stress on tissue
o Secrete fibrin ECM until more collagen
than cells
o Vessels parallel to wound regress as
well
7. Maturation
8. Remodelling
o Extra cells apoptose
o Remaining cells switch to maintain ECM
instead of creating it
9. Very low strength of tissue just after healing
takes months to regain tissue strength to
maximum of 70-80% tissue strength
10.
->Only bones can regain full strength, but this takes m-y

Granulation tissue: pink or red soft granular tissue with a granular appearance at the surface of a wound, which
is haemorrhagic and bleeds easily, and occurs due to the lack of epithelialation of the wound
Mulesing:

Employs 2nd intention healing to remove the folding of the skin

Sheep have been bred to have too much skin on rump to have more wool
Extra folds causes moistness and accumulation of dirt
Moistness compromises skin barrier and allows infection and proliferation of pathogens
Even further compromised skin barrier allows laying of fly eggs
Maggots hatch and damage the tissue even further

Link between innate and adaptive:

Macrophages phagocytose then produce cytokines to active

adaptive
Mast cells IgE on surface causing type 1 hypersensitivity
Complement

Complement cascade:

IMMUNOLOGICAL TESTING

Purpose of testing: determining

Whether an animal/population has been exposed to a pathogen

Whether an individual is shedding the pathogen (contagious)
Whether an individual is likely to be immune if exposed
Identifying latency/subclinical disease/ clinical disease

Non-specific = cross-reactive

Can detect:

Antigen test - antigen of the agent of disease

o Advantages
Does not need host response
Sometimes host response is cell-mediated
only and not humoral
Sometimes need to measure before host
response has kicked in
Host response may be variable
o Disadvantages
Antigen can degrade if improperly stored
Requires to be present in sig. C in blood/at site swabbed
Requires antigen-antibody reaction (?)
o By capture/sandwich ELISA
1. Bind capture antibody to plate ensures only desired antibody can bind
to reduce competition for plate binding site which could dim the signal
2. Saturate all other binding sites with non-specific
binding proteins
3. Wash with sample antigen to allow it to bind
4. Wash to remove any antigen that isnt well bound
5. Another species ab against the antigen is added
6. Yet another species ab which binds to all of the
other species antibody, and is enzyme-linked, is
added. This avoids having to create specific
 enzyme-linked 1ary antibodies for every antigen you want to test
expensive & time-consuming
7. Non-coloured substrate to E added and is transformed to a coloured
substrate
8. Detection using spectrophotometry
o Indirect immunohistochemistry (IHC)
By formalin-fixation of tissue
Crosslinks proteins so preserves morphology
Obscures antigenic sites, esp. >24h
Antigen can be retrieved by breaking cross-links by:
1. Heating in certain buffers
2. Digestion by trypsin
By freezing tissue
Ice crystals change morphology of tissue
Antigenic sites conserved
1. Prepare slide of tissue sample
2. Bind 1ary specific antibody to antigen-containing tissue sample
3. Bind 2ary antibody, either E-linked or fluorescent (anti-species 1) to
1ary antibody
o By latex agglutination test
1. Add latex beads bound with the antibody with the sample
2. If the antigen is present, the latex beads will clump
3. Operator determines if clumping present or not
Determination of agglutination is subjective
Antibodies secreted in response to the agent of disease but can have antibodies even if no antigen is
present
o By type
IgM recent infection
IgG most common
IgA mucosal infection
o By antibody ELISA
1. Antigen/pathogen bound to plate well
2. Patient ab incubated with plate, then washed off
3. Add fluorescent-labelled anti-patient-species ab
4. Visualise fluorescence under fluorescent microscope
o Indirect immunofluorescent antibody assay
1. Slide coated with antigen
2. Incubated with patient ab, then excess washed off
3. Incubate with fluorescent-marker labelled anti-patient ab
4. Shine with specific light wavelength to detect
o Hypersensitivity test:
1. Incubation of B and T cells with antigen
o Haemagglutination assay incubate RBCs coated with antigen with test serum and observe if
agglutinate
o IgG test
Assumption
Antigen has triggered the correct host response with the formation of B
lymphocytes

 Immunohistochemistry
o Formalin fixation cross-links
proteins to preserve tissue
morphology
Obscures antigenic sites
(exp. >24h)
o Freezing tissue
Conserves antigenic sites
Ice crystals affect
morphology
o Angiten retrieval in formalin
fixation breaks cross-links by
Digestion of cross-links
by trypsin
Heating in special buffers
Type of immune cells present can indicate
which type of agent is causing it histology
o Th1 test
o Proliferation assays incubate
cells with labelled nucleotides and
detect these
o Skin tests intradermal injection
of antigen and measuring if
inflammation (swelling) occurs
within 48h (if previously encountered)
Subtype of immune cells present depends on receptors and surface molecules/MHCs are present
Type of cytokines expressed and their abundance
o Cytokine ELISA labelled anti-cytokine probe Ab are used in an ELISA
o Flow cytometry
Cell/tissue-specific molecules released by necrotic cells indicates which tissue the infection affects
Histological presentation of inflammation

Parameters of antigen-antibody reactions:

Affinity likelihood of attraction

Avidity strength of attraction
Affected by:
o pH
o Ionic strength
o T
o Time incubated
o Concentration of reagents

Process of running immunology tests:

1. Design choice of reagents, type of test, etc.

a. Choice of Ab
i. Whole organism serum more chance of cross-reactivity, but cheap and easy to obtain
ii. Specificity to the host Ag less chance of cross-reactivity
iii. Polyclonal ab
1. Produced by injecting animal with pathogen and collecting serum
2. Mixture of Ab to range of epitopes of the pathogen
3. More chance of cross-reactivity
4. More amplified signal
iv. Monoclonal ab to single epitope
1. Produced by culturing a single B cell
2. More specific results
2. Optimisation maximise signal : noise
3. Ensure accuracy - adequate sensitivity and specificity according
to the purpose of the test
4. Define outcome thresholds which level/result indicates
disease
5. Determine predictive values

Parameters of diagnostic tests:

Sensitivity percentage of positive animals that are detected as

positive
 True positives
o Sensitivity =
True positives+ false negatives
o Highly sensitive tests can rule out a disease if a
person tests negative (snnout)
Specificity percentage of negative animals that are detected
as negative
True negatives
o Specificity =
True negatives+ false positives
o Highly specific tests can confirm a disease if a person
tests positive(sppin)
Predictive values probability of person having/not having a
disease based on their test result
o PPV:

true positives (sensitivity)( prevalence)

PPV = =
true positive+false positives ( sensitivity ) ( prevalence ) +(1specificity)(1 prevalence)
probability that a person with a + test result actually having the disease
with prevalence of disease
Since most diseases are rare, even with high selectivity and specificity tests, PPVs will be
low if not accompanied by clinical data
With clinical data, we limit the population to one with symptoms, where the prevalence of
disease is much higher, so a diagnostic test has much higher PPV in conjunction with
clinical data
truenegatives
o NPV: NPV = probability that a person with a test
true negatives +false negatives
result is actually free of the disease
with prevalence of disease

Problems with measures of usefulness: sensitivity, specificity, PPV, NPV

Sensitivity & specificity cant be used to calculate probability of having a disease in a single patient
PPV and NPV can used to calculate probability but vary between populations (due to different prevalence)
2x2 tables
o Give the wrong idea that PPV and NPV can be generalised for all populations
o Patients dont present as either having or not having a disease
Considerations:

Determining thresholds - sensitivity vs specificity

o Very infectious/dangerous diseases 100% sensitivity is preferred, even if animals identified
o Not very serious diseases/expensive treatment 100% specificity required to ensure no treatment
wasted
Predictive value probability that a subject with a certain test result truly do/dont have the disease.
Depends on size of population, specificity and sensitivity
Type of response raised by host some pathogens stimulate a strong humoral immune response, some a
strong cell-mediated immune response (e.g. tuberculosis, Johnes disease)
Predictive value
Causes of poor sensitivity
o Substance not present antigen only expressed at some stages of disease or incorrect experiment
design
o Incorrect T
o Incubation too short
o pH/ionic strength incorrect
o C too low
Source of ab
o Chemically
o By inoculating a laboratory animal
With entire pathogen - causes polyclonal Ab (Ab to whole epitope of pathogen)
Stronger signal
Cheaper
Easier to make
More chance of cross-reactivity
Culturing cell line from single B cell
Specific to single epitope
Cleaner results

Issues with tests:

Poor sensitivity
o Test incorrect/incorrectly designed for the stage of disease, e.g. testing for IgG in early infection

Assumptions for immune testing:

Indirect indicator only

Host-pathogen interaction follows a certain pattern
Technological parameters of the test

Common tests:

Faecal ELISA antigen test for Giardia, responsible for water-borne diarrhoea
o Detects antigen in 92% of microscopically-identified diseased individuals
o Detects 2 different antigens of the protozoa
o However, microscopic identification isnt 100% sensitive
o ELISA often detects Giardia more often than microscopy does
o Antigen test also detects inoculated trophozites
o At least as sensitive as microscopy method
Antibody ELISA for Rift Valley Fever virus in French ruminants
o IgM and IgG ab ELISA
o Measured against standard: virus neutralisation test/haemagglutination-inhibition test
o High specificity in sheep, goats, cattle for IgM and IgG
o Come in commercial kits: easier to use than current tests
o No explanation for the false positives as no known cross-reactivity possible
IgM indirect ELISA Herpes Simplex Virus 1 and 2
o Antigen-coated plate
o 99% specificity, 99% sensitivity
o Positive and negative result is based on OD cut-off range, with middle range considered
equivocal (sample should be retested)
o False +/- caused by:
Cross-reactivity with rheumatoid factor (RF)/other specific IgM which can react when in
high quantity
Person being auto-immune and not producing enough antibodies
Person being previously infected but currently having no antibodies
Samples taken too early in infection for antibodies to be present
Bovine tuberculosis
o Currently using skin testing with tuberculin, but not very accurate
o Primarily involves cell-mediated adaptive immunity
 o Intracellular bacterial infection so involves Tc, gamma-delta T and Th cells, especially Th1
involving IFN-gamma secretion
o Some IFN-gamma secreted by gamma-delta T-cells as well, but less
o Still looking for epitopes that could be tested
o Currently use skin test which uses tuberculin, common to pathogenic and non-pathogenic
mycobacteria strains (which are common in environment) so not specific, and result is culling
o ESAT-6 has higher specificity (& sensitivity) than tuberculin for skin tests
o Ideas for tests:
Lymphoblastogenic responses following antigen stimulation
IL-2R release from antigen-stimulated cells
Skin testing + IFN-gammaS
IFN-gamma release
ESAT-6 99.2% specificity
ESAT-6 and IFN-gamma related to clinical changes in disease
o Severe disease (high level of contagiousness) associated with Th0 cells (expressing both IFN-
gamma and IL-4)

COMMON PATHOGENS

Pathogen Type Antigens

Chlan MOMP (major outer
membrane protein)
Porin (regulates
flow of molecules
across the mb)
Adhesin (interacts
with cell mb during
entry to cell)

EPIDEMIOLOGY

Epidemiology: study of a disease and the factors that determine its occurrence in populations

Epidemiology industries:

Centre for Disease Control (CDC) epidemic intelligence service (EIS)

Role of epidemiology:

Measure risk factors for disease

Understand different determinants of subpopulations to manipulate disease control

Nodavirus:

RNA virus v. labile genome can evolve within a single host

Very prevalent
In fish
If infects fry (<42d), can cause death within several days
In adult fish (>42d), becomes latent and can infect eggs/fry by vertical transmission
Problem for high-density aquaculture
Affects certain species with different degree
Infects cells of retina in adult fish and causes them to explode, hampering feeding but not killing them
Related to salinity of water
More risk of disease when water is warm

Pacific Oyster Mortality Syndrome (POMS):

Existing Ostreid herpesvirus 1 evolved a virulent strain in France

Caused death of 50% of oysters in industry
Spread first to NZ, and only a few areas in Australia
Doesnt affect Sydney Rock Oysters, which is mostly used in Australia
Risk increases greatly when the water temperature >18C
Wiped out industry in Tasmania
Spreads by attaching to particles most effective if size of algae since this is oysters food
Larger, older oysters have lower mortality rate
Amount of time in water increases mortality rate
 Disease has higher occurrence near phytoplankton blooms since virus attaches to phytoplankton -> spatial
distribution
Lower prevalence in adults and in oysters raised above the water (i.e. spends less time in water)

Temporal patterns of disease: e.g. ebola, norovirus on a cruise ship

1. Few people are infected

2. Disease spreads to rest of population
3. Infected individuals either die off or eliminate the disease

Temporal outcome of infectious disease:

1. Infection
2. Latent period > incubating infection
3. Infectious/contagious period when able to infect another host -> clinical infection (when clinical signs are
present
4. Outcome

Influence on temporal pattern of diease:

Contagious period
o Number of virus particles sufficient for significant infection of next host
o Virus is being shed
o If disease can be spread without any clinical signs (e.g. coughing, sneezing) will precede clinical
infection period

Johnes (yonees) disease:

Chronic disease
2y latent period
Causes thickening of digestive tract epithelium, causes chronic wasting
Mycobacterium avium spp. Paratuberculosis sheep strain of mycobacteria
o Obligate pathogen of animals
o Can survive in the environment
o Faecal-oral, intrauterine and trans-mammary
o Vertical transmission (transmission to foetus)
Host factors
o Young animals more susceptible to infection, but dont develop disease until adult
o More prevalent in young animals
o Causes wastage
o Pacuibacillary low shedders
o Multibacillary high shedders
o Flock density
Environmental factors
o High stocking densities cause higher disease prevalence
o Found mostly in temperate environments in Australia
o Nutrition
o Soil type v. important higher Fe content = higher disease prevalence
o Water source
Each step of disease is associated to its own risk factors
No good test available to detect during incubation period
Start shedding in faeces before clinical signs present
Affects sheep, goats, cattle

Foot and mouth disease:

Incubation period = 2-14d

Causes severe disease in pigs and cattle
Infectious period starts before clinical signs
African buffalo is a carrier

Hendra virus:

Fatal in people
Exposure pathways in people
o Contact with an ill or dead horse before signs of HeV
o Contact with a healthy horse during a routine procedure
Dentistry
Stomach tubing

Types of epidemiological studies:

 Descriptive studies to record spread, species affected, etc. in a natural population
o Types
Investigation of outbreaks, e.g. blue tongue in cattle
Surveys
o Does not require an understanding of the mechanism or agent of disease
Analytical studies measure association between risk factors and disease
o Case-control study - measure difference in risk factor prevalence in populations with different
(known) incidences not very reliable
o Cross-sectional study take a representative sample of the whole population and measure both
disease prevalence and
o Cohort study large population measured over time, and then risk factors analysed for each
individual most reliable, but also most costly
Use placebo
Randomly allocate people into the 2 groups
Progression of studies:
o Descriptive study determine patterns of disease
Take a representative sample
Prevalence no. animals that have the disease
Incidence rate of new diseases over time
Histopathology
Medication provided
Feed provided
o Postulate a mechanism
o Develop and test improved management

Descriptive study:

1. Define target
a. Target population
2. Design a non-biased sampling strategy
a. Stratified/clustered sampling
b. Simple random/systematic random sampling

Epidemic: a widespread occurrence of an infectious disease in a community at a particular time

Pandemic: epidemic that has spread to a large proportion of the human population

VIRUSES

Viruses Bacteria Fungi Protozoan Metazoan

parasites parasites
Cultivable on No Yes
non-living
media
Size <300nm >300nm
diameter
Structure Nucleic acid Single cell
core + surrounded
protein coat by
proteoglycan
cell wall
Replication Parasitic Binary
fission
Survival No Yes
outside of
host?
Both DNA No Yes
and RNA
DNA Some
RNA Some
Metabolism No Yes
Treatment Antivirals (do Antibiotics
not kill)

Classified according to:

Nucleic acid type

o DNA/RNA
o Ss/Ds
o Sense (+)/Antisense (-)
o RT
o Segmented/not segmented
o Linear/complex
Symmetry of capsid
Presence of envelope gained from host cell endomb/plasma mb
Genome type
Sequencing

DNA/RNA viral characteristics:

Characteristic DNA RNA

Stability Stable Unstable prone to
mutations
Genetic material Stable, permanent Transient, labile
Cane be (+) or (-)
Location of replication Nucleus (usually, except Cytoplasm (usually)
for poxviruses)
Effect on viral Temporary upregulation
transcription of viral transcription
Viral replication Like host, using host Need to bring/encode own
mechanism machinery RNA pol to transcribe RNA
from RNA
Persistence of viral Remain in cell
genome
Mutation Unlikely Likely
The larger the virus, the Genome structure (+. -,
more control over contents) determines
replication of their transcription and
genome replication mechanism
Early genes ->DNA
binding proteins +
enzymes
Late genes -> structural
proteins
Examples Parvoviruses
Adenoviruses
Herpesviruses
Poxviruses

Enveloped/non-enveloped characteristics:
 Characteristic Enveloped Non-enveloped
Mechanism for release Budding, lysis, syncytium (from cell to Lysis
from cells cell)
Timing of release Immediate Has to accumulate before release
Environmental fragility Fragile Resistant to acid, heat, cold, proteases,
Easily inactivated by disinfectants detergents, drying
Stability Stable as long as DNA Very stable
Susceptibility to detection Lower, though higher if viral proteins Higher
displayed
Immune response triggered Humoral, cell-mediated Cell-mediated (protective Ig)
Ensures entry into cell is easier
Protects while extracellular
Mechanism of host cell By glycoproteins in envelope By special regions of capsid
attachment
->Vaccination often doesnt produce cell-mediated immunity -> poor protection against enveloped viruses

Virus entry into cells:

1. Attachment (either by mb glycoproteins or capsomeres)

2. Penetration
a. Endocytosis for non-enveloped viruses
b. Fusion with cell mb for enveloped viruses
3. Uncoating complete or partial
4. Eclipse period viral replication (cytoplasmic or nuclear, dep. on type)

DNA viruses (+) RNA viruses (-) RNA and ds RNA Retroviridae
viruses
5. mRNA transcribed 5. RNA pol translated 5. + RNA transcribed by 5. cDNA made by
from dsDNA directly from genome RNA pol already in virion reverse transcriptase
6. Viral proteins 6. RNA transcribed provided with virion from
translated directly from from + RNA for copying RNA
genome 6. cDNA integrated into
7. RNA pol transcribes (-) host genome
RNA from which (+) 7. Viral RNA and mRNA
copies are made produced from cDNA
using RNA pol

a. Transcription of early mRNA

i. Shuts down host protein/nucleic acid synthesis, OR
ii. Upregulates production of 2ndary viral mRNA
b. Translation of early proteins
c. Replications of viral DNA
d. Transcription of late mRNA
e. Translation of late proteins
f. Assembly of virions
6. Acquisition of viral envelope by budding from inner nuclear mb (enveloped virions only)
7. Release
Virus:

Obligate intracellular parasite

Restricted to certain cell types
Structure
o Envelope derived from host membranes
o Capsid
Role
Protect genome
Delivers genome into host cell
Composed of identical protomers
(capsomeres)
Shape often used for identification
Icosahedral
o 20 equilateral triangle
faces, 12 vertices, 30
edges
o Optiminum strength
and area formed from
repeating subunits
Helical
Complex
Embedded glycoprotein peplomeres/spikes
o Nucleic acid
o Nucleocapsid complex of proteins and nuclei acids that protect the genetic information
o DNA/RNA

Measuring genotypic diversity: highest diversity of all organisms

Growth characteristics in culture/in vivo

Serological markers, e.g. monoclonal aBs
Nucleotide sequence

Viral mutations:

Common due to
o Rapid population expansion
o Poor fidelity of viral DNA and RNA pols
Types
o Point mutations
o Deletions/insertions
o Inclusion of host DNA into viral genome
Rate affected by
o Enzyme(s) used to replicate genome higher in RNA pols than DNA pols
o Whether RNA or DNA virus
Effects
o Change host range
o Reduce virulence especially when passed through several cell cultures (due to loss of genetic
material)
o Generation of new virus variants - by
Molecular recombination
Between viruses
Between viruses and host cell
Genetic reassortment
Phenotypic mixing (mixing of proteins from diff. viruses when repackaging virions)
o Gradually reduce virulence of virus pop as a whole due to persistence of a few resistant viruses
and rapid reproduction from the host
o Antigenic shift acquisition of completely new gene from other virus
o Antigenic drift gradual accumulation of point mutations

->Canine parvovirus 2 (CPV2), which is only recent, thought to have evolved from:

Feline panleucopaenia virus (FPV, also a parvovirus) due to single AA change in capsid
FPV vaccine tissue culture
Ancestor of CPV2 in wild carnivores

->Influenza viruses can grow in any cultured cell due to change in Haemagglutinin

Host specificity/tissue tropism: ability of virus to selectively infect cells in particular organs
 Viruses code for viral enhancers which regulate tissue-specific transcription in order to vary expression of
their genome according to cell type
Need correct interaction between cell receptors and viral proteins

Mechanism of spread in the body:

Remain localised for a localised infection

Via lymphatics
o By infecting circulating leukocytes (monocytes, macrophages, lymphocytes)
Monocyte-associated (e.g. canine distemper virus, bluetongue virus, FIP)
Lymphocyte-associated viraemia (e.g. FIV, Mareks disease)
Erythrocyte-associated viraemia (e.g. bluetongue virus, African swine fever virus,
malaria)
Macrophage-associated resist phagocytosis and are carried around in macrophage
o Can then enter blood circulation
Viraemia
o Via blood circulation (1ary viraemia) entry by:
Passive passage through basement mb
Infecting endothelial cells and spreading through by replication causes thrombosis,
haemorrhage, oedema and circulatory shock due to endothelial cell damage
o 2ndary viraemia further spread to organs by replication and infects parenchyma
CNS
By blood vessels in meninges and choroid plexus
By migrating though peripheral nerves
Foetus - transplacental

->Generalised infection when virus transverses basement mb of epithelium to infect sub-epithelial tissues

Effects of viruses:

Body system/cell Symptom Underlying mechanism

Vascular endothelial cell Thrombosis Vasculitis (damage to endothelial
Haemorrhage cells)
Oedema
Circulatory shock
Skin Papules
Vesicles
Pustules
Ulceration Inflammatory accumulation of
Scabbing fluid between dermis and
epidermis
Ecchymoses Decrease of platelet numbers in
Petecchial rashes the skin
CNS 1. Lytic infections
a. Neuronal necrosis
b. Neuronophagia
(phagocytosis by
microglia)
c. Perivascular
infiltration
2. Lytic
a. Neuronal
degradation
b. Vacuolation
c. Demyelination
Foetus Abortion (e.g. EHV1)
Foetal absorption (e.g.
akabane, parvovirus)
Foetal malformation (BVDV)
Foetal tolerance
BVDV: Bovine viral diarrhoea virus
Viraemia: presence of a virus in the blood

Viral shedding: in body fluids expelled through body orifices

Shedding/transmission route Examples

Skin Inflammatory products
(pus/exudate)
Infected skin cells VZV
Hair/feather follicles PBFD
Vesicular fluid VSV, FMDV
Milk CAEV
Urine Equine rhinovirus, CAV1, canine
distemper virus
Blood Blood itself
Biting arthropod Akabane, bluetongue virus, EIAV
Genital secretions EHV3, BHV1, HSV2
Ingestion of virus-infected meat FMDV
Genetic (through passing on Retroviruses
host DNA)
VZV: Varicella-Zoster virus
FMDV: foot and mouth disease virus
PBFD: Psittacine beak and feather disease
CAEV: Caprine arthritis encephalitis virus
CAV1: canine adenovirus 1
EIAV: Equine Infectious Anaemia Virus
EHV3: Coital exanthema
BHV1: Infectious vulvoganitis-balanoposthitis
HSV2: Herpes Simplex Virus 2

Myxomatosis:

Affects European rabbits only

Caused by myxomavirus, a poxvirus
Transmitted by mosquito bites
Lethal
Introduced to control rabbit pops in Australia
Virulence gradually decreased to 50% due to survival of more resistant strains over winter month
(<mosquitoes)

Typical viruses:

Avian paramyxo virus deadly virus in pigeons

Hendra virus deadly virus in horse
o Weakness
o Loss of balance
o Death
Rhinovirus common cold
Canine parvovirus can survive in the environment for 12m
o Non-enveloped DNA virus
o Causes neurological GIT, respiratory symptoms, death
o Attacks actively-dividing cells
o >8w: immature enterocytes, bone marrow cells
o 4-8w: + cardiomyocytes
o Neonate: all cells
o Only recent thought to have evolved from:
Feline panleucopaenia virus (FPV, also a parvovirus) due to single AA change in capsid
FPV vaccine tissue culture
Ancestor of CPV2 in wild carnivores
Human influenza viruses
o Like all mammalian influenza viruses, derived from antigenic shift genetic re-assortment
between avian viruses and non-virulent mammalian strains in the pig (common host)
o Binds to mb by haemagglutinin for entry
o Exits host cell thanks to neuraminidase
Feline parvovirus
o Cerebellar hypoplasia in kittens infected 2w before 2w after birth
o Gastroenteritis
o Commonly vaccinated against
Feline leukaemia virus
Feline panleukopaenia
o Transmission by faecal-oral route
o Takes 2-7d to travel to intestines/bone marrow
o Shed in faeces within 3-6w for 5-7d
o Affects:
Lymphoid tissue
Intestinal crypt epithelium
Bone marrow progenitor cells affects replication
o
Feline immunodeficiency virus
o Neoplasia
o Immune
 Calici virus
Herpes virus
o EHV-1 (abortions)
o HSV-1 (cold sores)
Poxviridae
Feline coronavirus (FCoV) mutates to become FIP (Feline Infectious Peritonitis)
Feline herpesvirus
o URT disease
o Can stay latent for years
o Causes conjunctivitis and upper respiratory tract infection
o Persist in sensory nerve ganglia and re-emerge during times of stress
Epstein-Barr Virus (EBV) very common virus but does not usually cause illness
o Spread by salivary glands
o Diagnosed by blood test
o Long-term immunity from initial exposure
o Contributes to neoplasia
Upregulates oncogene bcl-2
Causes chromosomal rearrangement
Translocates c-myc gene to upregulate it
Simian Immunodeficiency Virus (SIV) non-human primates
Avian leucosis virus
o Chronic viremia (chicks)
o Transient viremia (adults)
o Leukemia
Avian influenza
o H5N2 point mutation in region coding for Haemagglutinin, causing N-linked glycosylation
exposing cleavage site, causing virus to become 8 times more virulent
Foot and Mouth disease virus only cloven-footed animals
o Non-enveloped RNA virus
o Lysis of epithelial cells on feet and mouth
o Virus excreted through all secretions in large V
o Persists in pharynx
FIP (Feline Infectious Peritonitis)
o Caused by coronavirus
o Causes type III hypersensitivity
Virus prevents body from eliminating it, so Ag-Ab deposits in blood vessel wall
->vasculitis causing
Oedema
Protein-rich abdominal effusion
Lymphocytic choriomeningitis virus infection (mice)
o Infects meninges, epedydma, choroid plexus
o In CNS, Tc response to virus causes brain damage and death
o Treated with immunosuppressive drugs
CAEV (Caprine Arthritis-Encephalitis Virus) viral protein v. similar to myelin basic protein, so production of
Ab to CAEV damages host myelin

Viral nomenclature:

Order: -virales
Family: -viridae
Sub-family: -virinae
Genera: -virus
Species according to
o Anatomical location
o Geographic location
o Discovering scientist
o Disease type
o Body system affected

Favourable traits of viruses:

Wide host trophism

o Allow many animals to get infected
o But also makes the virus not specialised or that host limited survival
Ability to replicate by budding (less likely to trigger immune system)
Survival in the environment (envelope)
Family Size Structure Gen Effects Infection Prop Examp
of virus etic mechani ertie les
mat sm s
eria
l
Retroviru 2 copies of same ssRNA, each Latent/n Use Avian
ses containing 3 genes: on- leucosi
RT
(retroviri Gag (capsid proteins) producti s virus,
(reve
dae) ve but
Pol (reverse transcriptase) transfor
rse
trans
Env (envelope proteins) ming
cript
ase)
to
form
cDNA
from
ssRN
A
Use
integ
rase
(IN)
to
integ
rate
into
host
geno
me
Herpesvi 150n Cytocida Latent, Good EBV,
rus m l/ latent recurrent at HSV-1,
(herpesvi Intracyto infections evadi HSV-2 ,
ridae) plasmic Contain ng chicken
inclusion homologu immu pox
bodies, es of ne (return
intranucl oncogene syste as
ear s m shingle
inclusion Reacti s, hide
bodies, vation in
syncitia when lympho
Shut stress id
Enveloped down ed tissue)
host Hide
protein in
synthesi lymph
s oid
Contribu tissue
te to or NS
neoplasi Dont
a surviv
e in
enviro
nmtn
Poxvirida 300x Enveloped Line Intracyto Create Scabby
e 200n ar splasmic skin mouth
(poxvirus m dsD inclusion lesions (orf),
es) NA bodies smallp
ox

Adenovir 70- Icosahedral capsid Line Intranucl Rhinovi

us 100n Nonenveloped ar ear rus
m dsD inclusion
NA bodies

Papillom Circ Encode

 Transmision efficiency
o Variability of transmission methods (horizontal, vertical)
o Triggering host to spread the virus (coughing, runny nose, etc.)
Low virulence ensure the survival of the host for the longest amount of time
Mutation to evade new mechanisms
Survival in the host
o Wide-cell trophism allow them to infect as many cells as possible
o Evasion of the immune system
Lodging itself in the NS
Travelling up and down nerves (e.g. rabies)
o Latency
o Insertion into the host genome
o Fast replication

->Often take part of the envelope of host cell to envelope themselves ensures evasion from immune system,
but also makes it less likely to be
->NS susceptible to infection because of low regeneration potential launch inflammation only in serious cases

Nucleocapsid: nucleic acid and protein complex which contains the genome

Transmission:

Horizontal from one individual to another

Vertical
o Congenital infection
o Genetic transmission through

Types of viruses:

Tests for retroviruses:

Test for RNA

Test for inserted gene in DNA

Viral replication:

Most RNA viruses replicate in cytoplasm

Most DNA viruses replicate in nucleus
Types:
o Cytocidal/lytic infection (e.g. canine parvovirus)

o Persistent infection
Productive can persist up to several years in the host
Latent
Non-productive transforming
No new virions created
No virions present in tissues
1. Virus recognises susceptible, permissive host cell by interaction between viral protein and specific mb
receptor
2. Attachment
3. Entry into cell of virus/genetic material
4. If DNA:
a. Translation by viral/hosts RNA pol to form viral packaging proteins, etc.
b. DNA replicated
5. Viral particles + genetic material packaged into vesicles of mb
6. Release
a. Syncitium
b. Lysis
c. Budding

Infection:

1. Capsid proteins bind to cell receptors

2. Binding triggers removal of capsid
3. Genome enters cell by direction of the capsid

Viral mutations: often used to alter host range or virulence

Viral recombination transfer of genetic material between closely-related viruses infection the same cells
Two types:
o Antigenic drift gradual accumulation of point mutations
 o Antigenic shift sudden acquisition of a new gene due to recombination (most common) or
reassortment with another virus

Requirements for infection a host cell:

Susceptibility host cell must have specific mb receptors

Permissivity host cell must be able to support viral replication (have an active replication/protein
expression mechanism)
Ability to reach such cells
Specific proteins for binding to the host cell
o Haemagglutinin (HA/H) allows virus to attach to epithelium
o Neuraminidase (NA/N) allows virus to detach when leaving the cell

Effect of a virus on a cell: all classified as signs of disease

Disruption of cellular function

o Inhibition of host cell nucleic acid synthesis
Interferes with host replication enzymes & proteins
Produce DNAses that only lyse host DNA
Displace synthesis with own DNA synthesis by competition
o Shutdown of host cell protein synthesis
o Chemical damage by toxins (proteins)
Induction of cell death (cytocidal)
o Through cell lysis (e.g. herpesvirus, rabbit calicivirus)
o Induction of cell lysis by immunologic means present non-self glycoproteins on mb which trigger
immune system
Persistence in the host cell
o Production (non-cytocidal) virus produced (at varying rate) without affecting cell metabolism
(e.g. old distemper virus)
Rate of cell destruction < rate of cell replacement
Can cause low-level inflammation
Can impede growth in long term
Important effect on CNS due to low cell replacement rate
o Latency in cells but non-productive (e.g. retrovirus, herpesvirus)
o Non-productive but transforming virions not produced, but viral genes/products affect cell
function (e.g. retroviruses)
Activation of inappropriate immune response
o Hypersensitivity reaction e.g. FIP

Effects on cell morphology:

Inclusion bodies
o Intranuclear (suggests ) (e.g. herpesviruses, adenoviruses, parvoviruses)
Degenerate cellular DNA
Cowdry body (eosinophilic deposits of nucleic acids and proteins)
Masses of viral proteins and nucleic acids
o Intracytoplasmic (RNA viruses, e.g. poxviruses, paramyxoviruses, reoviruses, rabies viruses)
Masses of viral nucleocaspids
Masses of viral protein and nucleic acid
Negri body
Crystalline aggregate of virions
o Round/irregular-shaped
o Acidophilic/basophilic
Alterations to cell mb structure inclusion of glycoproteins
o Viral envelope antigens
o Host histcompatability antigen
o Viral structural protein knobs and spikes
Formation of syncytia spread of viral products between cells while escaping effects of host defenses
Hameadsorption adsorb haematocytes thnks to glycoproteins in their mb
Cytopathic effect (CPE) destruction of tissue structure/certain cells specific to virus family

Interference: resistance of already-infected cells from superinfection by the same/different virus by:

Another (interfering) virus

Host-produced interferons (IFNs) cytokines that are secreted transiently in response to viral infection
o Bind to plasma mb of other cells
o Stimulates DNA binding factor by signal transductioin
o DNA binding factor binds to interferon-reponsive genes which upregulate >20 genes
responsible for inhibiting viral replication
o 3 types: , ,
 Characteristic IFN IFN IFN
Potency Low Low 100x more potent
Inducing agent Virus Virus Immune
stimulation
Produced by Leucocytes Fibroblasts, epithelial NK cells
cells
Effect Antiviral Antiviral Immune
modulation
Action protein protein synthesis CTL, NK activity
mechanism synthesis

Mechanism of entry into the body: and host defences at these points of entry

Through mucosa
o Respiratory mucosa attach to receptors on epithelial cells and infect them. Host defences:
>10m particles trapped in nasal mucosa
5-10m carried to trachea and bronchioles
<5m inhaled in lungs and destroyed by alveolar macrophages
o Urogenital mucosa, e.g. herpesviruses often through tears in mucosa
o GIT mucosa
Two mechanisms:
Infect cells in oropharynx, then carried to intestinal tract
Infect intestinal mucosa directly after being swallowed
Host defences:
Mucus
Gastric enzymes and acids
Bile
IgA
Oesophagus rarely infected
Gastric secretions have no effect on coronaviruses, parvoviruses, rotaviruses common
cause of diarrhoea
o Conjunctiva, e.g. adenoviruses
Through artificial break in skin
o Scratch/bite
o Intradermal needle
Injection by vector directly into bloodstream
o Biting arthropods, e.g. mosquitoes, ticks, sandflies
o Iatrogenic needles or procedures
Infecting body surface cells

Mechanism of disease production:

Immunosuppression
o Destruction of T-lymphocytes
o Production of inhibitory cytokines (e.g. EPV with IL-10)
o Down-regulation of class I or II MHC expression
Cytocidal damage to cells
Epithelial damage predisposing to 2ndary bacterial infection e.g. rhinoviruses, parvovirus, parainfluenza
virus 3
Oncogenesis
o By insertion of v-onc (virus-incorporated proto-oncogene) into the genome by retrovirus
After incorporation of proto-oncogenes (c-onc) into retrovirusesduring retrotranscription
instead of viral gene (e.g. FeSV, requiring FeLV)
Cant replicate independently due to lack of certain genes
Require presence of helper virus in cell to provide missing capsid proteins/RT to allow
replication
Viral LTRs have to favour its transcription
o Insertion of c-onc by DNA viruses genes designed to immortalise host cell by:
Providing or promoting growth stimulation genes
Inhibiting checks of the cell cycle
o Insertion of viral genomes in the ORF of c-onc causing up-regulation
o Viral products up-regulate (by LTR-binding) or prevent transcriptional control of c-onc
Non-cytocidal can be as or even more severe than cytocidal
o Incitation of a severe immune response
o Hypersensitivity - immune response it triggers damages the tissues itself, e.g. type II in FIP, type
IV LCM
o Molecular mimicry viral proteins resemble host proteins, so Ab created against virus attacks
itself, e.g. CAEV
EPV: Epstein-Barr Virus
LCM: Lymphocytic choriomeningitis virus infection

Type of virus infection: viruses can follow several of these patterns, depending on the species/time of infection

According to duration of virion production period

o Persistent (months to life) may cause
Neoplasia in later life, e.g. FeLV
Immunopathological disease, e.g. CDV
Current disease, by being regularly
reactivated, e.g. herpesvirus
Rapid spread of virus in population due to
carrier animals
o Latent infections after recovery from a 1ary acute
infection
Virus is maintained in latent stage by
production of few select proteins that
maintain it
Few proteins produced cant be detected
by conventional tests
When reactivated, virions start being
produced again
o Chronic infections continuous virus production
o Acute infections (e.g. CDV)
o Slow infections very long preclinical phase
Slowly progressive lethal disease
Viruses replicate slowly but surely and
escape any immune response
Can infect other people during preclinical period
E.g. HIV, FIV, CAEV

Diagnosis of viral infection:

Detection of viral antigen

o Immunofluorescence
o ELISA
o Immunodiffusion
o Immunohistochemistry
Detection of entire virus
o Viral isolation
o Electron microscopy
Detection of viral nucleic acid
o PCR
o Genetic probes (hybridisation)
Immune response to virus
o Ab
ELISA
Western Immunoblot Assay
Serum Virus Neutralisation Test (VN)
Haemagglutination Inhibition (HI) test
Haemadsorption-Inhibition (HAD-I) test

Titre: relative antibody concentration

Serology: use of antigen-antibody reactions for the diagnosis of disease

Types
o Presence of Ab
Monoclonal only one epitope on one antigen
Polyclonal many epitopes on one or more antigens
o Presence of Ag
Titre = 1/greatest C giving a + result
Purpose
o Detection of Ag/Ab
o Identificawtion of Ag/Ab
o Quantification of Ag/Ab

The Role of Nutrition in Disease

The role of nutrition in disease:

 Part of environment in HPEI
Disease can lead to further nutritional deficiency
Nutritional deficiency -> immunosuppression

Influence of nutritional deficiency on disease:

Nutritional deficiency Metabolic Disease consequences

consequences
Starvation Glycogen levels depleted
Gluconeogenesis, esp.
from AA, for cells that
absolutely require
glucose
Breakdown of non-
essential proteins, esp.
skeletal muscle
Breakdown of adipose
tissue -> free FA to feed
cells that dont
absolutely require
glucose
Cessation of protein and
fat synthesis
Glucagon,
glucocorticoids secreted
Insulin secretion
inhibited
Energy supply comes
from CHO and AA

Metabolism in systemic infections:

Most energy taken from carbohydrates & AAs

Most substrates for gluconeogenesis used for APRPs
Fat utilisation for energy diminished
expenditure of energy due to
o catabolic state
o body T, causing faster heat loss to environment
Loss of appetite -> undernutrition
Malabsorption if in the digestive tract
Endocrine changes
o glucagon - gluconeogenesis
o glucocorticoids
o TH
o GH
o inuslin pressure on supply of glucose
loss of WS vitamins and minerals due to
o catabolic state
o Breakdown of tissues
Il-1 produced by macrophages, esp. when phagocytosing bacteria
o Stimulates IL-2 produced -> activates T-cells, stimulates osteoclasts
o Changes set point of body T in hypothalamus
o ceruloplasmin production -> available Cu in blood for microorganisms to use
o uptake of Fe, Zn into liver -> available for microorganisms
o uptake of AA into liver -> available for gluconeogenesis
o Production of albumin -> proteins carried in blood for other uses
o APRPs (acute phase reactant proteins) production, e.g.
antitrypsin (inhibits trypsin synthesis in infectious agent)
Heptoglobin (binds haemoglobin to prevent access to Fe)
-2-macroglobulin (2M)
Seromucoid
C-reactive protein
Diminishment of gluconeogenesis in favour of APRP production
Hypoglycaemia due to [insulin], causing all remaining glucose to enter cells that dont necessarily need
it competition with cells that do need it
->Larger combined effect of both than of either individually

Ceruloplasmin: major copper-carrying protein and ferroxidase enzyme, having a role in both iron and copper
metabolism
APRPs: Acute Phase Reactant Proteins, proteins which are produced by the liver when the body is experiencing
systemic infection in order to inhibit the growth or kill the infectious agent

Effect of malnutrition on ability to resist infection:

secretion of antibodies (IgA) across mucosal surfaces more low-grade, local infections due to low-
pathogeneticity microorganisms invading mucosal surfaces
Humoral resistance (IgG) not greatly effected
Cell-mediated immunity diminished
Complement diminished
Phagocytosis impaired chemotaxis
Typical signs of infection
o Not enough energy for fever
o Not enough WBCs in blood usually in normal range
o Poor inflammatory response
o Tested by absent cutaneous hypersensitivity to tuberculin
Cause false negatives for certain immunity tests that rely on host response
More frequent, severe, long-lasting infections, with higher mortality

Analgy: absence of inflammatory response to an infectious agent or foreign body

Treatment of sick, malnourished animals:

Provision of high amounts of energy (either fat or CHO)

Provision of nutrients involved in: (to help overcome infections)
o Protein synthesis
Protein
o Cell division
o Nucleic acid metabolism

Most important nutrients for infected animals:

Energy (either fat or CHO)

Nutrients involved in
o Protein synthesis
Protein to allow IgA formation and maintenance of mucosal surfaces, esp. skin &
respiratory tract
Hypoproteinaemic animals are prone to:
o Skin infections
o Viruses that usually only affect other species
Important for:
o All Ig production
o Phagocytosis and chemotaxis
Both amount and quality needs high amount of limiting AAs
o Casein (Biological value=0.95) best profile
o Gluten (BV=0.4-0.5)
o Cell division
o Nucleic acid metabolism
o Colostrum in neonates prevents immunity during neonatal stage, and prevents development of
adult immunity
o Micronutrients
Ca
K
P - resistance to GI tract infections
o Trace elements:
Cu
Zn
Mn
Fe
More Fe absorbed into liver when infected
Competition between use for replication in microorganism and use in host -
[blood Fe]
Little absorption in the SI
secretion of Fe-binding proteins when starved, esp. transferrin in blood, tissue
and secretions
o Vitamins
 VitA required for protection against infection across MM
VitD -