UTE OF INTEGRAT

DEFENSE MECHANISMS
I Non specific immunity
General protective mechanisms that kill or prevent the multiplication of
pathogens
Innate or inborn...
Predates adaptive immune response
Found in all multi-cellular organisms
Provides protection against a wide variety of pathogens
Distinguishes self from non-self perfectly
Immune
Surface
Is a two tier defense system Defenses Response
• The skin & mucus membrane
• Inflammation

II Specific immunity
Refers to mechanisms that are activated individually after a Inflammatory Response
microbe or some other foreign material invades an animal body

Acquired...
Not present from birth but acquired during lifetime, developed by the organism in
response to a disease or a vaccine (measles; mumps; smallpox; polio ) 02/11/10
 CELLS CHEMICAL BARRIERS
PHYSICAL BARRIERS
granulocytes,
Skin, mucous membrane
monocytes, pH, enzymes
macrophages

MUCUS AND CILIA chemical - activities carried

Mucus traps out by molecules
salts - secreted by sweat
microorganisms and
glands in skin
prevents them from cellular - activities carried out by cells
acids - low pH (HCl in
reaching and colonizing normal microbiota compete with
stomach; lactic and other skin
the epithelium pathogens for attachment sites and
acids produced by normal
nutrients as well as producing factors
environmental microbiota)
toxic to pathogens
lipids - fatty acids secreted by
conditions - dryness phagocytes - macrophages and
sebaceous glands and by gall
polymorphonuclear leukocytes (PMN)
bladder
flushing action - blinking are leukocytes that engulf and destroy
enzymes - lysozyme
particles on mucous membranes by a
of eyelid, peristalsis, (secretions), digestive
process known as phagocytosis
urination enzymes (stomach, small
intestine)
Innate Immunity: Functions

Initiates an inflammatory response

Reaction to injury or infection

Trauma to tissues or cells
Presence of foreign matter (self vs. non-self)
Infectious agents (viruses, bacteria, fungi)

Identifies and eliminates pathogens

 Non-adaptive recognition systems

 Activates molecules that target the microbe and aid in it’s identification

These factors may be surface expressed, released from

immune cells or are present within circulatory system

02/11/10
Innate Immunity: Cellular
Components
 Granulocytes
 Polymorphonuclear leukocytes fight pathogens
(PMN, neutrophils)
inflammation √
 Eosinophils allergic and
 Basophils (blood) hypersensitivity reactions
 Mast Cells (tissues)
fight pathogens
 Mononuclear Phagocytes inflammation √
 Monocytes (blood) cytotoxicity
 Macrophages (tissue) immune regulation

02/11/10
 Neutrophils (PMN) :
 Present in blood (60-70% of WBC)
 Not normally present in tissues
 Short lifespan - 12 hours
 Functions:
First cell at the site of infection/injury
Ingest and kill microbes after bactericidal mechanisms activated
(binding to pathogen)
- Produce cytokines/chemokines (initiate inflammation)

Mononuclear Phagocytes:
• Blood - monocytes (1-6% WBC)
• Tissues - macrophages
– Long lifespan – many months
– found in tissues (ex., gastrointestinal tract, skin,)
• Functions:
– Phagocytize and kill after bactericidal mechanisms activated
– Produce cytokines/chemokines (initiate inflammation)
02/11/10
02/11/10
 ACUTE INFLAMMATION

Acute inflammation is a rapid response to an injurious agent that serves to

deliver mediators of host defense—leukocytes and plasma proteins—to the
site of injury. TIME Feb. 23, 2004

Acute inflammation has three major components:

(1) alterations in vascular caliber that lead to an

increase in blood flow;

(2) structural changes in the microvasculature that

permit plasma proteins and leukocytes to leave the
circulation; and

(3) emigration of the leukocytes from the

microcirculation, their accumulation in the focus of
injury, and their activation to eliminate the offending
agent
 Two Phases of Acute
Inflammation:

Immediate
Histamine-mediated Temporary (8 - 10 minutes)
fluid release Prolonged (A few days)

Delayed

Observable damage to tissues and capillaries

02/11/10
 EDEMA

A hallmark of acute inflammation is increased vascular

permeability leading to the escape of a protein-rich fluid
(exudate) into the extravascular tissue. The loss of protein
from the plasma reduces the intravascular osmotic pressure
and increases the osmotic pressure of the interstitial fluid.
Together with the increased hydrostatic pressure owing to
increased blood flow through the dilated vessels, this leads to
a marked outflow of fluid and its accumulation in the interstitial
tissue. The net increase of extravascular fluid results in
edema.
Vascular/tissue changes in Acute Inflammation are typified by:

 increased vascular
permeability and
vessel dilatation,

 a protein rich fluid

(exudate) from the
blood entering the
tissue,

 cellular infiltrate: the

early arrival of
neutrophils replaced
later by macrophage
and occasional
lymphocytes, then
fibroblasts for
healing

02/11/10
The sequence of events in the journey of leukocytes from the vessel lumen to
the interstitial tissue, called extravasation, can be divided into the following
steps:
1. In the lumen: margination, rolling, and adhesion to endothelium.. In
inflammation, the endothelium has to be activated to permit it to bind leukocytes, as
a prelude to their exit from the blood vessels.

2. Transmigration across the endothelium (also called diapedesis)

3. Migration in interstitial tissues toward a chemotactic stimulus

02/11/10
 INFLAMMATORY CASCADE
TNF-alpha ;IL-1β
Arachidonic Acid Metabolites
Phospholipase A2 releases arachidonic acid from
membrane phospholipids and goes into:
 lipoxygenase pathway
 LTB4: chemotactic for granulocytes and macrophage
 LTC4, LTD4, LTE4: potent vasopermeability and
bronchial spasm
 cyclooxygenase pathway
PGI2: vasoconstriction
PGD2, PGE2, : vasodilation
 lipoxins (12-lipoxygenase on neutrophil LTA4)
 vasodilation, reduces LTC4 vasoconstriction

02/11/10
02/11/10
 Omega 6 Fatty Acid Omega 3 Fatty Acids
(Linoleic Acid) (alpha-linolenic acid)

Gamma-linolenic acid Eicosapentaenoic Acid

(GLA)
Evening Primrose Oil (EPA)
Borage Oil
Black Current Oil

COX Lipoxygenase

Arachidonic Acid
Prostaglandins Less Inflammatory
PGE1, PGE3 Leukotrienes
(Favorable)
COX Lipoxygenase
Docosahexaenoic acid
(DHA)
Prostaglandins (PGE2)
Inflammatory
Leukotrienes
02/11/10
CYCLOOXYGENASE PATHWAY
3 important products
 Thromboxane A2
–Aggregates platelets and causes vasoconstriction

 Prostacyclin (PGI2)
–Endothelial cells inhibits platelet aggregation and causes vasodilation

 Prostaglandins PGE2, PGF2 and PGD2

–Variety of actions on vascular tone and permeability

LIPOXYGENASE PATHWAY
• Leukotrienes
• Leukotriene B4 is a potent chemotactic agent
• Leukotrienes C4, D4, E4

Potent mediators of increased vascular permeability on venules only

Up to 1000 times as potent as histamine in producing increased vascular
permeability 02/11/10
 CHEMICAL MEDIATORS OF INFLAMMATION

Definition: Any messenger that acts on blood vessels, inflammatory cells, or

other cells to contribute to an inflammatory response. (Pretty much anything...)

 Exogenous
 Endotoxins
 Endogenous
–Plasma
–Leukocytes
–Endothelial cells
–Fibroblasts
 CYTOKINES
 Transmitters for cell-to-cell chatting
Modulate cell function
 Primarily from activated macrophages and granulocytes

Pro-inflammatory Cytokines
• Tumor necrosis factor-α
• Interleukin-1
• Interleukin-6
• Chemokines ( LTB4; MAP etc )

The importance of these lies in their pivotal role in

inflammation.

02/11/10
 IL-I and TNF-alpha
“Master Cytokines”
 Origin
 Monocytes
 Macrophages
 Similar in action
 Endothelium
 Acute phase proteins
 Fibroblasts
ajor diseases linked to TNF and its family members
Autoimmune Hematopoiesis Protection from Innate Tumor Immune
Deficiency Bacterial inflection Immunity regression surveillance
Syndrome
(AIDS)

Crohn’s Systemic lupus

disease erythematosus

Alzheimer’s
disease

TNF
Osteoporosis/
Multiple Bone
sclerosis resorption

Transplant Septic
rejection shock

Diabetes Lymphoproliferative
(type II) diseases

Rheumatoid Pulmonary
arthritis fibrosis

Heart failure

Atherosclerosis
Liver Allergic Fever Tumor Tumorigenesis
disease asthma metastasis

02/11/10
Aggarwal BB, Nature Rev Immunol. 2003 Sep;3(9):745-56
When a host encounters an injurious agent,
Acute Inflammation…. Turns chronic ? ? ?
phagocytes that reside in all tissues try to get rid of
these agents. At the same time, phagocytes and other
host cells react to the presence of the foreign or
abnormal substance by liberating cytokines, lipid
messengers, and the various other mediators of
inflammation. Some of these mediators act on
endothelial cells in the vicinity and promote the efflux
of plasma and the recruitment of circulating
leukocytes to the site where the offending agent is
located.
As the injurious agent is eliminated and anti-inflammatory
mechanisms become active, the process subsides and the host
returns to a normal state of health. If the injurious agent cannot
be quickly eliminated, the result may be chronic inflammation.
The recruited leukocytes are activated by the injurious agent and
by locally produced mediators.
02/11/10
 Chronic Inflammation
In contrast to acute inflammation, which is manifested
by vascular changes, edema, and predominantly
neutrophilic infiltration, chronic inflammation is
characterized by:

• Infiltration with mononuclear cells,

cells which include
macrophages, lymphocytes, and plasma cells.
• Tissue destruction, induced by the persistent
offending agent or by the inflammatory cells.
• Attempts at healing by connective tissue replacement
of damaged tissue,
tissue accomplished by proliferation of
small blood vessels (angiogenesis) and, in particular,
fibrosis

02/11/10
 Differences between Acute and Chronic Inflammation.
Acute Chronic

Duration Short (days) Long (weeks to months)

Onset Acute Insidious

Specificity Nonspecific Specific (where immune response is

activated)
Inflammatory cells Neutrophils, macrophages Lymphocytes, plasma cells,
macrophages, fibroblasts
Vascular changes Active vasodilation, increased permeability New vessel formation
Fluid exudation and + –
edema
Cardinal clinical signs + –
Tissue necrosis – (Usually) + (ongoing)
+ (Suppurative and necrotizing inflammation)

Fibrosis (collagen – +
deposition)
Operative host responses Plasma factors: complement, immunoglobulins, Immune response, phagocytosis, repair
properdin, etc; neutrophils, nonimmune
phagocytosis
Systemic manifestations Fever, often high Low–grade fever, weight loss, anemia

Changes in peripheral Neutrophil leukocytosis; lymphocytosis (in viral Frequently none; variable leukocyte
blood infections) changes, increased plasma
immunoglobulin
02/11/10
AUTOIMMUNE DISEASES

• Immune system mistakes the body’s own cells &

tissues for ‘nonself ’ and attacks… targetting the
organs of a person’s own body causing dreaded
auto --immune diseases
• Occur more frequently in women than men
• Social,economic & health impact is far reaching
extending to family, to employers, co-workers and
friends

02/11/10
 SOME AUTOIMMUNE DISEASES
Nervous system:
Multiple sclerosis Myasthenia gravis

02/11/10
 The Parasympathetic
System
 The parasympathetic nervous system also
called the craniosacral system contains
ganglia in the midbrain,medull oblongata
and sacrum.
 The first two, the cranial ganglia of the
parasympathetic system, give impulses to
the facial, oculomotor, glossopharyngeal,
and vagus nerves.
 The sacral group of parasympathetic
nerves originate at the second, third, and
fourth vertebrae and extend nerves to the
bladder, distal colon, rectum, and genitals.
Postganglionic parasympathetic neurons
secrete acetylcholine and are thus
called “cholenergic.”
Blood: Haemolytic anaemia

Thrombocytopenia
Thrombocytopenia

Blood vessels: Temporal arteritis

Wegener’s granulomatis

Skin: Psoriasis

Dermatitis herpetiformis

Vitiligo
02/11/10
 Ulcerative colitis (IBD)
Gut: Crohn’s disease (IBD)

Ulcerative colitis (IBD)

Crohn’s disease (IBD)

Autoimmune hepatitis
Endocrine glands:
Diabetes mellitus (Type-I)

Grave’s disease

( Hyperthyroidism)

Hashimoto’s thyroidoitis
( hypothyroidism)

Multiple organs:

Rheumatoid arthritis*

Systemic lupus erythematosus* (SLE)

* also called connective tissue ( muscle, skeleton, tendons,

CLASSIFICATION OF
ARTHRITIS
Inflammatory Noninflammatory

Acute Chronic Osteoarthritis

Infectious arthritis, Polyarticular Pauciarticular

Gout ,rare initial
presentation of
chronic arthritis Rheumatoid Arthritis, Psoriatic arthritis, Reactive
Systemic Lupus arthritis
Erythematosus,
02/11/10
 Chronic inflammation in joints and surrounding tissues

When body tissues are inflamed, the disease is in a flare,

but remissions can last for years. Flare symptoms
include:
Fatigue
Lack of appetite
Low-grade fever
Muscle and joint aches
Stiff, swollen, and painful joints 02/11/10
 MHC
T cell Activation by
Arthritogenic antigen
APC T cell
TCR

Activation
TNF-α IL-2 IL-1 IFN-
Regulation by γ
Cytokines IL-8 TNF-β iNOS IL-6
Inhibition
TGF-β IL-4 IL-10

Activation of: Synovial cells Vascular adhesion molecules B cells

Mechanisms
of Joint Metalloproteinases PMN’s, Lymphocytes, Immunoglobulin
Destruction: macrophages into joint
02/11/10
Scientific curiosity (study) is
not about winning Nobel Prize
but serving science

Venkatraman Ramakrishnan
Nobel Laureate in Chemistry
2009
02/11/10
02/11/10