Chapter 1: Introduction and Natural Immunity

1960
Cells responsible for immune response were identified and
characterized

Immunology and Serology

Immunity and Immunization

Immunology
The study of hosts reactions when foreign substances are
introduced into the body
Antigen
Foreign substances that induces immune response
Variolation (1500)
Developed by Chinese
Exposing individuals to material from smallpox lesions
Theory: If a healthy individual was exposed as a child or
young adult, effects of the disease are minimized
Edward Jenner (1700)
Relationship between exposure to cowpox and immunity to
smallpox
Vaccination
From the Latin word vacca meaning cow
Injecting cellular material that provide protection
Cross-immunity
Phenomenon in which, exposure to one agent produces
protection against other agent
Louis Pasteur
First attenuated vaccine
Attenuation
Change; remains as basis for immunizations
May occur through:
o
Chemical
o
Heat
o
Aging

Cellular versus Humoral Immunity

Ellie Metchnikoff
Phagocytosis (cells eat cells)
o
Foreign objects introduced to transparent starfish
larvae become surrounded by motile cells
Immunity to disease was based on action of scavenger cells
Theory of Humoral Immunity
Noncellular elements in the blood were responsible for
protection from microorganisms
Almoth Wright
Linked 2 theories by showing that immune response
involved both cellular & humoral elements
o
Opsonins
Circulating factors
Coat bacteria so that they become more
susceptible to phagocytosis
o
Antibodies
Serum factors
Specific proteins
o
Acute phase reactants
Nonspecific factors
Increase nonspecifically in any infection
Natural or Innate Immunity
Ability of individual to resist infection by means of normally
present body function
Non-adaptive/ nonspecific
SAME for all pathogens
NO PRIOR EXPOSURE REQUIRED
Factors that influence Mechanism of Natural Immunity
1. Fatigue
2. Age
3. Nutrition
4. Genetic Determinants
5. Stress

Acquired Immunity
Specific for individual pathogen
REMEMBER PRIOR EXPOSURE
response upon repeated exposure

**Both systems (Natural and Acquired Immunity) are essential to

maintain good health and are dependent on one another for maximal
effectiveness

Two (2) parts of Natural Defense System

1. Internal
a. Cellular Mechanisms
b. Humoral Factors
2. External

External Defense System

Keep microorganisms from entering the body
Internal Defense System
Promote phagocytosis which results in foreign cell
destruction
o
Inflammation
Brings cells and humoral factors to are in need of
healing

External Defense System

External Defense System

Composed of structural barriers that prevent most infections
from entering the body
a. Unbroken skin
b. Mucosal Membrane surfaces

Skin
Major structural barrier
Secretions
Discourages the growth of microorganisms
o
Lactic acid
Sweat
Skin (pH 5.6) and Vagina (pH 5)
o
Fatty acid
Sebaceous glands
Maintain pH 5.6
o
Mucous secretions + cilia
Nasopharynx
Clears 90% of deposited materials
o
Urine
Flushing action
Slight acidity
Genitourinary tract
o
Hydrochloric acid
Stomach
pH 1, halts microbial growth
o
Tears and Saliva
Contains lysozyme that attacks cell wall of gram +
bacteria
o
Normal flora

Competitive exclusion
Keeps
pathogens
from
establishing
themselves

Internal Defense System

Internal Defense System

Second part of natural immunity
Cells and soluble factors plays essential parts
Recognize molecules that are unique to infectious organisms
e.g. recognizing mannose which is not evident in human
cells
Phagocytosis
Engulfment of cells or particulate matter

Chapter 1: Introduction and Natural Immunity

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Immunology and Serology

Most important function of the internal defense system

Enhanced by soluble factors/ Acute phase reactants

a.
b.
c.

Acute-Phase Reactants

Acute-Phase Reactants
Normal serum constituents
Increases rapidly by at least 25% due to:
a. Infection
b. Injury
c. Trauma
Produce primarily by HEPATOCYTES within 12-24 hours
Cytokines
Intercellular signaling polypeptides
Cell messengers
a. IL-1
b. IL-6
c. TNF-
Mainly produced by MONOCYTES and MACROPHAGES at
the site of inflammation
C-Reactive Protein (CRP)
Trace constituent of serum
Increases rapidly within 2-6 hours following infection
Increase 100x-1000x
Peak Value: 48 hours
Member of Pentraxins
o
Protein with 5 subunits
Main substrate is phosphocholine
Capable of:
a. Opsonization
b. Agglutination
c. Precipitation
d. Complement activation
Binding is calcium-dependent and nonspecific
Able to act as defense until specific antibodies can be
produced (Acts before antibodies are produced)
Most widely used indicator of inflammation
noninvasive means of following the course of malignancy
and organ transplantation
Normal levels:
a. Men 1.5 mg/L
b. Women 2.5 mg/L
CRP Levels
a. Malignancy
b. Organ rejection
c. Bacterial and viral infection
d. Tuberculosis
e. Myocardial infarction
f.
Ischemic stroke

Mannose-Binding Protein
Aka Mannose-Binding Lectin
A trimer that acts as a opsonin
Calcium-dependent
Widely distributed on mucosal suface
Similar to C1q
Binding activates complement cascade
Normal concentrations: 10 g/ mL
MBP recurrent yeast infection

Alpha1-Antitrypsin
Major component of - band when serum is electrophoresed
General plasma inhibitor of Elastase (Protease)
o
Elastase
Endogenous enzyme that can degrade elastin and
collagen
Damages lung tissue in chronic pulmonary
inflammation
Mop up, counteracts the effects of neutrophil invasion
Regulates expression of proinflammatory cytokines
AAT
a. Premature emphysema
b. Idiopathic pulmonary fibrosis
Homozygous inheritance leads to:
a. Cirrhosis
b. Hepatitis
c. Hepatoma
Can also react with any serine protease

Haptoglobin
2- globulin
bind irreversibly to free hemoglobin released by intravascular
hemolysis
Haptoglobin + Free hemoglobin cleared by Kupffer cells
and parenchymal cells
plasma haptoglobin due to de novo synthesis in the liver
Increases 2x-10x following:
a. Inflammation
b. Stress
c. Tissue necrosis
Normal plasma concentration: 40-290 mg/dL
Function
a. Protects from kidney damage
b. Prevent loss of iron
c. Protection against oxidative damage by free
hemoglobin
o
Free hemoglobin
Powerful oxidizing agent
Generate peroxides and hydroxyl radicals

Fibrinogen
Most abundant coagulation factors
Forms the fibrin clot
Dimer
Normal levels: 100-400 mg/dL
Cleaved by thrombin to form fibrils that make up the fibrin
clot
Clot formation:
a. Increase the strength of the wound
b. Stimulates endothelial cell adhesion and
proliferation
c. Creates a barrier that helps prevent the spread of
microorganisms further into the body
Promote aggregation of RBC
Fibrinogen Levels
o
risk for coronary artery disease in women

Ceruloplasmin

** CRP Levels is a risk factor in Myocardial infarction and Ischemic

stroke

Serum Amyloid A
Increase 1000x
Apolipoprotein synthesized in the liver
Normal levels: 30 g/L
Associated with HDL; cholesterol metabolism
Contributes to site if tissue injury clean up
Recycles cholesterol and phospholipids for reuse un building
new membranes in acute inflammation
Bacterial Infection (SAA Levels) > Viral Infection (SAA
Levels)

Complement
Series of serum proteins
Mediates inflammation
o
Classical Cascade
Nine (9) proteins activated by bound antibodies in
a sequence
Major functions:

Opsonization
Chemotaxis
Lysis of cells

Chapter 1: Introduction and Natural Immunity

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Immunology and Serology

Principal copper-transporting protein

Acts as ferroxidase
o
Feroxidase
Oxidizes iron from Fe2+ to Fe3+
Means of releasing iron from ferritin for binding to
transferrin
o

Wilsons disease
Autosomal recessive genetic disorder
Depletion of ceruloplasmin
Massive increase of copper in tissues
Copper accumulates in the liver and brain, cornea,
kidneys, and bones

2.
3.
4.
5.

Eosinophils
12-15 m in diameter
1-3% of circulating WBC
in parasitic infections, allergic reactions
Less efficient than neutrophils in phagocytosis because of
the lack of digestive enzymes
Main function:
o
Neutralize basophil and mast cell products
o
Kill parasites
Nucleus: Bilobed, ellipsoidal, eccentric
Cytoplasm: Filled with large orange to red-orange granules
a. Primary Granules
Contains:
Acid phosphatase
Arylsulfatase
b. Eosinophil-Specific Granules
Contains:
Major basic protein
Eosinophil cationic protein
Eosinophil peroxidase
Eosinophil-derived neurotoxin

Basophils
Less than 1% of circulating WBC
Smallest granulocyte (10-15 m)
IgE binds to Basophil cell membranes and granules release
constituents when in contact with antigen
Lacks hydrolytic enzymes but contains peroxidase
Contains coarse, densely staining deep-bluish-purple
granules which obscure the nucleus for hypersensitivity
reactions
a. Histamine
Vasoactive amine that contracts smooth muscle
b. Heparin
anticoagulant
c. Eosinophil-chemotactic factor

Mast Cells
Resemble basophils but larger
CT cells of mesenchymal origin
Small round nucleus and more granules
Life span: 9-18 months
For hypersensitivity reactions
Granules contain:
o
Acid phosphatase
o
Alkaline phosphatase
o
Protease

Monocytes
Mononuclear cells
Largest cells in peripheral blood
12-20 m diameter: average diameter 18 m
Irregularly folded or horseshoe-shaped nucleus that
occupies one half of the cell
Cytoplasm stains dull grayish blue and has a ground glass
appearance containing digestive vacuoles
4-10% of total circulating WBC
Stay in peripheral blood for up to 70 hours
Becomes macrophages (macrophages precursors)
Granules:
a. 1st type
Similar to lysosomes of neutrophils
Contains:

Cellular Defense Mechanisms

Five (5) Principal Types of WBC (Leukocytes)

1. Neutrophil
2. Eosinophil
3. Basophil
4. Monocyte
5. Lymphocyte

** Neutrophil, eosinophil, and basophil are granulocytes

Myeloid line
WBC that participate in phagocytosis
Arise from common precursor in the marrow

Neutrophil
Aka Polymorphonuclear neutrophilic leukocyte (PMN)
50-70% of total peripheral WBC
10-15 m in diameter
Nucleus: 2 & 5 lobes
Life span: 5 days
immediately in acute infection
Large number of neutral staining granules
a. Primary/ Azurophilic Granules
Contains:
Myeloperoxidase
Elastase
Proteinase 3
Lysozyme
Cathepsin G
defensins
b. Secondary Granules
Contains:
Collagenase
Lactoferrin
Lysozyme
Reduced NADPH oxidase
c. Tertiary granules
Newly discovered
Contains:
Gelatinase
Plasminogen activator
Lysosomes
Separate compartments that contain acid hydrolase
Marginating
Allow neutrophils to move from circulating blood to the
tissue by diapedesis
Diapedesis
Movement through the blood vessel walls
Selectins
Receptors that make neutrophils sticky and enhance
adherence to endothelial cells
Chemotaxins
Chemical messengers that cause cells to migrate in a
particular direction

Factors that are Chemotactic to Neutrophils

1. Complement

Proteins from coagulation cascade

Products from bacteria and virus
Platelet activating factor
Secretion from mast cells, lymphocyte, macrophages and
other neutrophils

Chapter 1: Introduction and Natural Immunity

b.

Peroxidase
Acid phosphatase
Arylsulfatase
2nd type
Contains:
- glucuronidase
Lysozyme
Lipase
No alkaline phosphatase

Tissue Macrophages
Arise from monocytes
Monocyte to macrophage
Enlarges between 25-80 m
Contains no peroxidase
Motility is slow; not as efficient as neutrophil
Life span: months
Macrophage + cytokines/ microorganism = macrophage
becomes activated

Cytokines
Chemical messengers released by T lymphocytes
Monocyte-Macrophage system
Initiate and regulate the immune respons

Immunology and Serology

Specific names of Macrophage according to location

1. Alveolar macrophage lungs
2. Kupffer cells liver
3. Microglial cells brain
4. Histiocytes connective tissue

Function of Macrophage
1. Microbial killing
2. Tumoricidal activity
3. Intracellular parasite eradication
4. Phagocytosis
5. Secretion of cell mediators
6. Antigen presentation

Dendritic cells
Covered with long membranous extensions
Main function:
o
Phagocytose antigen and present it to helper T
lymphocyte
Descendent of myeloid lines
Most potent phagocytic cell

1.
2.
3.
4.

Physical contact between WBC and foreign particle

Formation of phagosome
Fusion with cytoplasmic granules to form phagolysosome
Digestion and release of debris to the outside

Opsonins
To
prepare
for
eating
Serum proteins that attach to a foreign substance and help
prepare it for phagocytosis
Neutralizes surface charge on foreign particle
o
CRP
o
Complement components
o
Antibodies

Respiratory or Oxidative Burst

Occurs within the cell as the pseudopodia enclose the
particle within a vacuole

Inflammation

Inflammation
Overall reaction of the body to injury or invasion by infectious
agent

Classification based on location

1. Langerhans cells - skin
2. Interstital dendritic cells heart, lungs, liver, kidney, GIT
3. Interdigitating dendritic cells T lymphocyte areas of
secondary lymphoid tissue and thymus

4 Cardinal Signs or Clinical Symptoms

1. Redness
2. Swelling
3. Heat
4. Pain

Toll-like Receptors
Very similar molecules with toll found on human leukocytes
and some nonleukocyte cell types
Highest concentration of these receptors occurs on
monocytes, macrophages, and neutrophils
Enhances natural immunity
There are 11 slightly 11 different TLRs in humans
a. TLR2
Recognizes teichoic acid and peptidoglycan (gram
positive bacteria)
b. TLR4
Recognizes LPS (gram negative bacteria)
c. TLR1
Recognizes Mycobacteria

Major Events Associated with Inflammation

1. Inc. blood supply to infected areas
2. Inc. permeability caused by retraction of endothelial cells
3. Migration of WBC (Neutrophils) to surrounding tissue
4. Migration of macrophages to injured area

Histamine
Chemical mediator
Release from injured mast cell
Cause dilation of blood vessels and adds blood flow to
affected area

Acute-Phase Reactants
Soluble mediators

Amplification
Occurs through formation of clots by the coagulation system
and triggering of fibrinolytic system

Phagocytosis

4 Main Steps in Phagocytosis

Chapter 1: Introduction and Natural Immunity

Neutrophils
Mobilized within 30-60 minutes
Major cell type in acute inflammation
Emigration: 24-48 hours
Proportional to level of chemotactic factors
Macrophages

Immunology and Serology

Peaks at 16-48 hours

Clear areas by phagocytosis

Chronic Inflammation
Prolonged inflammation