Chapter 1: Introduction and Natural Immunity  Acquired Immunity

- A type of resistance that is characterized by:

 1960 1. specificity for each individual pathogen or microbial
- Cells responsible for immune response were identified and agent
characterized 2. ability to remember a prior exposure, which results
in an increased response upon repeated exposure.
Immunity and Immunization
**Both systems (Natural and Acquired Immunity) are essential to
 Immunology maintain good health and are dependent on one another for maximal
- The study of host’s reactions when foreign substances are effectiveness
introduced into the body
 Antigen  Two (2) parts of Natural Defense System
- Foreign substances that induces immune response 1. Internal
 Immunity 2.
- The condition of being resistant to infection.
 Variolation (1500)  External Defense System
- Developed by Chinese  Keep microorganisms from entering the body
- Exposing individuals to material from smallpox lesions  Internal Defense System
- Theory: If a healthy individual was exposed as a child or  Promote phagocytosis which results in foreign cell and
young adult, effects of the disease are minimized organisms destruction
 Edward Jenner (1700)  Catgories:
- Relationship between exposure to cowpox and immunity to a. Cellular Mechanisms
smallpox b. Humoral Factors
 Vaccination  Inflammation
- From the Latin word “vacca” meaning cow - Brings cells and humoral factors to are in need of healing
- Injecting cellular material that provide protection
 Cross-immunity External Defense System
- Phenomenon in which, exposure to one agent produces
protection against other agent  External Defense System
 Louis Pasteur - Composed of structural barriers that prevent most infections
- First attenuated vaccine from entering the body
 Attenuation or change a. Unbroken skin
- remains as basis for immunizations b. Mucosal Membrane surfaces
- May occur through:
o Chemical  Skin
o Heat - Major structural barrier
o Aging  Secretions
- Discourages the growth of microorganisms
Cellular versus Humoral Immunity o Lactic acid
- Sweat
 Ellie Metchnikoff - Maintain the Skin (pH 5.6) and Vagina (pH 5)
- Phagocytosis (cells eat cells) o Fatty acid
o Foreign objects introduced to transparent starfish - Sebaceous glands
larvae become surrounded by motile cells - Maintain the skin pH 5.6
- Immunity to disease was based on action of scavenger cells o Mucous secretions + cilia
 Theory of Humoral Immunity - Nasopharyngeal passages;
- Noncellular elements in the blood were responsible for Clears 90% of deposited materials
protection from microorganisms o Urine
 Almoth Wright (1903) - Flushing action + Slight acidity;
- Linked 2 theories by showing that immune response Remove many potential pathogens
involved both cellular & humoral elements from the genitourinary tract
o Opsonins o Hydrochloric acid
- Circulating factors - Causes acidity of the stomach
- Coat bacteria so that they become more - keeps the pH as low as 1
susceptible to phagocytosis - serves to halt microbial growth
o Antibodies o Lysozyme
- Specific proteins included in Serum factor - an enzyme found in many secretions such as
o Acute phase reactants tears and saliva, attacks cell wall of gram +
- Nonspecific factors bacteria
- Increase nonspecifically in any infection o Normal flora
 Natural or Innate Immunity  Competitive exclusion
- Ability of individual to resist infection by means of normally o Keeps pathogens from establishing
present body function themselves
- Non-adaptive/ nonspecific  Yeast infections
- SAME for all pathogens o due to Candida albicans
- NO PRIOR EXPOSURE REQUIRED o result of wiping out normal flora that
would ordinarily compete with
 Factors that influence Mechanism of Natural Immunity opportunists
1. Fatigue
2. Age
3. Nutrition
4. Genetic Determinants
5. Stress
Internal Defense System  Serum Amyloid A
- Apolipoprotein synthesized in the liver
 Internal Defense System - Molecular weight of 11,685 daltons
- Second part of natural immunity - Normal levels: 30 µg/L
- Cells and soluble factors plays essential parts - In Plasma, associated with HDL; cholesterol metabolism
- Designed to recognize molecules that are unique to - Contributes to site if tissue injury clean up
infectious organisms - Recycles cholesterol and phospholipids for reuse un building
- e.g. recognizing mannose in microorganism which is not new membranes in acute inflammation
evident in human cells - Increase significantly more in bacterial infections than in viral
 White blood cells infections.
- seek out and destroy foreign cells by participating in  Complement
phagocytosis - Series of serum proteins that are normally present
 Phagocytosis - Function: Mediates inflammation
- Engulfment of cells or particulate matter by leukocytes, o Classical Cascade
macrophages, and other cells. - Nine (9) proteins activated by bound antibodies in
- process destroys most of the foreign invaders that enter the a sequence
body - Major functions:
- Most important function of the internal defense system a. Opsonization
- Enhanced by soluble factors called Acute phase reactants b. Chemotaxis
c. Lysis of cells
Acute-Phase Reactants
 Mannose-Binding Protein
- Aka Mannose-Binding Lectin
 Acute-Phase Reactants
- A trimer that acts as a opsonin
- Normal serum constituents
- Calcium-dependent
- Increases rapidly by at least 25% due to:
- Able to recognize foreign carbohydrates
a. Infection
- Widely distributed on mucosal suface
b. Injury
- Similar to C1q
c. Trauma
- Binding activates complement cascade
- Produce primarily by HEPATOCYTES (liver parenchymal
- Normal concentrations: 10 µg/ mL
cells) within 12-24 hours in response to increase cytokines
- ↓ MBP – recurrent yeast infection
 Cytokines
- Intercellular signaling polypeptides
 Alpha1-Antitrypsin
- Cell messengers: interleukin-1β (IL-1β), interleukin-6 (IL-6),
- Major component of α- band when serum is electrophoresed
and tumor necrosis factor-alpha (TNF-α) are mainly
- General plasma inhibitor of proteases released from
produced by MONOCYTES and MACROPHAGES at the site
leukocytes
of inflammation
o Elastase
-
- Endogenous enzyme that can degrade elastin and
 C-Reactive Protein (CRP)
collagen
- Trace constituent of serum (originally an antibody to the c-
- Damages lung tissue in chronic pulmonary
polysaccharide of pneumococci)
inflammation
- Increases rapidly within 4-6 hours following infection
- Mop up, counteracts the effects of neutrophil invasion
- Peak Value: 48 hours
- Regulates expression of proinflammatory cytokines
- Plasma half-life: 19 hours
- ↓ AAT
- Elevated levels: bacterial infections, rheumatic fever, viral
a. Premature emphysema
infections, malignant diseases, tuberculosis, and after a
b. Idiopathic pulmonary fibrosis
heart attack.
- Homozygous inheritance leads to:
- Median CRP value for an individual increases with age.
a. Cirrhosis
- Molecular weight of 118,000 daltons
b. Hepatitis
- Member of Pentraxins
c. Hepatoma
o Protein with 5 subunits held by noncovalent bonds
- Can also react with any serine protease
- Main substrate is phosphocholine
- Capable of:
 Haptoglobin
a. Opsonization; coating of foreign particles
- α2- globulin
b. Agglutination
- molecular weight of 100,000 daltons
c. Precipitation
- Function: bind irreversibly to free hemoglobin released by
d. Complement activation
intravascular hemolysis
- Binding is calcium-dependent and nonspecific
- Haptoglobin + Free hemoglobin  cleared by Kupffer cells
- Able to act as defense until specific antibodies can be
and parenchymal cells in the liver
produced (Acts before antibodies are produced)
- ↑ plasma haptoglobin – due to de novo synthesis in the liver
- Most widely used indicator of inflammation
- Increases 2x-10x following:
- noninvasive means of following the course of malignancy
a. Inflammation
and organ transplantation
b. Stress
- Threshold for high cardiovascular risk:
c. Tissue necrosis
Concentration of > 2 mg/L
- Normal plasma concentration: 40-290 mg/dL
- Normal levels:
- Function
a. Men – 1.5 mg/L
a. Protects from kidney damage
b. Women – 2.5 mg/L
b. Prevent loss of iron
- ↑ CRP Levels
c. Protection against oxidative damage by free
a. Malignancy
hemoglobin
b. Organ rejection
o Free hemoglobin
c. Bacterial and viral infection
- Powerful oxidizing agent
d. Tuberculosis
- Generate peroxides and hydroxyl radicals
e. Myocardial infarction
f. Ischemic stroke

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

stroke
 Fibrinogen c. Tertiary granules
- Most abundant coagulation factors - Newly discovered
- Forms the fibrin clot - Contains:
- molecule is adimer with a molecular weight of 340,000  Gelatinase
daltons  Plasminogen activator
- Normal levels: 100-400 mg/dL
- Cleaved by thrombin to form fibrils that make up the fibrin  Lysosomes
clot - Separate compartments that contain acid hydrolase
- Clot formation:  Marginating pool on blood vessel walls
a. Increase the strength of the wound - contain half of the total neutrophil population, while the
b. Stimulates endothelial cell adhesion and rest circulate freely for approximately 6 to 10 hours.
proliferation  Marginating
c. Creates a barrier that helps prevent the spread of - Allow neutrophils to move from circulating blood to the
microorganisms further into the body tissue by diapedesis
- Promote aggregation of RBC  Diapedesis
- ↑ Fibrinogen Levels = ↑ risk for coronary artery disease in - Movement through the blood vessel walls
women  Selectins
- Receptors that make neutrophils sticky and enhance
 Ceruloplasmin adherence to endothelial cells
- A single polypeptide chain with a molecular weight of  Chemotaxins
132,000 daltons - Chemical messengers that cause cells to migrate in a
- Principal copper-transporting protein; particular direction
Binding 90 to 95% of the copper found in plasma by
attaching six cupric ions per molecule  Factors that are Chemotactic to Neutrophils
- Acts as ferroxidase 1. Complement
o Feroxidase 2. Proteins from coagulation cascade
- Oxidizes iron from Fe2+ to Fe3+ 3. Products from bacteria and virus
- Means of releasing iron from ferritin for binding to 4. Platelet activating factor
transferrin 5. Secretion from mast cells, lymphocyte, macrophages and
o Wilson’s disease other neutrophils
- Autosomal recessive genetic disorder
- Depletion of ceruloplasmin  Eosinophils
- Massive increase of copper in tissues - 12-15 µm in diameter
- Copper accumulates in the liver and brain, cornea, - 1-3% of circulating WBC
kidneys, and bones - ↑ in parasitic infections, allergic reactions
- Less efficient than neutrophils in phagocytosis because of
Cellular Defense Mechanisms the lack of digestive enzymes
- Main function: Neutralize basophil and mast cell products
 Five (5) Principal Types of WBC (Leukocytes) and Kill parasites
1. Neutrophil - Nucleus: Bilobed, ellipsoidal, eccentric
2. Eosinophil - Cytoplasm: Filled with large orange to red-orange granules
3. Basophil - take up the acid eosin dye
4. Monocyte a. Primary Granules
5. Lymphocyte - Contains:
 Acid phosphatase
** Neutrophil, eosinophil, and basophil are granulocytes  Arylsulfatase
b. Eosinophil-Specific Granules
 Myeloid line - Contains:
- WBC that participate in phagocytosis  Major basic protein
- Arise from common precursor in the marrow  Eosinophil cationic protein
 Eosinophil peroxidase
Granulocytes: Neutrophils, Eosinophils, and Basophils  Eosinophil-derived neurotoxin

 Neutrophil  Basophils
- Aka Polymorphonuclear neutrophilic leukocyte (PMN) - Less than 1% of circulating WBC
- 50-70% of total peripheral WBC - Smallest granulocyte (10-15 µm)
- 10-15 µm in diameter - IgE binds to Basophil cell membranes and granules release
- Nucleus: 2 & 5 lobes constituents when in contact with antigen
- Life span: 5 days - Lacks hydrolytic enzymes but contains peroxidase
- ↑ immediately in acute infection - Contains coarse, densely staining deep-bluish-purple
- Large number of neutral staining granules granules which obscure the nucleus
a. Primary/ Azurophilic Granules a. Histamine
- Contains: - Vasoactive amine that contracts smooth muscle
 Myeloperoxidase b. Heparin
 Elastase - anticoagulant
 Proteinase 3 c. Eosinophil-chemotactic factor-A
 Lysozyme
 Cathepsin G  Mast Cells
 defensins - Resemble basophils but are connective
b. Secondary Granules tissue cells of mesenchymal origin and larger.
- Contains: - Small round nucleus and more granules
 Collagenase - Life span: 9-18 months
 Lactoferrin - For hypersensitivity reactions by binding IgE
 Lysozyme - Granules contain:
 Reduced NADPH oxidase o Acid phosphatase
o Alkaline phosphatase
o Protease
 Monocytes  Toll-like Receptors
- AKA Mononuclear cells - Very similar molecules with toll found on human leukocytes
- Largest cells in peripheral blood and some nonleukocyte cell types
- 12-22 µm diameter: average diameter 18 µm - Highest concentration of these receptors occurs on
- Irregularly folded or horseshoe-shaped nucleus that monocytes, macrophages, and neutrophils
occupies 1/2 of the cell - Enhances natural immunity
- Cytoplasm stains dull grayish blue and has a ground glass - There are 11 slightly different TLRs in humans
appearance due to fine dust like granules; contains digestive a. TLR2
vacuoles - Recognizes teichoic acid and peptidoglycan (gram
- 4-10% of total circulating WBC positive bacteria)
- Stay in peripheral blood for up to 70 hours b. TLR4
- Becomes macrophages (macrophages precursors) - Recognizes LPS (gram negative bacteria)
- Granules: c. TLR1
a. 1st type - Recognizes Mycobacteria
- Similar to lysosomes of neutrophils
- Contains: Phagocytosis
 Peroxidase
 Acid phosphatase  4 Main Steps in Phagocytosis
 Arylsulfatase 1. Physical contact between WBC and foreign particle
b. 2nd type 2. Formation of phagosome
- Contains: 3. Fusion with cytoplasmic granules to form phagolysosome
 Β- glucuronidase 4. Digestion and release of debris to the outside
 Lysozyme
 Lipase
 No alkaline phosphatase

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

 Cytokines  Explanation:
- Chemical messengers released by T lymphocytes 1. Physical contact occurs as neutrophils roll along until they
 Monocyte-Macrophage system encounter the site of injury or infection.
- Initiate and regulate the immune respons o Diapedesis: a mean of penetration to the tissues
o Chemotaxis: aids Diapedesis, whereby cells are
 Specific names of Macrophage according to location attracted to the site of inflammation by chemical
1. Alveolar macrophage – lungs substances such as soluble bacterial factors,
2. Kupffer cells – liver complement components, or C-reactive protein.
3. Microglial cells – brain 2. Receptors on neutrophils or monocytes come into contact
4. Histiocytes – connective tissue with the foreign particle surface, enhanced by opsonins.
o Opsonins:
 Function of Macrophage  derived from the Greek word meaning “to
1. Microbial killing prepare for eating.”
2. Tumoricidal activity  are serum proteins that attach to a foreign
3. Intracellular parasite eradication substance and help prepare it for
4. Phagocytosis phagocytosis.
5. Secretion of cell mediators  Includes C-reactive protein, complement
6. Antigen presentation components, and antibodies
 may act by neutralizing the surface charge on
 Dendritic cells the foreign particle, making it easier for the
- Covered with long membranous extensions cells to approach one another
3. Once attachment has occurred, the cellular cytoplasm flows
- Main function:
around the particle and eventually fuses with it.
o Phagocytose antigen and present it to helper T
o Respiratory or oxidative burst: an increase in oxygen
lymphocyte
consumption that occurs within the cell as the
- Descendent of myeloid lines
pseudopodia enclose the particle within a vacuole.
- Most potent phagocytic cell
o Forms: Phagosome.
4. The phagosome is gradually moved toward the center of the
 Classification based on location
cell.
1. Langerhan’s cells - skin
5. Contact with cytoplasmic granules takes place, and fusion
2. Interstital dendritic cells – heart, lungs, liver, kidney, GIT
between granules and the phagosome occurs.
3. Interdigitating dendritic cells – T lymphocyte areas of
o Phagolysosome: the fused elements
secondary lymphoid tissue and thymus
6. The granules then release their contents, and digestion
occurs.
 Toll
7. Any undigested material is excreted from the cells by
 a protein originally discovered in the fruit fly Drosophila,
exocytosis.
where it plays an important role in antifungal immunity in the
o Killing:
adult fly.
 oxygen-dependent
 results from the generation of bactericidal
metabolites
 Heavily opsonized particles takes 20 seconds
to kill
Resting cells  Histamine
 derive their energy from anaerobic glycolysis - Chemical mediator
 When phagocytosis is triggered = respiratory burst produces - Release from injured mast cell
greater energy via oxidative metabolism - Cause dilation of blood vessels and adds blood flow to
affected area: Results: redness and heat
Hexose monophosphate shunt - Increased permeability of vessels allows fluids in the plasma
 used to change nicotinamide adenine dinucleotide to leak to the tissues: Results: swelling and pain associated
phosphate (NADP) to its reduced form by adding a with inflammation
hydrogen. = NADPH
 Soluble mediators
NADPH - Includes Acute-Phase Reactants
 donates an electron to oxygen in the presence of NADPH - Initiate and control the response
oxidase.
 Amplification
NADPH oxidase - Occurs through formation of clots by the coagulation system
 a membrane-bound enzyme and triggering of fibrinolytic system
 only activated through conformational change triggered by
microbes themselves.  Neutrophils
 may depolarize the membrane, allowing hydrogen and - attracted to the site of injury or infection by the chemotaxins
potassium ions to enter the vacuole - Mobilized within 30-60 minutes after the injury
 central to the killing of microbes; because its dysfunction - Major cell type in acute inflammation
causes chronic granulomatous disease. - Emigration: 24-48 hours
 Forms O2 – (superoxide) - Proportional to level of chemotactic factors

Superoxide  Macrophages
 highly toxic - Migration peaks at 16-48 hours
- Clear areas by phagocytosis
 can be rapidly converted to more lethal products
 superoxide dismutase (SOD) converts superoxide to
 Chronic Inflammation
hydrogen peroxide by adding hydrogen ions
- Prolonged inflammation
 when hydrogen combines with the superoxides, the pH - Result: tissue damage and loss of function
increases and activates proteases that contribute to
microbial killing.

Hydrogen peroxide (hydroxyl radical OH)

 an important bactericidal agent
 is more stable than any of the free radicals
 effect is potentiated by the formation of hypochlorite ions;
through the action of the enzyme myeloperoxidase

Hypochlorite ions
 are powerful oxidizing agents.

Inflammation

 Inflammation
- Overall reaction of the body to injury or invasion by infectious
agent (Cellular and humoral mechanisms are involved)

 4 Cardinal Signs or Clinical Symptoms

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

 Major Events Associated with Inflammation

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