Chapter 1 - The Defense of the Body
Inoculation : vaccination
Variolation : method of vaccination first applied to immunize against variola (smallpox).
An avirulent strain can provoke an immune response, without causing the disease.
Commensals are organisms that do not normally cause disease, but live in symbiosis with
their hosts.
Pathogens are organisms that can cause disease if they are able to pass through the
defensive mechanisms of an individual. Primary pathogens cause diseases even in low
numbers (have high virulence). Opportunistic pathogens: low virulence can only cause
disease if administered in very high doses or if immune defenses are impaired.
The entry of a pathogen or vaccine into the animal body can alter the expression of a very
large number of molecules, which are all extensively interlinked.
1. Physical barriers
a. skin, mucus, urine, bacteria (commensal), enzymes etc.
2. Innate immunity
a. cells, chemicals ; defensins, lysosomes
b. Activated immediately as a pathogen penetrates the epithelial barriers. The
pathogens are detected due to their chemical and structural difference.
c. Sentinel cells recruit leukocytes that can destroy most invading organisms.
The complement system is a set of complex enzyme pathways that are lethal
to invaders.
d. macrophages, dendritic cells, neutrophils, natural killer cells
3. Adaptive immunity (acquired)
a. Recognizes and destroys invaders, subsequently learning from it, building a
memory.
b. Uses cell surface receptors to recognize foreign invaders.
c. T and B lymphocytes
d. Two branches: extracellular (exogenous) invaders → humoral immune
response (antibodies found in fluids) vs. the intracellular
(endogenous) invaders → cell-
mediated immune response
(specialized cells destroy infected or
abnormal cells).
Antibodies are the protective molecules found in
serum, protecting against antigens. Antibodies are
highly specific and can only bind to (and neutralize)
the antigen that stimulates their production.
Antibodies produced after repeated injections are
better able to bind and neutralize the toxin that those
produced early in the immune response.
The level of antibodies in serum is regulated and eventually stops rising after multiple doses
of antigen or exposure.
,The immune system identifies and destroys abnormal or foreign cells (graft rejection). This
immune response is not transferable from one individual to another. The response is
performed by lymphocytes from the spleen, lymph nodes or blood.
Promotion immune responses: helper T cells. Inhibition: regulatory T cells.
Chapter 2 - Innate Immunity: The Recognition of Invaders
Inflammation concentrates defensive cells (leukocytes) and antimicrobial molecules at the
sites of microbial invasion and tissue damage. Many protective proteins (antibodies and
complement components) are normally only found in blood and can only enter tissues during
inflammation.
Either exogenous (PAMPs) or endogenous signals (DAMPs) can activate the innate
immune system. They are recognized by pattern recognition receptors (PRRs) on sentinel
cells.
● Pathogen-associated molecular patterns (PAMPs)
○ receptors of microbes that are essential for microbial survival, and are
commonly shared by entire classes of pathogens.
○ Most cell-associated receptors are found on cell membranes, within the
cytosol, and within cytoplasmic vesicles.
Types of PRRs:
- Toll-like receptors (TLRs); located on cell surfaces or within the cells, subsequently
extracellular or intracellular invaders. They are expressed on sentinel cells located on
or near the surface of the body. Sentinel cells include macrophages, mast cells,
dendritic cells and epithelial cells of the respiratory and GI tract.
- TLR11 is only found on dendritic cells, macrophages and epithelial cells in the
mouse urinary tract.
PAMP binds to its corresponding TLR, passing signals to the cell →
multiprotein signaling complexes, signal transduction cascade initiation,
and pro-inflammatory molecule production by the cell.
Caspases are proteolytic enzymes that play key roles in the initiation of inflammation.
Different TLRs trigger the production of different cytokine mixtures, and different PAMPs
trigger distinctly different responses.
- RIG-1-like Receptors (RLRs); expressed within the cytosol. Recognize viral dsRNA,
which differs structurally from mammalian RNA. Once activated, the RLRs activate
caspases and trigger signaling pathways, leading to the production of type I IFNs
(antiviral cytokines).
- NOD-like Receptors (NLRs); detect pathogens within the cytosol. NOD1 recognizes
bacterial peptidoglycans, NOD2 recognizes muramyl dipeptide for intracellular
bacteria. Binding activates the NF-kB pathway, triggering the production of
proinflammatory cytokines, and defensins.
- C-type Lectin Receptors (CLRs); C lectins bind carbohydrates, requiring Ca2+.
Major pathogen recognition by dectins.
Types of PAMPs:
- Bacterial Lipopolysaccharides: found in the cell walls of many bacteria
- Bacterial Peptidoglycans: major constitution of cell walls, alternating polymers of N-
acetyl glucosamine and N-acetylmuramic acid.
1
, - Bacterial DNA: bacterial DNA contains unmethylated cytosine guanosine, and
deoxyguanosine nucleotides.
- Viral Nucleic Acids: viruses consist of a nucleic acid core surrounded by a layer of
proteins, and possibly a lipid envelope. Their nucleic acids differ structurally from
animal nucleic acids, recognizable for PRRs.
● Damage-associated molecular patterns (DAMPs)
○ alarmins can be released when cells die or are generated when connective
tissue is damaged, or by stimulated sentinel cells. They can have potent anti-
microbial properties or can recruit and activate cells of the innate immune
system and promote adaptive immune responses.
○ Mitochondria resemble bacteria, thus damaged cells might induce an immune
response.
○ High mobility group box protein-1 (HMGB1): binds DNA molecules and
ensures that they are folded correctly & triggers inflammation. Binds to TLR2
and 4, ensuring prolonged inflammation.
○ Heparan sulfate found in cell membranes and extracellular matrix is shed into
tissue fluids following injury. Heparan sulfate binds and triggers TLR4.
P-type lectins (pentraxins): CRP and SAP; acute-phase proteins, which increase greatly in
number during infection or after trauma. They activate complement and stimulate leukocytes.
C-type lectins (collectins): require calcium to bind carbohydrates, the C-terminal domain
binds to carbohydrates, the N-terminal domain interacts with cells or complement
components. MBL is found in high levels in serum, and can bind oligosaccharides, and
activates the complement system.
Sentinel cells: contain diverse PRPs that can recognize and respond to both DAMPs and
PAMPs induced by invading microbes,
● Macrophages, capture, kill and destroy microbial invaders.
● Dendritic cells,
● Mast cells, major role in allergic reactions
Chapter 3 - Innate Immunity: Proinflammatory and Antimicrobial
Mediators
Macrophages, dendritic cells and mast cells are activated when PAMPs or DAMPs bind to
their PPRs. As a result, they synthesize and secrete a mixture of molecules that trigger
inflammation, inhibit microbial growth and initiate the first steps in adaptive immunity.
Mediator cells are released by the signaling cells and diffuse to nearby receiving cells, where
they bind to receptors and trigger responses. Cytokines can affect many different cell types,
and cells rarely secrete a single cytokine at a time.
Tumor necrosis factor-a, interleukin-1 and IL-6 are the major three cytokines.
Activated cells also secrete chemokines, which attract defensive cells to sites of microbial
invasion.
- Tumor Necrosis factor-a : produced by macrophages, monocytes, T cells and mast
cells. Promotes inflammation, cell enhancement, cell activation and toxicity.
- Interleukin-1: promotes inflammation, affects metabolism and blood flow, cell growth,
and enhances Th2 cytokine production.
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, - Interleukin-6: produced by macrophages, T cells and mast cells. Its production is
triggered by bacterial endotoxins, and it affects both inflammation and adaptive
immunity.
(for more details see figures)
Chemokines: coordinate the migration of cells and hence dictate the course of many
inflammatory and immune responses, produced by sentinel cells. Most chemokines are
produced by sentinel cells in infected or damaged tissues and attract other cells to this site.
Five major symptoms of inflammation: heat, redness, swelling, pain and loss of function.
Immediately after injury, the blood flow in the small capillaries decreases, providing the
leukocytes with an opportunity to attach to blood vessel walls, after which capillaries dilate.
The dilated blood vessels also leak, so that fluid moves from the blood into the tissues,
causing edema and swelling. Changes in the endothelial cells lining the blood vessels permit
neutrophils and monocytes to adhere, and if necessary blood platelets bind to injured sites,
inducing a clotting reaction. The primary leakage is caused by blood leaking from capillaries,
secondary leakage is caused by leukocyte migration and increased vascular permeability.
Vasoactive cells may be derived from inactive precursors in plasma, or from macrophages
and mast cells, neutrophils, basophils and platelets, or from damaged tissue cells.
Vasoactive amines:
● Histamine is a vasoactive amine, stimulating endothelial cells to produce nitric oxide
which is a vasodilator, while at the same time promoting blood vessel leakage.
● Serotonin is a vasoactive amine which promotes vasoconstriction, subsequently
increasing blood pressure.
Vasoactive peptides
● Anaphylatoxins promote histamine release from mast cells.
● kallikreins act on kininogens to generate small vasoactive peptides called kinins.
They increase vascular permeability, stimulate neutrophils and trigger pain receptors.
Vasoactive lipids
● prostaglandins
● PAF → aggregates platelets, enhances neutrophil adhesion and emigration
Thrombin is the main clotting enzyme, which acts on fibrinogen in tissue fluid and
plasma to produce insoluble fibrin. Activation of the coagulation cascade initiates
fibrinolytic system, leading to the activation of plasminogen activator → plasmin
(fibrinolytic enzyme). In destroying fibrin, plasmin releases peptide fragments
that attract neutrophils.
Products of sentinel cells do two things: increase vascular permeability and attract white
blood cells.
Antibacterial peptides: defensins and cathelicidins. They can interact with the
phospholipids in cell membranes.
Lysozymes cleave the bond between N-acetyl; muraminic acid and N-acetyl glucosamine
and destroys cell wall peptidoglycans in Gram-positive bacteria. Found in all body fluids
except CSF and urine.
The complement system is an innate defense subsystem that consists of a complex
mixture of enzymes, regulatory proteins, and receptors. It can be activated by exposing a
microbial cell wall to serum proteins, or when antibodies bind to the cell wall. Complement
components bind irreversibly to bacteria and initiate phagocytosis.
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