Immunology Chapter 2
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Immunology Chapter 2
What is the difference between immune responses for combating extracellular vs. intracellular pathogens?
1. Extracellular - vulnerable to innate macrophages and adaptive Abs which promote uptake and destruction by phagocytosis
2. Intracellular - Attacked by innate NK cells or adaptive cytotoxic T cells; macrophages activated by helper T cells kill pathogens hiding inside macrophages
What are the various ways pathogens damage host tissue?
1. Exotoxins - secrete extracellular toxins that damage tissue
2. Endotoxins - secrete intracellular toxins that triger phagocytes to release cytokines causing disease
3. Cytopathic - direct damage to infected cell
1. Ag:Ab complexes - activate neutrophils and Mfs
2. T cells - kill infected cells
3. Abs - can cross react w/host tissue
What are the natural barriers to infection provided by epithelia?
1. Mechanical - tight junctions, mucus movement, tears
2. Chemical - Fatty acids, low pH, lysozyme in tears/saliva
3. Microbiological - normal flora competition for nutrients
What are the major categories of antibacterial peptides and enzymes?
1. Lysozyme - eat through the peptidoglycan layer of bacterial cell walls causing them to lyse
2. secretory phospholipase A
- hydrolyzes phospholipids in the cell membrane, killing the cell
1. Defensins - amphipathic peptide, that bores holes in the membrane of bacteria, fungi, and viruses
2. Cathelicidins - disrupt bacterial membranes
3. Histatins - Made in the mouth that act against pathogenic fungi
What are the 3 complement pathways and how are they activated?
Complement is a system of pattern recognition receptors and effector molecules that detect and destroy microorganisms
1. Lectin - ficolins and mannose binding lectin bind to carbs on the pathogen surface
2. Classical Pathway - C1q binds to pathogen or with Abs bound to pathogen surface
3. Alternative - C3 hydrolyzes to initiate eventual deposition of C3 convertase on microbial surface
How is the lectin pathway activated?
1. Ficolins have a trimeric cluster of carbohydrate binding domains that bind oligosaccharides containing acetlyated sugars
2. Mannose-binding lectins have a trimeric cluster of carbohydrate binding domains that bind mannose and fructose
What are the proteins of the classical pathway
1. C1q - Binds directly to pathogen or indirectly to Ab bound to pathogen, thus activating C1r
2. C1r - Cleaves C1s activating it
3. C1s - Cleaves C4 and C2
1. C4b - binds pathogen and opsonizes it; binds C2 for cleavage by C1
2. C4a - mediates inflammation
1. C2a - Cleaves C3 and C5
2 C2b - Precursor to vasoactive C2 kinin
1. C3b - Opsonizes pathogen; binds C5 for cleavage by C2a
2. C3a - mediates inflammation
Describe how the alternative complement pathway can be activated by spontaneous activation of C3.
1. C3 undergoes spontaneous hydrolysis to C3(H
O), which binds to factor B allowing it to be cleaved by factor D into Ba and Bb
2. The C3(H2O) complex is a C3 convertase, cleaving more C3 into C3a and C3b
3. Factor B binds C3b on the cell surfact and is cleaved to Bb by factor D
What are the proteins of the alternative pathway?
1. C3b - binds pathogen; binds B for cleavage by D
2. Bb - active enzyme of C3 and C5 convertase
3. D - cleaves B to Ba and Bb when it is bound to C3b
4. Properdin - binds bacterial surfaces and stabilizes C3bBb convertase
What comprises the C3 and C5 convertases for each pathway?
1. Lectin/Classical - C4b2a
2. Alternative C3 - C3bBb
1. Lectin/Classical - C4b2a3b
2. Alternative - C4b2a3b and C3b
What is the general work of complement regulatory proteins?
They interact with C3b and eith prevent the convertase from forming or promote its rapid dissociation.
1. CR1, H, MCP and DAF bind to C3b on host cells
2. C3b bound to H, CR1, and MCP is cleaved by factor I to yeild inactive C3b (iC3b).
3. C1IHN dissociates C1r and C1s from the active C1 complex
4. CD59 prevents final assembly of the membrane-attack complex at the C8 to C9 stage
5. Factor I - cleaves C3b and C4b
What are the major complement receptors and their functions?
1. CR1 - Promotes C3b and C4b decay; stimulates phagocytosis; erythrocyte transport of immune complexes
2. CR2 - Part of B cell co-receptor; Epstein-Barr virus receptor
3. CR3 - Stimulates phagocytosis
4. CR4 - Stimulates phagocytosis
5. CRIg - Phagocytosis of circulating pathogens
6. C5a receptor - Binding of C5a activates G protein
7. C3a receptor - Binding of C3a activates protein
What is the most important action of C
To facilitate phagocytosis of pathogens
How do C5a, C3a, and C4a cause local inflammatory responses
1. They cause smooth muscle contraction and increased vascular permeability and blood flow
2. Induce synthesis of adhesion molecules which increases binding of phagocytes to endothelial cells
3. Activate mast cells to release histamines
4. The increased vessel diameter and permeability leads to fluid and protein accumulation
5. Fluid accumulation increases lymphatic drainage, bringing pathogens to lymph nodes where they are cleared
What is MAC
Membrane attack complex - a complex that forms pores in pathogen membranes causing them to lyse
What are the rxns leading to the formation of the MAC
1. C5b binds C6 and C7
2. C5bC6C7 complexes bind to membranne via C7
3. C8 binds to the complex and inserts into the cell membrane
4. C9 binds to the complex and polymerizes and forms a pore in the membrane
What are the regulatory rxns of the C cascade
1. C1q binding to Ag:Ab complexes activated C1r and C1s--->C1 inhibitor (C1INH) dissociates C1r and C1s from the active C1 complex
2. C4b2a is the active C3 convertase, cleaving C3 to C3a and C3b--->CAF, C4BP and CR1 displace C2a from the C4b2a complex. C4b bound by C4BP, MCP, or CR1 is cleaved to inactive forms C4d and C4c
3. The C5 convertase cleave C5 to C5a dn aC5b--->CR1 and H displace C3b and act as cofactors in the cleavage of C3b by Factor I
4. The terminal components of complement form a membrane pore (MAC)--->CD59 prevents final assembly of the MAC at the C8 to C9 stage