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?
- Direct mechanisms
- 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
- Indirect mechanisms
- 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 A2 - 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(H2O), 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?
- C3 Convertases
- 1. Lectin/Classical - C4b2a
- 2. Alternative C3 - C3bBb
- C5 Convertases
- 1. Lectin/Classical - C4b2a3b
- 2. Alternative - C4b2a3b and C3b2Bb
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