January 31 notes

Immunology, January 31, 2008

I. Host-pathogen co-evolution
a. Ewald’s hypothesis: over time pathogens and hosts co-evolve towards a mutualism, in most cases, because:
1. Very virulent pathogens will kill off hosts (if you kill everyone who will be left)
2. Gene frequencies in the population of host shifts so that host population innate immunity to pathogen is increased.
i. Killer Australian bunnies!: 99% died, but 1% just happened to have innate immunity to fight the virus off; bunny population returned several years later
Jackolopes-American rabbits that have a papillomavirus (cool fact)
b. Innate immunity is very conserved
i. Innate immune molecules of vertebrates & invertebrates are very similar
ii. Innate immunity prolly came on scene just after evolution of multicellular animals
c. Acquired immune system dependent on innate immunity
i. Dendrtic APCs needed for T- & B-cell to function
ii. Inflammation is caused by innate immune cells secretions to site of infection
II. Molecules recognized by innate immunity
a. Unique to particular classes of microbes
Including: gram (+), gram (-), viruses, fungi
b. Conserved within large classes of microbes
*Microbes have short generation times, so have huge evolutionary advantage over multicellular animals
*innate immune system relatively unchanges among animals
*explained by the fact that microbial structures that the innate immune system recognize are NECESSARY for microbes to survive
c. Examples
i. Bacterial cell envelope components
-LPS: necessary for gram (-) outer membrane structure
-LTA: necessary for cell wall integrity of bacteria
-peptidoglycan: necessary to keep osmotic pressure in equilibrium for gram (+) & (-)
ii. Microbe-specific nucleic acid motifs
*dsRNA
-only RNA viruses will be associated with dsRNA
-dsRNA necessary for RNA virus replication
*unmethylated CpG-containing DNA
-animals have CpG sequences, too, but sequences are methylated
-bacteria, fungi have CpG sequences that aren't methylated, which are recognized by innate immunity

III. Innate immune system mechanisms
a. Epithelia
*barriers are best defense!
-most epithelia on topological outside have LOTS of microbes
*some epithelia (guts, alveoli) have to be fairly microbe free for efficient nutrient/gas exchange
*So, in gut/alveoli, secrete chemicals that limit microbial growth:
1)mucous
2)bile-dissolves many gram (+) and (-) bacteria
3)fatty acids-dissolves some bacteria
4)antimicrobial peptides
b. Antimicrobial peptides- short peptides with cationic and amphipathic properties that allow them to create pores in the membranes of bacteria.
**Stored in granulocytes (eosinophils, neutrophils, basophils) and epithelia
-Some AMP's are effective against particular pathogens: eosinophils- eukaryotic parasites, neutrophils- bacterial
**Specific epithelial cells store AMP's- alveoli and Paneth cells (specialized cells in crypts of small intestine)
**AMP's can harm our cells too, just not at low conc.
** Bacteria defenses against AMP's: minimizing - charge of membrane, cover themselves in biofilm (complex matrix of lipids, carbohydrates secreted by some bacteria
i. Defensins
ii. Cathelicidins
c. Opsonins: "handle" that a phagocyte attaches to that allows the phagocyte to engulf microbe
i. Collectins: soluble protein in blood and at mucosal surfaces
*attach to carbohydrates on microbes via carbohydrate recognition domain (CRD)
*form polymers to bind microbial surfaces
1. Surfactant proteins A and D (SP-A and SP-D): found in respiratory tract
*SP-A: attach to polysaccharide capsule
*SP-D: attach to polysaccharide in LPS
ii. Ficolins
1. L-ficolin and H-ficolin
*bind to n-acetyl glucosamine (NAG), a component of peptidoglycan
2. Mannose-binding lectin (MBL)
*mannose is present in microbial cell surfaces, not ours
*can activate complement cascade by binding microbial surface and is bound by MASP (Mannose-binding lectin Associated Serine Protease)
iii. C3b (complement component)-also an opsonin
d. Complement: discovered after acquired immunity, works with acquired immune system
*>30 proteins, part of innate immune system
*amplifies inflammatory responses
*allows opsonization of microbes
*formation of Membrane Attack Complex (MAC)
i. Complement components (complement Cascade)
*complement proteins always around, but inactive
*activated by being cleaved into fragments
-b fragment catalyzes next step in pathway
-a fragment induces inflammatory response
1. C1, C2, C4
2. C3
a. C3 convertase
b. C3b
3. C5
4. C6, C7, C8, C9 = Membrane attack complex (MAC)
ii. Classical pathway
1. Antibody or pentraxin binds to microbial surface
2.C1 binds to Ab's constant region
3.Conformational change in C1 subunits so that can now cleave C2 into C2a and C2b
-C2b is attached to microbe via C1
4.C2b or C1 cleaves C4 into C4a and C4b
-C4b is attached to microbe via C2b
-forms C4bC2b=C3 convertase
5.C3 convertase cleaves C3 into C3a and C3b
-C3b is opsonin itself
*leads to MAC formation
*amplifies complement production
-C3a: inflammatory activator
*recruits neutrophils
*triggers additional complement activation
6. C3b interacts with C3 convertase to make C3 convertase into C5 convertase
7.C5 convertase cleaves C5 into C5a and C5b
-C5a is inflammatory activator
-C5b allows for construction of Membrane Attack Complex by recruiting C6, C7, C8, which all together recruit lots of C9 (forms hole)
iii. Alternative pathway
iv. Lectin pathway

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