Chapter 8- MHC’s & Antigen Presentation
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Transcript of Chapter 8- MHC’s & Antigen Presentation
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Chapter 8- MHC’s & Antigen Presentation
• Where we’re going in this– MHC I and II functions review– Genes for these proteins– Structure in detail, and how that relates to Ag
presentation– MHC’s and disease– Antigen presentation- some details, plus
learning about processing in the Golgi
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We need to be able to present lots of different peptides. For this we need a somewhat generic binding, and much diversity.
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More details in to come!
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More details in to come!
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“the nomenclature is somewhat confusing” HA!! MASSIVE UNDERSTATEMENT!!
Classical MHC’s- there are others as well
2 MB!
4 MB!
2 copies of each!
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A digression into mouse genetics
• The MHC genes typically are a package deal- Haplotypes
• We have inbred strains of mice- these are homozygous at the MHC’s, and have sets of MHC’s.
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Mouse MHC terms
• Syngeneic- identical- a mouse strain• Congenic- the same except at one
location- for our purposes, the same MHC haplotype- E.g., B10.A: a B10 mouse with a type A
haplotype
These terms will come into play later!
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Strains are produce by breeding; useful in determining the effects of MHC’s on immune response
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OK- back to MHCs- structure of MHC I
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MHC I structure
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Ends are closed; holds peptide of 8-10 AA’s
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MHCII- not only a dimer, but a dimer of dimers
Open cleft- hold 13-18 AA peptides
http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=7120
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Different MHCI’s
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With MHC I, the peptide can bulge; not so with MHCII
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Diversity! Multiple genes, now MANY alleles!
• MHC genes are polymorphic:• Human MHC I- HLA A: 370• HLA B: 660• HLA C: 190• Lots of diversity in MHC II as well- DP, DQ,
DR genes, and among the alpha and beta subunits.
• Total theoretical diversity of 4 X 1019 !
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Linkage disequilibrium
• The diversity isn’t as great as theoretically expected
• Some alleles are found together more than you would expect:
• HLA-A1- 0.16; HLA B8- 0.09;• Expecte 0.16X 0.09= 0.014; actual is
0.088- they are found together >6X as often as expected.
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Diversity- so what?
• Differences in immune responsiveness• Some MHC’s linked to disease
susceptibility
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Many are autoimmune
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So a completely heterozygous mouse would have 8 different MHC II molecules and six different MHC I molecules on its cell surfaces.
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What to know• I won’t test on this, but it’ll be helpful to know
– - H2 D,L,&K are MHC I’s in mice– HLA A,B,C are MHC I’s in people– Three MCH I genes in mice and people– Three MCH II genes in people, 2 in mice.
• They are polygenic and polymorphic• Structure of I and II’s- effect on size and types of
peptides bound.• Effects on immune response and disease
susceptibility, and why that might be.
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MHC Restriction
• Tough concept• Fundamentally, T cells only recognize Ag
presented by the MHC’s that they were trained to recognize in the thymus.
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These do exogenous Ag presentation
Uptake of 3[H]thymidine
Th cells
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These are seen as self
For this experiment, the Ag that’s presented is not seen- wrong MHC!
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Antigen Processing and
Presentation
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• Processing: Breaking up the antigen into pieces that fit into the MHC I or II groove.
• Presentation: putting the peptides on the groove.
• Again, endogenous and exogenous antigens
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These are MHC II APC’s Non-pro’s get activated by inflammation!
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“The TUNNEL OF DEATH!”
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LMP’s- induced by infection, make production of MHC I peptides more likely
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These are Chaperone proteins
ERp57- ER protease, mw 57K- exoprotease, trims down to ~8 AA’s!
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Now- onto exogenous- receptor- mediated endocytosis, OR phagocytosis
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HLA-DM- non-classical MHC- catalyst for exchange of CLIP for peptide
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What to know• Definitions- processing, presentation, MHC
restriction- evidence for the latter.• Tell the story of antigen presentation, beginning
with the antigen until it’s on the surface of the cell-
• MHCI- roles of ubiquitin, LMP’s, proteasome, TAP, tapasin, calreticulin, calnexin (chaperones)
• MHC II- roles of invariant chain, CLIP, MHC DM, endocytic processing.