Ag processing/presentation
Terms
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- What does self-MHC restriction refer to, why is it significant?
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Refers to the fact that T cells are only activated by antigens bound to self-MHC.
This contrasts B cells, which can bind any antigen floating around. - What is the first step in activating T cells?
- PROCESSING antigen and presenting on self-mhc.
- 2 Principles of Antigen processing/presentation:
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1. the Ag must be degraded into little pieces to fit the MHC cleft.
2. The Ag must meet the MHC molecule in order to be presented. - Before they present, MHC molecules are found where in the cell?
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-Rough endoplasmic reticulum and Golgi complex.
Because both are proteins made like any other protein in a cell. -
What is processed by the endogenous pathway?
What Class of MHC are these restricted to? -
Proteins generated from inside the cell.
-Viruses
-Self proteins
-Tumor proteins
Restricted to MHC1 - What molecules are involved in the cytosolic (endogenous) pathway?
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-Ubiquitin
-ATP
-Proteosome - What is Ubiquitin for?
- A signal; it binds antigens and signals the proteosome to degrade it.
- What happens to degraded proteins in the cytosol?
- -transport to RER - that's where MHC proteins are.
- What transports antigenic fragments to the RER after degradation by proteosomes?
- TAP
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What is the structure of TAP;
What does it prefer to bind? -
a heterodimer -> TAP 1 and 2.
antigens of 8 to 13 amino acids, with hydrophobic ends. - Without ____ and _____ MHC class 1 will not reach the membrane.
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Peptides 8-13 aa.
beta-microglobulin - Which class of MHC is the exogenous pathway restricted to?
- MHC2
- What antigens are presented by Class 2 MHC, and which pathway are they presented via?
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Exogenous pathway --> antigens not produced from within the cell.
-Proteins that were ingested - phagocytosed or by receptor-mediated endocytosis (bcells_ - to be presented by APCs to Thelper cells - steps in the endocytic, exogenous pathway:
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1. Eat antigen (with receptor or phagocyt)
2. Endosome fuses with lysosome.
3. Enzymes in lysosome hydrolyze enzyme. -
Mechanisms to inhibit pathways
-Endogenous
-Exogenous -
Endogenous: inhibit protein synthesis, inhibit production of b-microglobulin
Exogenous: give drugs to increase pH of lysosomes - won't degrade antigen. - What special molecule transports MHC2 out of golgi to meet antigen fragments?
- Invariant chain.
- What does invariant chain bind?
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-antigen binding cleft of MHC
-most is degraded after MHC gets out of golgi body, but a CLIP is left. -
What must happen before Ag can bind MHC2?
What HELPS this process? -
-MHC must be taken out of golgi by invariant chain.
-CLIP must be taken out of Ag-binding cleft
Nonclassical class 2 MHC - What two nonclassical MHCs are involved in CLIP removal?
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HLA-DM and HLA-DO.
HLA-DO --> DO remove clip
HLA-DM --> prevent removal -
What are lipid Ags presented by?
By what process? -
CD1: a nonclassical class 1 MHC
Via the exogenous pathway. -
What does MHC present to?
MHC1:
MHC2: -
MHC1 presents Antigen to Tc cells.
MHC2 presents Antigen to Th cells - What is the major Ag between histoincompatible individuals of same species? Why? When does it react?
- MHC; because it's polymorphic. In an allograft.
- Structure of MHC1: what two proteins, how are they arranged?
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a chain (a1, a2, a3 domains)
b-microbulin -- necessary for expression on cell surface!! - What is the role of B-microglobulin?
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Supporter of the alpha protein.
Not involved in anything really, just there. - What is the structure of MHC2, how is it arranged?
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alpha chain (a1, a2) Beta chain (B1/B2).
a1/b1 are the cleft
a2/b2 are Ig domains - Class 1 and 2 MHC have similar binding clefts; 3 ways they are different?
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1. Cleft
2. Ag they bind
3. What they recognize - Difference in class 1/2 MHC clefts:
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1 - closed end
2 - open end -
What do the clefts bind?
-MHC1
-MHC2 -
MHC1 binds Ag with 8-10 aa.
MHC2 binds Ag wtih 13-18 aa. -
chemically, what kinds of Ag's bind
-Class 1 MHC cleft
-Class 2 MHC cleft -
1: conserved en dresidues deep in the cleft.
2. Motifs at a constant elevation. - 2 Genetic characteristics that make MHC able to bind many different Ag's;
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1. Polygenic - each person has Multiple genes encoding MHC molecules.
They DON'T REARRANGE.
2. Polymorphic - within ONE species, alleles for MHC vary btwn individuals. - Where is the most polymorphic variation of MHC seen?
- At the binding clefts
- What is MHC's role in susceptibility to disease?
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Your amount of less-effective MHC compared to that in the population makes a difference.
If you have MORE ineffective MHC than others, you're at a higher risk of contracting the disease of the Ag that would bind that MHC. - What are good and bad relative risk values?
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1 implies no higher risk
Anything greater than one implies increased risk to develop the disease.