MHC

Question 1

how does MHC regulate T cells and NK cells?

Answer 1

stimulates T and inhibits NK

Question 2

MHC r/t transplant graph rejection

Answer 2

must must must be identical in the MHC/HLA or else you will reject. even if you only differ there and are exactly the same in the genome (entirely.)
the MHC is CRITICAL. (10-14 days.)

Question 3

HLA

Answer 3

the human MHC - human leukocyte antigen

Question 4

genes encoded in the HLA complex are…

Answer 4

on the inside OR outside (MHC 1 and 2)

NOTE THAT :

TAP1 TAP2 LMP2 LMP7 DOA DMA DMBare all encoded by MHC 2 BUT they are not expressed on the membrane but they are vital to development and processing.

Question 5

MHC class 1 isotopes

Answer 5

HLA A, B, C - highly polymorphic. 3 subunts plus one B2 micro globulin. the micro glob is monomorphic. (also only 1 chain/protein helps to bind)

also have EFG which are less polymorphic - they regulate NK cells and are thought to maintain the embryo/fetus

Question 6

MHC class 2 isotopes

Answer 6

HLA DP DR DQ - alpha and beta - a1 a2 b1 b2

have two chains - a little less polymorphic but fairly high - both chains contribute to binding

Question 7

chromosome 6 organization and characteristics

Answer 7

Region class 2 –> 3 —> 1

class 2/region 2:
DP IIIIII
DQ IIIIII
DR IIIIIIII (longer because two betas and one alpha)

class 1 region 1:

B II
C II
A II

DR HAS MAJOR VARIABILITY

note - B2 micro glob is coded on a different chrome so not linked

Question 8

what is the importance of MHC 1 and 2 distribution?

Answer 8

it is how we make an immune response

Question 9

what has ZERO MHC 1 or 2?

Answer 9

RBC’s

Question 10

Where are there many MHC 1? and fewer?

Answer 10

many - T, B, Macro, Dend, Neutro

less- thymus, liver, kidney, brain

Question 11

Where are there many MHC 2? and fewer?

Answer 11

many- B, macro, dendritic and thymus
SO IN APC’s and thymus

and a very small amt in T cells but we don’t really know why. only activated T cells.

Question 12

what has both MHC 1 and 2?

Answer 12

APC’s and thymus

Question 13

MHC genes are expressed…

Answer 13

codominantly.

Question 14

trans-complement

Answer 14

in DR - so MORE DR molecules

Question 15

variability in MHC 1

Answer 15

super variable only in the spot where antigen binds. the other three a1 a2 a3 and b2microglob are slightly variable…

Question 16

variability in MHC 2

Answer 16

very variable on the binding spot of beta chain side (so half of the “U”) and in-between the bottom beta 2 and alpha 2.

slightly variable in b1 and b2 - and not at all variable in a1 or a2

Question 17

variablity MHC 1 v MHC 2

Answer 17

MHC 2 > MHC 1

really depends on shape of the groove too.

Question 18

MHC can bind ______ (#) peptides?

Answer 18

MANY!

Question 19

MHC restriction

Answer 19

T cells care about the plane of the membrane - so the antigen must fit in the TCR but ALSO the TCR and end of MHC bilaterally must fit end to end perfectly.

B cells don’t care about the plan of the membrane though.

when the antigen fits but the T cell and mHC don’t fit end to end that is MHC restriction!

Question 20

______ cells have MHC 1….?

Answer 20

ALL CELLS HAVE MHC1!

Question 21

MHC class 1 binds to?

Answer 21

CD8 - Alpha 3

Question 22

MHC class 2 binds to?

Answer 22

CD4 - Beta 2

Question 23

2 capabilities of APC’s

Answer 23

1. put peptides in class 1 and 2

2. activate naive T cells

Question 24

MHC 1 (CD8) CYTOSOLIC PATHWAY

Answer 24

1. antigens inside the cytosol are degraded by the proteosome (ubiquitin targeted pathway)
2. TAP molecules let it into the ER
3. inside ER peptides are bound to MHC 1 and they go to cell surface to show CD8 T cells

bc it happens in the cell this is usually a viral stuff

Question 25

what is a constitutive proteosome?

Answer 25

the kind that degrades

Question 26

what is an immunoproteosome?

Answer 26

IFN stimulated. it involves an immune response IFN induces changes in the specificity of the proteosome so that it can bettehr bind to MHC 1 IFN gamma induces PA28 (proteosome activator) which opens up one end of the p-some and this helps it not over degrade the peptide - and gets the protein inside the ER These also up regulate LMP 2 and 7

Question 27

How do you actually load peptides into the MHC 1 groove?

Answer 27

1. calnexin (chaperone) stabilizes the complex until beta 2 micro globulin binds 2. now that the entire thing is together - if forms a complete complex with 2 chaperones (calretiulcin and tapsin) and bonds with TAP, ERP57 and PDI. 3. the complex is totally complete with TAP delivers a peptide and it binds with the entire thing. 4. MHC class 1 then dissociates from the complex and is exported to the ER

Question 28

what happens to an unloaded MHC?

Answer 28

it is unstable and doesn't make it out to the membrane surface

Question 29

best peptide motif? how can this be remediated?

Answer 29

nonomer. or between 8-10 if a peptide fragment is longer than 10 peptides ERAP can come in and remove aa at the N terminal before it is exported from the ER (before the MHC is exported)

Question 30

ERAP

Answer 30

clips peptide motif to ideal 8-10

Question 31

MHC 2 - CD4 - VESICULAR PATHWAY

Answer 31

often bacterium because it infects a macrophage 1. exogenous antigens are taken up by a macrophage via vesicle. vesicular enzymes in the endosome are pretty basic. 2. as endosome ages the ph drops and it breaks down the protein. 3. this vesicle with peptide antigen fuses with a vesicle with MHC2 inside. 4. loading 5. MHC 2 then exposed to cell surface and exposed to CD 4 t cells

Question 32

How do we keep MHC 2 from binding in the ER before it gets out (it is MADE int he ER along with MHC1) ?

Answer 32

a chastity belt AKA "invariant chain" 1. vesicle carrying MHC2 and invariant chain leave the ER 2. as vesicle progresses the PH drops and eventually the invariant chain is degraded. however, the part in the groove (THE CLIP) stays attached. 3. the vesicle with MHC2 and CLIP can fuse with a vacuole with peptide antigens. 4 if an immune response ensues DM (HLA-DM) is unregulated and it facilitates the release of the CLIP and MHC 2 is now free to bind an antigen. *** if an immune response does not ensue HLA DO js up regulated and it keeps DM from allowing the clip to be released. keeps MHC 2 from binding anything….

Question 33

cross presentation

Answer 33

a good thing. when an MHC 1 is allowed to take up something that an MHC 2 would normally take up because it gets into the cytosoll. thus, MHC 1 can take it directly to CD8 cytotoxic killer t cells and avoid the latter soliloquy. this is good because things that tumors and viruses that get in intracellularly sometimes have a problem binding to APCs but also often get inside an APC and cause a lot of damage because they are like pirates. thus - this can be circumvented. also it limits immune response to self. regulatory.

Question 34

what do CD8 cells do next? CD4?

Answer 34

CD8 binds to viral infected cell and kills it CD4 either 1. binds to macrophage and activates it so cytokines are released 2. binds to a b cell which activates it and it becomes a plasma cell and released antibodies.