7. MHC and Spec Recog

Question 1

what is the MHC called in humans?

Answer 1

HLA (human leukocyte antigen)

Question 2

the T cell can only elicit a response when the TCR recognizes what?

Answer 2

appropriate peptide that has been processed and presented on a self MHC molecule

Question 3

where are MHC Class I molecs expressed?

Answer 3

surface of almost all cells of the body (with only marginal expression on RBCs and sperm)

Question 4

class I molecules are composed of what peptide(s)?

Answer 4

alpha chain (polypeptide) coded for inthe MHC locus (contains 3 domains, the first two of which are variable in sequence and make the groove for peptide binding, and the 3rd interacts with Beta-2 and is much less variable) and Beta-2 microglobulin (polypeptide) that is not found in the MHC locus

Question 5

how long must a peptide be to fit in the alpha1/alpha2 cleft of MHC class I?

Answer 5

8-10 aa’s

Question 6

the binding of the peptide into the class I protein is what type of interaction?

Answer 6

non-covalent, mediated by residues on the peptide and the aa’s in the class I cleft of alpha1/alpha2

Question 7

when two different class I proteins are compared, the polymorphisms (differences) are greatest where?

Answer 7

in the groove of the alpha1/alpha2 domains (esp for those residues that are pointing into the groove because they interact with different peptides)

Question 8

what are the loci that code for the class I polypeptides (Class I MHC) in humans?

Answer 8

HLA-A, HLA-B, HLA-C (proteins coded for in these loci all associate with Beta-2 microglobulin)

Question 9

_____ of MHC Class I associates with CD8 on cytotoxic T cells (another way to stabilize the complex)

Answer 9

alpha 3

Question 10

different MHC alleles bind different peptides, which often share what?

Answer 10

conserved features

Question 11

what happens to proteins in processing?

Answer 11

unfolded and pass through proteosome to become short peptides

Question 12

how are short peptides from the proteosome transported into the ER?

Answer 12

TAP (transporter associated with antigen processing)

Question 13

what is tapasin?

Answer 13

an ER membrane associated protein, is a chaperone that associates TAP with empty MHC Class I proteins in the ER

Question 14

Cytotoxic T cells are important in the elimination of ____ infected cells

Answer 14

virally (the virus may reproduce in a host cell but cannot be affected by antibody…while it grows in the host cell, some of the the viral protein will be associated with MHC Class I molecule….this complex can then be brought to the cell surface and then recognized as “different” fromothers and targeted for removal by cytotoxic T cells)

Question 15

three is co-expression of MHC Class I proteins from both chromosomes for which loci?

Answer 15

all three (A, B, and C) - therefore an indiv heterozygous at all three loci could have six different specificities all expressed on each cell with a Beta-2 microglobin molecule

Question 16

MHC Class II proteins are expressed on which cells?

Answer 16

antigen presenting cells (macrophages, monocytes, and B cells)

Question 17

the MHC Class II molecule is composed of what?

Answer 17

two polypeptide chains, an alpha chain and a Beta chain which associate but are NOT covalently attached

Question 18

the variable regions that interact with different peptides are which parts of the MHC Class II molecules?

Answer 18

alpha1 and beta1 domains of the two chains

Question 19

the complete class II molecule is made up of two chains that are coded for where?

Answer 19

both within the MHC

Question 20

what are the three well characterized MHC Class II genes?

Answer 20

DR, DP, and DQ…so each locus will comtain an alpha and beta chain for each of the genes (DRalpha and DRbeta, DPalpha and DPbeta, DQalpha and DQbeta)

Question 21

both chromosomes (maternal and paternal) will express their class II produces on APCs. This means what in a heterozygous individual?

Answer 21

that two different DRalpha and DRbeta gene products will be made. These 2 DRalpha and 2DRbeta can associate in any of four combinations with the only requirement being that a DRalpha needs to associate with a DRbeta (the same occurs at DP and DQ genes)

Question 22

CD4 binds to whta part of MHC Class II?

Answer 22

Beta2 domain

Question 23

where is most of the variability in MHC Class II?

Answer 23

Beta 1 part of the beta chain

Question 24

how long are peptides presented by class II MHC?

Answer 24

10-30 aa’s (usu about 13)

Question 25

when do APCs synthesize class II MHC proteins in the ER?

Answer 25

continually

Question 26

within the ER, each Class II MHC protein associates with what other protein?

Answer 26

the invariant chain that contains a peptide called class II invariant chain peptide (CLIP) which has high affinity for class II proteins and they thus associate (so the MHC Class II molec has the CLIP peptide present in the groove making it not accessible to other peptides)

Question 27

the class II protein containing vesicle fuses with endocytic vesicles that contain processed peptides….what facilitates the removal of the class II associated CLIP peptide and binding of other peptides to the MHC Class II?

Answer 27

DM (a chaperone)

Question 28

the MHC Class II molecs bind to the processed peptide as do class I molecs, but what makes them different?

Answer 28

class II bound peptides are obtained from extracellular microbes that are phagocytosed or pinocytosed

Question 29

what do helper T cells do when they bind a MHC Class II and foreign peptide?

Answer 29

produce cytokines (Th1 produce IFN-gamma which causes activation of APCs to facilitate phagocytosis, Th2 produce IL-4 and IL-5 which facilitate the production of antibody from B cells)

Question 30

the locus containing the MHC genes also contains other genes that have a connection to the immune system - egs?

Answer 30

TAP genes are part of the proteosome system which degrades proteins into peptide maps within the class II genes; complement genes (C4B, C4a, and C2) and cytokine genes (TNF and lymphotoxin) are mapped to the MHC complex

Question 31

the diversity of MHC molecules is in what?

Answer 31

the multiple genes and many alleles segregating in the population (permites uniqueness for the immune system b/w indivs)

Question 32

Among genetic loci that could contribute to autoimmunity, susceptibility to autoimmune disease has so far been most consistently associated with MHC genotype….explain for ankylosing spondylitis?

Answer 32

individuals who are HLA-B27 positive have 90-100 fold greater chance for development than do individuals lacking B27 (only 5-8 % of people with B27 have the disease but 95% of those with ankylosing spondylitis have B27)…perhaps initiated due to arthritogenic peptides, molecular mimicry, misfolding, or NK cells?