INTRA Proteasome TAP MHC I Golgi Calnexin Calreticulin Tapasin CD8 T C EXTRA Li MHC II Golgi Vesicle CLIP HLA-DM CD4 T H Summary.

INTRA

Proteasome

TAP

MHC I

Golgi

Calnexin

Calreticulin

Tapasin

CD8 TC

EXTRA

Li

MHC II

Golgi

Vesicle

CLIP

HLA-DM

CD4 TH

Summary

Exam EE129 Thursday 7:00pm

Help session: Tomorrow 6-8pm CIVL 3153

Alleles: different forms of one geneAllotypes: different forms of one protein (isoforms)

Polymorphic: alternative forms of one gene = Many allelesOligomorphic: a few forms of one gene = Few allelesMonomorphic: no polymorphism

Homozygous: same allele on both inherited chromosomesHeterozygous: different allele on both inherited chromosomes

MHC in humans is called HLA (human leukocyte antigen complex)

Figure 3-13 part 1 of 2

Variable

Invariant

No rearrangements or somatic changesDiversity is derived from 1) Gene families

2) Genetic polymorphism

HLA-A,B,C-present peptide antigens to CD8Tcells and interactwith NK-cells

HLA-E,G-interactwith NK-cells

HLA-F-?

HLA-DP,DQ,DR- present peptide antigens to CD4Tcells

HLA-DM,DO-regulate peptide loading of DP,DQ,DR

Human leukocyte antigen complexAbs used to ID MHC molecules react with leukocytes not RBCs

Figure 3-24 part 1 of 2

Heavy Chain

Heavy Chains

2-microglobulin on chr15• and chain = GeneA and GeneB• Complicated nomenclature you don’t need to know• Haplotype - combination of alleles inherited from Chr6• 2% meiotic recombination rate generates population diversity

Chr6

Chromosome Organization of HLA complex

• Cytokines coordinately regulate the group of genes - class I heavy chain and other associated genes

• TAP transporter, Tapasin, Proteasome subunits - LMP2 and LMP7

Interferon , , and ----> Class I , 2M, TAP, LMP2, LMP7

Interferon ----> CIITA ---> HLA II genes, li chain

MHC class II transactivator (CIITA) - deficiency leads to bare lymphcyte syndrome

MHC I (single peptide binding chain ): 3 genes present antigen

HLA-A, HLA-B, HLA-C

MHC II (two chains, and ): 3 genes present antigen

HLA-DQ, HLA-DP, HLA-DR

Each MHC II locus encodes a gene for the chain and a gene for the chain:

e.g. HLA-DQA, HLA-DQB => MHC II isoformsHLA-DPA, HLA-DPB => MHC II isoformsHLA-DRA, HLA-DRB => MHC II isoforms

Maternal: 3 MHC I genes HLA-AM, HLA-BM, HLA-CM

Paternal: 3 MHC I genes HLA-AP, HLA-BP, HLA-CP

Maternal: 3 MHC II genes HLA-DPAM, HLA-DPBM

HLA-DQAM, HLA-DQBM

HLA-DRAM, HLA-DRBM

Paternal: 3 MHC II genes HLA-DPAP, HLA-DPBP

HLA-DQAP, HLA-DQBP

HLA-DRAP, HLA-DRBP

6 different MHC I proteins on all cells

6 different MHC II proteins on all cells(some individuals have 8 due to two HLA-DRB genes)

Heterozygous

Homozygous = one DR type

Heterozygous = up to four DR types

Figure 3-34

Red – heterozygous for all the highly polymorphic HLA I and IIYellow - Homozygous for one locusBlue - Homozygous for two or three loci

Correlation is mainly with HLA class I

Figure 3-28 part 1 of 2

MHC

MHC isoform can bind multiple peptides

Figure 3-28 part 2 of 2

Figure 3-29

L-lysine V- valine R-arginineY-tyrosine W-tryptophan

Figure 3-30

Co-

Figure 3-31Large circles- total # antigenicpeptides that can be presentedvia MHCI & MHCII

small circles- total # antigenicpeptides that can be presentedvia an individual MHCI & MHCII haplotype

Figure 3-32 part 1 of 2

Advantages for heterozygous for the MHC

Figure 3-32 part 2 of 2

Recombination betweenalleles of the same gene

Generation of new MHC alleles

HLA B*5301-Found in Africanpopulations andassociated withresistance tosevere malaria

Figure 3-33 part 2 of 2

HLA B*4601- Found in southeast Asian populations andassociated with susceptibility to nasopharyngeal carcinoma.

Recombination betweenalleles of the differentgene

Generation of newMHC alleles

MHC selection by Infectious Disease

• Pathogens adapt to avoid MHC - recent MHC isoform may provide a survival advantage (hence higher frequency level)

• Epidemic diseases place survival advantages on those who can best present pathogenic peptides

• Only a minority of HLA alleles are common to all humans- most are recent and specific to ethnic groups

HLA Type and Disease Susceptibility

Ankylosing spondylitis B27IDDM DR4/DR3Multiple Sclerosis DR2Narcolepsy DR2Rheumatoid arthritis DR4Lupus (SLE) DR3AIDS (rapid) HLA-A29, HLA-B22

HLA-C16, HLA-DR11AIDS (slow) HLA-B14, B27, B57

HLA-C8, C14

MHC polymorphism and Organ Transplants

• Developing T cells that recognize complexes of peptide and MHC molecules on HEALTY tissue (self-peptides presented by self MHC) are DESTROYED

• This results in the preservation of T cells that recognize non-self MHC (allogenic MHC). Called alloreactive T cells (1-10%) of total T-cell repertoire

• IS is primed for rejection of foreign organs that express allogenic MHC