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

Exam EE129 Thursday 7:00pm Help session: Tomorrow 6-8pm CIVL 3153

Alleles: different forms of one gene Allotypes: different forms of one protein (isoforms) Polymorphic: alternative forms of one gene = Many alleles Oligomorphic: a few forms of one gene = Few alleles Monomorphic: no polymorphism Homozygous: same allele on both inherited chromosomes Heterozygous: 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 changes Diversity is derived from 1) Gene families 2) Genetic polymorphism

HLA-A,B,C -present peptide antigens to CD8 Tcells and interact with NK-cells HLA-E,G -interact with NK-cells HLA-F -? HLA-DP,DQ,DR - present peptide antigens to CD4 Tcells HLA-DM,DO -regulate peptide loading of DP,DQ,DR Human leukocyte antigen complex Abs 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 ,  2 M, 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 isoforms HLA-DPA, HLA-DPB => MHC II isoforms HLA-DRA, HLA-DRB => MHC II isoforms

Maternal: 3 MHC I genes HLA-A M, HLA-B M, HLA-C M Paternal: 3 MHC I genes HLA-A P, HLA-B P, HLA-C P Maternal: 3 MHC II genes HLA-DPA M, HLA-DPB M HLA-DQA M, HLA-DQB M HLA-DRA M, HLA-DRB M Paternal: 3 MHC II genes HLA-DPA P, HLA-DPB P HLA-DQA P, HLA-DQB P HLA-DRA P, HLA-DRB P 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 II Yellow - Homozygous for one locus Blue - 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-lysineV- valineR-arginine Y-tyrosineW-tryptophan

Figure 3-30 Co-

Figure 3-31 Large circles- total # antigenic peptides that can be presented via MHCI & MHCII small circles- total # antigenic peptides that can be presented via 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 between alleles of the same gene Generation of new MHC alleles HLA B*5301- Found in African populations and associated with resistance to severe malaria

Figure 3-33 part 2 of 2 HLA B*4601- Found in southeast Asian populations and associated with susceptibility to nasopharyngeal carcinoma. Recombination between alleles of the different gene Generation of new MHC 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 spondylitisB27 IDDMDR4/DR3 Multiple SclerosisDR2 NarcolepsyDR2 Rheumatoid arthritisDR4 Lupus (SLE)DR3 AIDS (rapid)HLA-A29, HLA-B22 HLA-C16, HLA-DR11 AIDS (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