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INTRA Proteasome TAP MHC I Golgi Calnexin Calreticulin Tapasin CD8 T C

Summary. EXTRA Li MHC II Golgi Vesicle CLIP HLA-DM CD4 T H. INTRA Proteasome TAP MHC I Golgi Calnexin Calreticulin Tapasin CD8 T C. Exam EE129 Thursday 7:00pm. Help session: Tomorrow 6-8pm CIVL 3153. Alleles: different forms of one gene

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INTRA Proteasome TAP MHC I Golgi Calnexin Calreticulin Tapasin CD8 T C

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  1. Summary EXTRA Li MHC II Golgi Vesicle CLIP HLA-DM CD4 TH INTRA Proteasome TAP MHC I Golgi Calnexin Calreticulin Tapasin CD8 TC

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

  3. 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)

  4. Figure 3-13 part 1 of 2 Variable Invariant No rearrangements or somatic changes Diversity is derived from 1) Gene families 2) Genetic polymorphism

  5. 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

  6. Figure 3-24 part 1 of 2  Heavy Chain

  7.  Heavy Chains

  8. Chromosome Organization of HLA complex Chr6 • 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

  9. Cytokines coordinately regulate the group of genes - class I heavy chain and other associated genes • TAP transporter, Tapasin, Proteasome subunits - LMP2 and LMP7

  10. 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

  11. 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

  12. Maternal: 3 MHC I genes HLA-AM, HLA-BM, HLA-CM Paternal: 3 MHC I genes HLA-AP, HLA-BP, HLA-CP 6 different MHC I proteins on all cells Heterozygous 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 II proteins on all cells (some individuals have 8 due to two HLA-DRB genes)

  13. Homozygous = one DR type Heterozygous = up to four DR types

  14. Figure 3-34 Correlation is mainly with HLA class I Red – heterozygous for all the highly polymorphic HLA I and II Yellow - Homozygous for one locus Blue - Homozygous for two or three loci

  15. Figure 3-28 part 1 of 2 MHC MHC isoform can bind multiple peptides

  16. Figure 3-28 part 2 of 2

  17. Figure 3-29 L-lysine V- valine R-arginine Y-tyrosine W-tryptophan

  18. Figure 3-30 Co-

  19. 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

  20. Figure 3-32 part 1 of 2 Advantages for heterozygous for the MHC

  21. Figure 3-32 part 2 of 2

  22. 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

  23. Figure 3-33 part 2 of 2 Recombination between alleles of the different gene Generation of new MHC alleles HLA B*4601- Found in southeast Asian populations and associated with susceptibility to nasopharyngeal carcinoma.

  24. 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

  25. HLA Type and Disease Susceptibility Ankylosing spondylitis B27 IDDM DR4/DR3 Multiple Sclerosis DR2 Narcolepsy DR2 Rheumatoid arthritis DR4 Lupus (SLE) DR3 AIDS (rapid) HLA-A29, HLA-B22 HLA-C16, HLA-DR11 AIDS (slow) HLA-B14, B27, B57 HLA-C8, C14

  26. 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

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