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Major Histocompatibility Complex Molecules

Major Histocompatibility Complex Molecules

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Major Histocompatibility Complex Molecules

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  1. Major Histocompatibility Complex Molecules

  2. Contents 1. Structure of MHCs and their polygeny 2. Polymorphisim of MHC 3. Interaction of MHC molecule and antigenic peptide 4. HLA and clinical medicine 5. Biological functions of MHC

  3. Section 1: Structure of MHCs and their polygeny Polygeny is defined as MHC complex that comprises many adjacent gene locus, encoding proteins with same or similar functions. MHC is divided into three categories.

  4. (一)Classical MHC I and MHCII molecules

  5. Structure of H-2 Structure of HLA

  6. class II class III class I class I centromere Schematicdiagram of HLA embryonic genes

  7. (二) HLA molecules encoded by MHC I and II genes 1. Distributions : Class I (HLA-A/B/C): all nucleated cells Class II (HLA-DR/DP/DQ): APC(Mf,DC,B), thymic epithelial cells, activated T cells 2. Structure: Class I :  (1 2 3 Tm C), 2m Class II:  (1 2 Tm C),  (1 2Tm C)

  8. membrane Class I MHC molecules MHC I类分子

  9. Schematic diagram of MHC I molecules

  10. membrane Class II MHC molecules MHC II类分子

  11. Schematic diagram of MHC II molecules

  12. MHC class I molecule MHC class II molecule Peptide-binding domain Immunoglobin-like domain Transmembrane segment Cytoplasm ic tail

  13. (三)Immune related genes 1. Genes encoding serum complement components : C4B、C4A、Bf、C2

  14. 2. Genes associated with antigen processing and presentation • Gene encoding low molecular weight polypeptide(LMP) • Gene encoding transporter associated with antigen processing(TAP) • HLA-DM gene • HLA-DO gene • Gene encoding TAP associated proteins tapasin

  15. 3. Non-classical MHC I(Ib)genes:HLA-E, HLA-G, HLA-F

  16. 4、Inflammation associated genes • Tumour necrosis factor gene family TNF、LTA、LTB • Transcriptional regulating gene or transcriptional factor-like gene family I-B、B144、ZNF173、ZNF178 • MHC I related gene(MIC)family • Hot shock protein gene family HSP70(molecular chaperone)

  17. Immune related genes Inflammation related genes Genes encoding complement components non-classical MHC I genes Genes associated with antigen processing and presentation Related encoding products

  18. Section 2: Polymorphism of MHC (一)The basic concepts of polymorphism

  19. Polymorphism: several alleles located on a single gene locus Haplotype: A set of genetic determinants located on a single chromosome Genotype: A set of genetic determinants located on both chromosomes Phenotype: The expressed characteristics of an individual Non-polymorphism, Homozygote, Heterozygote

  20. Haplotype heredity of HLA

  21. Phenotype,genotype and haplotype of HLA A B C Tester Phenotype Genotype Haplotype

  22. The Locus with the largest number of alleles are HLA-B(301)and HLA-DRB1(227) • HLA-A*0103 HLA-DRB1*1102

  23. I MHC class II molecules MHC class I molecules Polymorphism of MHC genes

  24. (二)Linkage disequilibrium and haplotype HLA-DRB1*0901 15.6% HLA-DQB1*0701 21.9% Probability of the two genes on the same chromosome: 3.4% The fact is 11.3% The Han nationality: A2-B46-Cw3-DR9-DQ9-Dw23 A33-B17-Cw2-DR3-DQ2-Dw3

  25. (三)The origin of HLA Polymorphism and its significance • Gene mutation • Gene recombinant • Gene switch Selection pressure

  26. Section 3: Interaction between MHC molecule and antigenic peptide peptide binding cleft peptide binding cleft

  27. (一)Molecular basis for the interaction between MHC molecule and antigenic peptide • Topography of conformational space • Anchor residue • Consensus motif • Specificity and flexibility of the binding

  28. Anchor residue MHC molecules Anchor

  29. peptide-MHC I complex Antigenic peptide MHC I molecules peptide-MHC II complex Antigenic peptide MHC II molecules Schematic diagram of the interaction between peptides and MHC I, II molecules

  30. Products of different HLA alleles selectively bind antigen peptides with specific consensus motif consensus motif products of alleles Class I molecules Class II molecules

  31. (二)Characteristic of the interaction between antigenic peptide and MHC molecules Flexibility: X amino acids which compose consensus motif can be variable in sequence and conformation . Anchor residues which the same MHC molecule demands can be more than one amino acid Antigenic peptides which bind different MHC molecules can have similar consensus motif.

  32. Section 4 HLA and clinical medicine 1. HLA and transplantation 2. Abnormal expression of HLA and clinical diseases HLA 3. Association between HLA and diseases HLA 4. HLA and medical jurisprudence

  33. Relative risk Disease Associated HLA allele Ankylosing spondylitis Acute anterior uveitis Goodpasture’ syndrome Multiple sclerosis Gluten-sensitive enteropathy Exophthalmic goiter Myasthenia gravis Systemic lupus erythematosus Insulin-dependent diabetes mellitus Rheumatoid arthritis Chronic pemphigus Hashimoto's disease Some autoimmune diseases associated significantly with HLA alleles

  34. Section 5 Biological functions of MHC (一)Involved in adaptive immune responses as antigen presenting molecules • Double recognition of peptide and MHC by T cell through TCR • Components bound by MHC and being presented can be self antigen, and even be MHC itself. • MHC is the main determinant of individual susceptibility for certain disease. • MHC is involved in the heterogenecity of species gene structure.

  35. (二)Involved in innate immune response as regulating molecules • Classical MHC III encoding complement components is involved in complement reaction and immune diseases • Products of non-classical MHC I and MIC gene can act as ligands, regulating the activities of NK cells and some killer cells • Inflammation related genes are involved in the initiation and regulation of inflammation, and play roles in stress responses.

  36. To master concepts of MHC • To master the molecular structure, tissue distribution and functions of human classical MHC genes • To be familiar with the structure and characteristic of MHC genes • To be familiar with the interaction between MHC molecules and antigenic peptide. • To understand immune related genes • To understand the roles of HLA in medicine and their significances