青岛大学基础医学院医学免疫学课件cha.ppt

Chapter 8 Major histocompatibility complex（MHC）and coding molecules 一. Conception of MHC 1histocompatibility: It is a phenomenon of non- histocompatibility between donor and recipient. 2histocompatibility antigen: represents the alloantigen of individual specificity. It also termed transplantation antigen. 3major histocompatibility antigen system, MHS: Antigens of causing vigorous rejection. 4major histocompatibility complex, MHC: A cluster of closely linked genes in one chromosome, encoding polymorphic cell-surface molecules, which are associated with regulation of immune response, antigen presenting and transplantation rejection. Section 1 Structure of MHC and polygene Structure of MHC is so complicated, its diversity is composed of polygene and polymorphism Polygene refers to that MHC is composed by multiple neighboring genetic loci, encodes produces to have the same or similar function. Classification of MHC: According to structure and function, MHC are divided into (1) classical class I and II MHC genes (2) genes associated with immune function 一. Classical class I and II MHC genes H-2 complex mouse MHC is localized on the seventeenth chromosome, composed of 4 genetic regions (K, I, S, and D regions). I region can be divided into A,A, E,E, etc. subregions. every genetic region or subregion contains at least one locus. Classical class I MHC loci: K, D, L Classical class II MHC loci: A,A, E,E Classical class III MHC loci: C4, Bf, C2 HLA complex HLA complex located on chromosome 6p21.31 ，224 genetic loci, 128 functional genes, 96 pseudogenes Classical class I MHC loci: A, B, C Classical class II MHC loci: DR, DP, DQ Classical class III MHC loci: C2, C4A, C4B, Bf 二. HLA molecules class I HLA and class II HLA molecules can be divided into four separate regions: peptide-binding region immunoglobulin-like region transmembrane region cytoplasmic region （一） class I HLA molecules 1.structure All class I HLA molecules consist of two noncovalently linked polypeptide chains: an MHC-encoded polymorphic polypeptide called chain （or heavy chain）, containing 3 extracellular domains, called 1, 2, and 3; a short hydrophobic segment ; and the carboxyl terminal residues. a non-MHC-encoded non- polymorphic polypeptide called 2-microglobulin（2m ） , interacts noncovalently with the extra-cellular portion of the chain and no direct attachment to the cell. The interactions of 2m with 1, 2 and 3 domain appear critical for maintaining class I molecules in their native conformation. npeptide-binding region: The 1and2 domain interact to form a peptide -binding cleft, The peptide-binding cleft has -helical sides and an eight-stranded antiparallel -pleated sheet floor. The cleft can fit peptides 8- 11 aa. long in a linear array. nIg-like region: consisting of 3 and 2m domains, belong to IgSF domain. 3 domain contains the binding site for the T cell co-receptors CD8. ntransmembrane region: This region forms an -helix that passes through the hydrophobic region of the plasma membrane lipid bilayer and anchors the MHC molecule in the membrane. ncytoplasmic region: the carboxy terminal portion related to signal transportation. 2.distribution Class I molecules are constitutively expressed on virtually all nucleated cells. 3.function endogenous antigen processing and presentation MHC restriction: The ability of T lymphocytes to respond only when they are presented with the appropriate antigen in association with either “self“ class I or class II MHC molecules. transplantation rejection T-cell differentiation （二） class II HLA molecules 1.structure The class II molecules contain two MHC-encoded polymorphic chains, an chain and a chain. The two class II molecules are structurally similar. chain contains 2 extra-cellular domains, called 1, 2, chain contains 2 extra-cellular domains too , called 1, 2. npeptide-binding region: The 1and 1 domain interact to form a peptide-binding cleft, The peptide-binding cleft has -helical sides and an eight-stranded antiparallel -pleated sheet floor. class II HLA molecules bind peptides varying from 12 to 25 aa. nIg-like region: consisting of 2 and 2 domains, belong to IgSF domain. 2 domain contains the binding sites for the T cell co-receptors CD4. ntransmembrane and cytoplasmic regions: similar to that of chain of class I HLA molecule. 2.distribution Class II molecules are normally expressed on only dendritic cells, B lymphocytes, macrophages, and thymus epithelium, activation T cells. The expression of MHC molecules is increased by cytokines produced during both innate and adaptive immune responses. 3.function exogenous antigen processing and presentation MHC restriction transplantation rejection T-cell differentiation genetic control of immune response HLA molecule structure Ag binding clef distribution function class HLA 45kD 1+2 nucleated cells endogenous antigen (A,B,C) 2m 12kD CD8+Tc restriction class II 35kD APC, exogenous antigen activation T CD4+Th restriction HLA 28kD 1+1 (DR, DQ, DP) 三Genes associated with immune function （一）genes encoding some components of complement classical class III HLA genes, coding C4B、C4A、Bf、C2 （二）genes associated with antigen processing 1. LMP gene: including LMP2 and LMP7 locus, coding proteosome, that degrades endogenous antigen into peptides. 2. TAP gene: including TAP1 and TAP2 locus, coding TAP（transporter associated with antigen processing）, that transports endogenous antigen peptides from the cytosol into the endoplasmic reticulum. 3. TAP associating protein gene: coding TAP-associated protein（tapasin）, transporting and presenting endogenous antigen 4. HLA-DM gene: including DMA and DMB locus, coding DM molecules, that is involved in exogenous antigen peptide binding to class II molecules. 5. HLA-DO gene: including DOA and DOB locus, coding DO molecule, negative regulating DM molecule. （三）non-classical class I HLA genes HLA-E、 HLA-G 、HLA-F 1、 HLA-E: binding to CD94/NKG2A（KLR） , inhibition NK activation 2、 HLA-G: binding to some KIR KLR （四）genes associated with inflammation nTNF gene family ntranscription regulation gene family : I-kBNF-kB nMHC class I chain-related molecules（MIC） gene family: including MICA and MICB gene, MIC A/B molecules NKG2D nHSP gene family nCYP21 gene Section 2 MHC polymorphism 一. Conception of polymorphism Polymorphism refers to multiple alleles at a particular genetic locus. The causes of polymorphism producing : 1. multiple alleles 2. co-dominance HLA complex has 1556 loci HLA-A（250）、HLA-B（490）、HLA-C（ 119）、HLA-DRA（3）、HLA-DRB1（315 ）、 HLA-DRB3（38）、 HLA-DQA1（22 ）、HLA-DQB1（53）、HLA-DPA1（20） 、HLA-DPB1（99）、HLA-E（6）、HLA-G （15）、MICA（54）、TAP（10）、other （62）. naming of HLA: HLA gene locus +*+ allele example: HLA-A *0103;HLA-DRB1*1102 generic type HLA molecules have 161 specific antigens nHLA-A（27）、HLA-B（59）、HLA-C （10）、HLA-DR（24）、HLA-DQ（9 ）、HLA-DP（6）、HLA-Dw（26） nHLA-A、B、C、DR、DQ antigens apply serology testing; HLA-Dw antigens apply mixture lymphocyte reaction （MLR）testing. 二. Linkage disequilibrium and haplotype linkage disequilibrium: The genes closely link in one chromosome is more probability than randomly appear on one chromosome. haplotype: The set of MHC alleles present on each chromosome is called an MHC haplotype. genotype: all the genes possessed by an individual; in practice it refers to the organization of HLA genes in two chromosomes. phenotype: HLA specific antigenic type of an individuals genotype. 三. production and significance of HLA polymorphism ngene recombination, gene conversion and gene mutant lead to polymorphism. nselection pressure Section 3 Interaction between MHC molecules and antigen peptides 一. molecular basis of peptide binding to HLA molecules 1. Formation of peptide -binding cleft: 1,2 ( class I) and 1,1(class II) form the -strands in the floor and the -helices of the sides of the cleft. 2. The binding of peptides to MHC molecules is mediated by residues both in the peptides and in the clefts of the MHC molecules. 1) size of peptide-class I 811 residues long size of peptide-class II 1216 residues long 2) anchor residues 3) consensus motif: x-L/M- x-x-x-x-x-x-L/V（A*0201） 二. Characteristics of peptide-MHC interaction 1. The binding of peptides to MHC molecules possesses definite specificity, because specific MHC molecules by right of needed consensus motif can bind selectively to peptides. 1) The peptides must be linear array, the MHC molecules do not discriminate between foreign peptides and self peptides 2) peptides of binding class I MHC molecule are about 9 amino acid; binding class II MHC molecule are about 15 amino acid. 3) The binding of peptides to MHC molecules is a non-covalent interaction. 2. flexibility: Each class I or class II MHC molecules has a single peptide-binging cleft that can accommodate many different peptides having consensus motif. Section 4 HLA and clinical medicine 一. HLA and organ transplant reject