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1、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 an
2、tigen.,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 pre
3、senting 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 functio
4、n. 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 (
5、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 chromo
6、some 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-bi
7、nding 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 dom
8、ains, 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 wit
9、h 1, 2 and 3 domain appear critical for maintaining class I molecules in their native conformation.,peptide-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 f
10、it peptides 8-11 aa. long in a linear array.,Ig-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. transmembrane region: This region forms an -helix that passes through the hydrophobic region of the plasma membrane
11、lipid bilayer and anchors the MHC molecule in the membrane. cytoplasmic 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
12、 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
13、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.,peptide-binding region: The 1and 1 domain interact to form a peptide-binding
14、 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.,Ig-like region: consisting of 2 and 2 domains, belong to IgSF domain. 2 domain contains the binding sites for the T cell co-rec
15、eptors CD4. transmembrane 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 b
16、y 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 C
