MAJOR HISTOCOMPATIBILITY COMPLEX

MAJOR HISTOCOMPATIBILITY COMPLEX (MHC): Is a segment of the short arm (p) of chromosome 6 containing several genes These genes are critical to immune functions. HLA system (together with ABO system) constitutes the major histocompatibility complex(MHC) MHC was first identified as being important in rejection of transplanted tissues Distribution:  Of both HLA &ABO varies greatly in different types of tissues: rich in endothelial cells. small amounts in hepatocytes. absent in CNS.

MHC codes for three classes of proteins: 1.MHC class I 2.MHC class II 3.MHC class III Class I antigens:  HLA-A, HLA-B, HLA-C.  Carried on all nucleated cells and platelets.  the major function of the class I gene is presentation of peptide antigens to cytotoxic T-cells  Consist of two polypeptide chains: 1- A long transmembrane α protein chain. 2- A short β protein chain ( β 2 -microglobulin)

Class I antigens

Class II antigens:  Products of HLA-D region, which include HLA-DR, HLA-DQ, HLA-DP  Consist of two different ( α & β ) non covalently linked transmembrane glycoproteins.  Restricted to Dendritic cells, B-cells, activated T-cells, macrophages and monocytes.  They present processed antigenic peptides to T helper cells. Class III antigens: Include  complement proteins coded by the MHC: C4, C2, Bf.  Some cytokines: TNFα and TNF β.

Class II antigens

MHC ANTIGEN - BINDING SITES Class I Class II

C OMPARISON : MHC C LASS I AND II S TRUCTURE

INHERITANCE: TThe order of the MHC genes on chromosome 6 is: A, C, B, C2, Bf, C4, D HHLA-A, -B, -C and -D are the most polymorphic in humans. TThese four loci are closely linked and are inherited as a single entity called h aplotype (the particular combination of MHC alleles found on one parental chromosome). TThe number of haplotypes is v.large  unimaginable genotypes. NOMENCLATURE: IIs by a combination of letters (HLA-A, HLA-B) in order of description.

NUMBERING: Of class I antigens is non-overlapping: e.g. A 1, A 2, A 3, B 4, B 5, B w 6, B 7, B 8.  Some are subtyped: e.g. HLA A 9 : HLA-A 23  A 23(9) HLA-A 24  A 24(9)  Alleles can now be given terms e.g. HLA-B * 2712 Of class II antigens: numbering includes reference to the particular heavy or light chain locus : HLA-DQA 1 *, HLA-DQA 2 * for the two DQ A-chain loci. HLA-DQB 1 *, HLA-DQB 2 * for the two DQ B-chain loci.

METHODS FOR DETECTION OF HLA ANTIGENS: 1. Of class I antigens:  By the Two stage lymphotoxicity test : first stage: lymphocytes seperated and then incubated with antigen(of known class I specificity) second stage: complement is added : cells carrying the corresponding Ag will be killed and can be visualised by adding a dye (eosin) 2. Of class II antigens : by one of the following methods: a. serological techniques e.g. seperated B-lymphocytes are incubated with sera absorbed by platelets(do not carry class II Ags)to remove class I Ags. Detects HLA-DR

b. Cellular techniques: ee.g. MLR(mixed lymphocyte reaction) DDetects HLA-DP antigens. CCells from unrelated individuals are mixed together(one with known HLA is inactivated and used as a stimulus). ffailure to react indicates that test cells carry the same HLA-D. c. DNA typing methods.

HLA antibodies:  HLA-A, -B, -C & -DQ can induce Ab formation by transfusion or pregnancy.  Detected in 96% of massively transfused patients.  Appear in 15% of women after the 1 st pregnancy.  Appear in 25% of women after the 2 nd pregnancy.  Appear in 35% of women after the 3 rd pregnancy.  mostly of class I specificity(HLA-B is twice as prevalent as HLA-A)  Are usually IgG, immune Abs(1% show IgM Abs) Clinical Importance of HLA Abs: 1. Mediate graft rejection. e.g. IgG can cause hyperacute kidney rejection. 2. Can cross placenta. 3. Can cause immunological refractoriness of random donor platelet transfusion.