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MAJOR HISTOCOMPATIBILITY COMPLEX

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)

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MAJOR HISTOCOMPATIBILITY COMPLEX

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  1. MAJORHISTOCOMPATIBILITY COMPLEX

  2. 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.

  3. MHC codes for three classes of proteins: • MHC class I • MHC class II • 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 tocytotoxicT-cells • Consist of two polypeptide chains: 1- A long transmembraneαprotein chain. 2- A short β protein chain (β2-microglobulin)

  4. Class I antigens

  5. 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 transmembraneglycoproteins. • Restricted toDendritic 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: TNFαand TNFβ.

  6. Class II antigens

  7. MHC antigen-binding sites Class II Class I

  8. Comparison: MHC Class I and II Structure

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

  10. NUMBERING: Of class I antigens is non-overlapping: e.g. A1 , A2 , A3 , B4 , B5 , Bw6 , B7 , B8. • Someare subtyped: e.g. HLA A9: HLA-A23  A23(9) HLA-A24  A24(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-DQA1* , HLA-DQA2* for the two DQ A-chain loci. HLA-DQB1* , HLA-DQB2* for the two DQ B-chain loci.

  11. METHODS FOR DETECTION OF HLA ANTIGENS: • 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) • Of class II antigens: by one of the following methods: • 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

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

  13. 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 1st pregnancy. • Appear in 25% of women after the 2nd pregnancy. • Appear in 35% of women after the 3rd 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: • Mediate graft rejection. e.g. IgG can cause hyperacute kidney rejection. • Can cross placenta . • Can cause immunological refractoriness of random donor platelet transfusion.

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