MAJOR HISTOCOMPATIBILITY COMPLEX. MAJOR HISTOCOMPATIBILITY COMPLEX (MHC): Is a segment of the short arm (p) of chromosome 6 containing several genes These.

MAJORHISTOCOMPATIBILITY 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 II3.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-cellsConsist of two polypeptide chains:

1- A long transmembrane α protein chain.

2- A short β protein chain (β2-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 TNFβ.

Class II antigens

MHC ANTIGEN-BINDING SITES

Class I

Class II

COMPARISON: MHC CLASS I AND II STRUCTURE

INHERITANCE:The order of the MHC genes on chromosome 6 is: A , C , B , C2 , Bf , C4 , DHLA-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.largeunimaginable genotypes.

NOMENCLATURE:Is by a combination of letters (HLA-A , HLA-B) in order of description.

NUMBERING: Of class I antigens is non-overlapping: e.g.

A1 , A2 , A3 , B4 , B5 , Bw6 , B7 , B8.

Some are 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.

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.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.

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 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: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.