Transcript Immunology_Lecture9MHC

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 (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 , 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
unimaginable 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:
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c.
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.
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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.
2.
3.
Mediate graft rejection. e.g. IgG can cause
hyperacute kidney rejection.
Can cross placenta .
Can cause immunological refractoriness of random
donor platelet transfusion.