The polymorphism of major histocompatibility complex molecules

There is extensive polymorphism of the major histocompatibility complex (MHC) class I and class II molecules (Figure 20.5).

CD3 complex of signalling molecules

Figure 20.4 The aP T-cell receptor complex. The aP TCR is composed of two polypeptide chains, each with a variable (open ovoid) and constant (closed ovoid) domain. Peptide plus MHC is recognized by the combined variable regions. The TCR is surrounded by the CD3 complex of transmembrane signalling molecules. This is composed of four types of polypeptide chain, Y, S, e and Z that are present as three pairs: £ with S, £ with Y and a pair of Z-chains or Z plus n (a splice variant of Z with a longer intracellular tail). Most monoclonal antibodies against CD3 are directed against antigenic determinants on CD3e. Most peripheral T cells express CD4 or CD8 with their TCR. In the thymus, the TCR is first expressed on thymocytes that express both CD4 and CD8, allowing the possibility for selection on the basis of either class II or class I-recognizing properties (see section on T-cell development).

These were first recognized as targets for allograft rejection and the allelic forms of the MHC molecules differ in the fine structure of their MHC-binding grooves. This is reflected in differences in the range of peptides that different MHC alleles can present to T cells. Crossover during meiosis is relatively rare; consequently. the alleles on each chromosome 6 are usually inherited en bloc and are named the MHC haplotype of that chromosome. It follows that approximately one in four siblings share the same MHC haplotype on both chromosomes. For the purposes of stem cell transplantation, the patient and donor must usually be fully matched for HLA alleles and thus only 25% of siblings are appropriate for donation.

Highly inbred strains of mice have the same MHC haplotype on both chromosomes and accept grafts from each other. Analysis of the immune response of such mice indicates that some strains of mice are poor responders to certain antigens, whereas other strains produce high responses to the same antigen. Analysis of the response to different antigens does not necessarily show the same pattern for high and low responders. Cross-breeding experiments show that strains of mice responding well to a certain protein have an MHC allotype that is particularly good at presenting a peptide from the antigen to T cells. It is possible to rank the capability of particular alleles to present specific pep-tides to TCR.

Certain MHC alleles are associated with relative protection against specific infections. Conversely, some alleles, or combinations of alleles, are associated with a greater chance of developing autoimmunity. Many diseases, including diabetes mellitus, Graves' disease and ankylosing spondylitis, are distinctly more common in individuals with a particular MHC allele or MHC haplotype. It seems logical that in evolution most alleles have been retained because they have certain advantages without too many disadvantages. The advantages of an allele might relate to a particular infection that is prevalent in one part of the world, but almost unknown in another; for example, the HLA-B53 allele has a high prevalence in West Africa and is associated with relative protection from a potentially lethal form of malaria.

The generation of antigen-specific receptors on T and B lymphocytes

The genes that encode the antigen-combining or variable (V) part of the antigen-specific receptors of both B cells and T cells show marked similarities, which indicate that the gene complexes have evolved from a common precursor gene during the process of evolution. Both the immunoglobulin and TCR variable-region genes have to undergo a process of gene rearrangement from their germline configuration before they can encode an antigen recognition structure. This process is a key element in

Class II MHC genes

Class I MHC genes

DP DQ

DR

B C A

110 20 56 28

458 3

592 175 325 Number

of alleles

Centromere

□ Class II beta-chain genes Class II alpha-chain genes □ Class I genes

Figure 20.5 MHC polymorphism. This is a simplified diagram of the main genes that encode MHC class I and MHC class II molecules and their exceptional polymorphism.

Mhc Class Molecules Diagram

Figure 20.5 MHC polymorphism. This is a simplified diagram of the main genes that encode MHC class I and MHC class II molecules and their exceptional polymorphism.

Table 20.1 The variable region genes of human T- and B-cell antigen receptors.

Gene complex

Chromosomal location

Gene segments Type

Approximate number

Ig heavy chain

14q32.3

VH

51

DH

~27

Jh

6

CH

10

Ig kappa light chain

2p12

Vk

40

Jk

5

CK

1

Ig lambda light chain

22q11

Vx

~29

Jx

4

Cx

4

TCR alpha chain

14q11.2 (contains TCR S locus)

Va

~70

Ja

61

Ca

1

TCR delta chain

14q11.2 (between Va and Ja of TCR a)

V5

~4

D5

3

J5

3

C5

1

TCR beta chain

7q32.5

52

2

13

2

TCR gamma chain

7p15

VY

12

JY

5

C

2

C, constant regions; D, diversity segments; J, joining segments; V, variable sements. Where the number of functional gene segments is uncertain, this is denoted byThere are many non-functional gene segments (pseudogenes); these are disregarded in this table. Because TCR a- and S-genes are encoded in the same gene complex on chromosome 14, successful rearrangement of the TCRa genes inevitably results in looping out of the S-genes so that a- and S-genes cannot be co-expressed.

C, constant regions; D, diversity segments; J, joining segments; V, variable sements. Where the number of functional gene segments is uncertain, this is denoted byThere are many non-functional gene segments (pseudogenes); these are disregarded in this table. Because TCR a- and S-genes are encoded in the same gene complex on chromosome 14, successful rearrangement of the TCRa genes inevitably results in looping out of the S-genes so that a- and S-genes cannot be co-expressed.

the differentiation of lymphocytes from haemopoietic stem cells. The location and composition of the B- and T-cell receptor gene complexes and the details of their variable regions are given in Table 20.1. Although there are considerable differences in the organization of the gene complexes, the mechanism of variableregion gene rearrangement appears to be similar.

The genetic organization of the variable-region genes and the way in which they are rearranged can generate a huge diversity of antigen recognition structures for subsequent display on the surface of mature B and T lymphocytes. For T cells, this is the only way in which diversity of V region structure is achieved. In B cells, there is an additional mechanism that increases the variable-region gene repertoire. This is a somatic hypermutation mechanism that is activated during B-cell maturation in germinal centres and which introduces mutations into the rearranged immunoglobulin variable-region genes. It is discussed in detail in the section on antibody responses.

There are six pairs of genes that encode antigen-specific receptors - three for immunoglobulin (k and X light chains, and heavy chains) and three for TCRs (P, y and a combined a and S locus - see Table 20.1). Each has variable-region and constant-region gene segments and, before comparison of the individual members, the structure of the variable-region gene segments that encode immunoglobulin heavy chain and the way in which these are rearranged during B-cell development will be described to exemplify the common features.

Germline IgH

variable-region genes

Upstream

Genes after DJ rearrangement

V segments D segments J segments

Transcription

Fully rearranged IgH variable-regions genes

Ribosomes IgH mRNA

First looped-out

Juxtaposed D and J recombination signalling sequences n

Second looped-out section

Juxtaposed V and D recombination signalling sequences n

Figure 20.6 Immunoglobulin heavy-chain variable-region genes and their rearrangement. The germline structure of the variableregion gene complex is shown in the top line. The genes are present in this form in haemopoietic stem cells. The approximate number (n) of VH, Dh and JH segments are given in Table 20.1. The constant-region genes are downstream of the V region genes. The first of these, |l, encodes the IgM heavy chain constant-region domain. This is followed in sequence by S, y3, yl, a non-functional pseudo-e gene, al, y2, y4, £ and a2. The boxes represent exons and lines introns. During rearrangement, first one of the J segments becomes aligned with one of the D segments and the intervening sequences are deleted; DJ rearrangement is always attempted on both chromosomes 14. The aligned DJ pair on one chromosome 14 then becomes linked to one of the V segments on that chromosome, and again intervening sequences are deleted. If this V

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