12. Summary

24.11 The major histocompatibility locus codes for many genes of the immune system

Key terms defined in this section
Transplantation antigen is protein coded by a major histocompatibility locus, present on all mammalian cells, involved in interactions between lymphocytes.

The major histocompatibility locus occupies a small segment of a single chromosome in the mouse (where it is called the H2 locus) and in man (called the HLA locus). Within this segment are many genes coding for functions concerned with the immune response. At those individual gene loci whose products have been identified, many alleles have been found in the population; the locus is described as highly polymorphic, meaning that individual genomes are likely to be different from one another. Genes coding for certain other functions also are located in this region.


Histocompatibility antigens are classified into three types by their immunological properties. In addition, other proteins found on lymphocytes and macrophages have a related structure and are important in the function of cells of the immune system:


Class I proteins are the transplantation antigens. They are present on every cell of the mammal. As their name suggests, these proteins are responsible for the rejection of foreign tissue, which is recognized as such by virtue of its particular array of transplantation antigens. In the immune system, their presence on target cells is required for the cell-mediated response. The types of class I proteins are defined serologically (by their antigenic properties). The murine class I genes code for the H2-K and H2-D/L proteins. Each mouse strain has one of several possible alleles for each of these functions. The human class I functions include the classical transplantation antigens, HLA-A, B, C.


Class II proteins are found on the surfaces of both B and T lymphocytes as well as macrophages. These proteins are involved in communications between cells that are necessary to execute the immune response; in particular, they are required for helper T cell function. The murine class II functions are defined genetically as I-A and I-E. The human class II region (also called HLA-D) is arranged into four subregions, DR, DQ, DZ/DO, DP.


The complement proteins provide the class III MHC. Their genetic locus is also known as the S region; S stands for serum, indicating that the proteins are components of the serum. Their role is to interact with antibody-antigen complexes to cause the lysis of cells in the classical pathway of the humoral response.


The Qa and Tla loci proteins are found on murine hematopoietic cells. They are known as differentiation antigens, because each is found only on a particular subset of the blood cells, presumably related to their function. They are structurally related to the class I H2 proteins, and like them are polymorphic.


We can now relate the types of proteins to the organization of the genes that code for them.




Figure 24.29 The histocompatibility locus of the mouse contains several loci that were originally defined genetically. Each locus contains many genes. Spaces between clusters that have not been connected are indicated by queries.

The murine MHC locus is summarized on the map of Figure 24.29. The classical H2 region occupies 0.3 map units; the adjacent region occupies another 1.0 map units. In molecular terms, this "small segment" of the chromosome is sizable; the 1.3 map units together potentially represent ~2000 kb of DNA (for review see Steinmetz and Hood, 1983; Flavell et al., 1986). It is, however, possible for MHC functions to be provided by far fewer genes, as in the case of the chicken, where the MHC region is 92 Kb and has only 9 genes (Kaufman et al., 1999).


The H2K genes map at the left end, and the H2D/L genes map at the right end. The class II and class III genes map between. Most of the polymorphism in individual genes occurs in those of the H2 type. The adjacent region extends for another map unit; within it are genes coding for the differentiation antigens. We may regard them as extending the region of the chromosome devoted to functions concerned with the development of lymphocytes and macrophages. Variation in the number of genes between different mouse strains seems to occur largely in the Qa and Tla loci.


The class I mouse genes reside in clusters. The genes in each cluster usually are oriented in the same direction; adjacent genes tend to be more closely related, which suggests that they have originated by ancestral tandem duplications. Other genes also lie in the MHC locus. Within the D/L class I region lie the genes for the subunits of tumor necrosis factor (TNF), a protein that is involved in inflammatory diseases.


Next to the H2-D/L locus are the Qa and Tla loci. The ~10 Qa genes are closely related to the H2 genes. The Tla region contains ~20 genes, but they are less well related to the classical H2 sequences.




Figure 24.30 The human major histocompatibility locus codes for similar functions to the murine locus, although its detailed organization is different. Genes concerned with nonimmune functions also have been located in this region.

The human MHC locus is 3600 kb, about twice the length of the murine locus. As outlined in Figure 24.30, it contains similar functions, although not in the identical order. It contains 224 genes (including 128 whose protein products have not yet been identified) (The MHC sequencing Consortium, 1999). The major difference from mouse is that the class I HLA-A, B and C genes all are located in the same region (extending over >1000 kb), contrasted with the separation between murine H2-K and H2-D/L. The relative organization of the class I, II, and III genes is otherwise generally similar; moving from the telomere toward the centromere, there are the class I genes, followed by the class III genes and the class II genes for DR, DQ, DP.




Figure 24.31 Class I and class II histocompatibility antigens have a related structure. Class I antigens consist of a single (a) polypeptide, with three external domains (a1, a2, a3), that interacts with b2 microglobulin (b2 m). Class II antigens consist of two (a and b) polypeptides, each with two domains (a1 & a2, b1 & b2) with a similar overall structure.

All MHC proteins are dimers located in the plasma membrane, with a major part of the protein protruding on the extracellular side. The structures of class I and class II MHC proteins are related, although they have different components, as summarized in Figure 24.31.


Class II antigens consist of two chains, α and β, whose combination generates an overall structure in which there are two extracellular domains.


All class I MHC proteins consist of a dimer between the class I chain itself and the β2-microglobulin protein. The class I chain is a 45 kD transmembrane component that has three external domains (each ~90 amino acids long, one of which interacts with β2 microglobulin), a transmembrane region of ~40 residues, and a short cytoplasmic domain of ~30 residues that resides within the cell.


The β2 microglobulin is a secreted protein of 12 kD. It is needed for the class I chain to be transported to the cell surface. Mice that lack the β2 microglobulin gene have no MHC class I antigen on the cell surface.




Figure 24.32 Each class of MHC genes has a characteristic organization, in which exons represent individual protein domains

The organization of class I genes summarized in Figure 24.32 coincides with the protein structure. The first exon codes for a signal sequence (cleaved from the protein during membrane passage). The next three exons code for each of the external domains. The fifth exon codes for the transmembrane domain. And the last three rather small exons together code for the cytoplasmic domain. The only difference in the genes for human transplantation antigens is that their cytoplasmic domain is coded by only two exons.


The exon coding for the third external domain of the class I genes is highly conserved relative to the other exons. The conserved domain probably represents the region that interacts with β2 microglobulin, which explains the need for constancy of structure. This domain also exhibits homologies with the constant region domains of immunoglobulins.


What is responsible for generating the high degree of polymorphism in these genes? Most of the sequence variation between alleles occurs in the first and second external domains, sometimes taking the form of a cluster of base substitutions in a small region. One mechanism involved in their generation is gene conversion between class I genes.


Pseudogenes are present as well as functional genes; at present we have some way to go before estimating the total number of active genes in the region.


Like the class I genes, the class II and class III genes also are interrupted, with the exons related to protein domains (see Figure 24.31). There are fewer genes in these classes, ~10 each.


The gene for β2 microglobulin is located on a separate chromosome. It has four exons, the first coding for a signal sequence, the second for the bulk of the protein (from amino acids 3 to 95), the third for the last four amino acids and some of the nontranslated trailer, and the last for the rest of the trailer.


The length of β2 microglobulin is similar to that of an immunoglobulin V gene; there are certain similarities in amino acid constitution; and there are some (limited) homologies of nucleotide sequence between β2 microglobulin and Ig constant domains or type I gene third external domains. All the groups of genes that we have discussed in this chapter may have descended from a common ancestor that coded for a primitive domain.


This section updated 1-6-2000




Reviews
Flavell, R. A., Allen, H., Burkly, L. C., Sherman, D. H., Waneck, G. L., and Widera, G. (1986). Molecular biology of the H-2 histocompatibility complex. Science 233, 437-443.
Steinmetz, M. and Hood, L. (1983). Genes of the MHC complex in mouse and man. Science 222, 727-732.

Research
Kaufman, J. et al. (1999). The chicken B locus is a minimal essential major histocompatibility complex.. Nature 401, 923-925.
The MHC sequencing Consortium (1999). Complete sequence and gene map of a human major histocompatibility complex.. Nature 401, 921-923.



Genes VII
Genes VII
ISBN: B000R0CSVM
EAN: N/A
Year: 2005
Pages: 382

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