An enormous diversity is exhibited by the MHC molecules within a species and within individuals. This variability echoes the diversity of antibodies and T-cell receptors, but the source of diversity for MHC molecules is not the same. Antibodies and T-cell receptors are generated by several somatic processes, including gene rearrangement and somatic mutation of rearranged genes (see Table 5-2). Thus, the generation of T and B cell receptors is dynamic, changing over time within an individual. By contrast, the MHC molecules expressed by an individual are fixed in the genes and do not change over time. The diversity of the MHC within a species stems from polymorphism, the presence of multiple alleles at a given genetic locus within the species. Diversity of MHC molecules in an individual results not only from having different alleles of each gene but also from the presence of duplicated genes with similar or overlapping functions, not unlike the isotypes of immunoglobulins. Because it includes genes with similar, but not identical structure and function (for example, HLA-A, -B, and -C), the MHC may be said to be polygenic.
The MHC possesses an extraordinarily large number of different alleles at each locus and is one of the most polymorphic genetic complexes known in higher vertebrates. These alleles differ in their DNA sequences from one individual to another by 5% to 10%. The number of amino acid differences between MHC alleles can be quite significant, with up to 20 amino acid residues contributing to the unique structural nature of each allele. Analysis of human HLA class I genes has revealed, as of early 2002, approximately 240 A alleles, 470 B alleles, and 110 C alleles. In mice, the polymorphism is similarly enormous. The human class II genes are also highly polymorphic and, in some cases, there are different gene numbers in different individuals. The number of HLA-DR beta-chain genes may vary from 2 to 9 in different haplotypes, and approximately 350 alleles of DRB genes have been reported. Interestingly, the DRA chain is highly conserved, with only 2 different alleles reported. Current estimates of actual polymorphism in the human MHC are probably on the low side because the most detailed data were obtained from populations of European descent. The fact that many non-European population groups cannot be typed using the MHC serologic typing reagents available indicates that the worldwide diversity of the MHC genes is far greater. Now that MHC genes can be sequenced directly, it is expected that many additional alleles will be detected.
This enormous polymorphism results in a tremendous diversity of MHC molecules within a species. Using the numbers given above for the allelic forms of human HLA-A, -B,
- Hydrogen bonds with -MHC molecule
- Hydrogen bonds with -MHC molecule
| Conformation of peptides bound to class I MHC molecules. (a) Schematic diagram of conformational difference in bound peptides of different lengths. Longer peptides bulge in the middle, whereas shorter peptides are more extended. Contact with the MHC molecule is by hydrogen bonds to anchor residues 1 /2 and 8/9. (b) Molecular models based on crystal structure of an influenza virus antigenic peptide (blue) and an endogenous peptide (purple) bound to a class I MHC molecule. Residues are identified by small numbers corresponding to those in part (a). (c) Representation of a1 and a2 domains of HLA-B27 and a bound antigenic peptide based on x-ray crystallographic analysis of the cocrystallized peptide-HLA molecule. The peptide (purple) arches up away from the p strands forming the floor of the binding cleft and interacts with twelve water molecules (spheres). [Part (a) adapted from P. Parham, 1992, Nature 360:300, © 1992 Macmillan Magazines Limited; part (b) adapted from M. L. Silver et al., 1992, Nature 360:367, © 1992 Macmillan Magazines Limited; part (c) adapted from D. R. Madden et al., 1992, Cell 70:1035, reprinted by permission of Cell Press.]
and -C, we can calculate the theoretical number of combinations that can exist by multiplying 240 X 470 X 110, yielding upwards of 12 million different class I haplotypes possible in the population. If class II loci are considered, the 5 DRB genes B1 through B5 have 304, 1, 35, 11, and 15 alleles respectively, DQA1 and B1 contribute 22 and 49 alleles, respectively and, DPB1 96 alleles; this allows approximately 1.8 X 1011 different class II combinations. Because each haplotype contains both class I and class II genes, the numbers are multiplied to give a total of2.25 X 1018 possible combinations of these class I and II alleles.
The calculation of theoretical diversity in the previous paragraph assumes completely random combinations of alleles. The actual diversity is known to be less, because certain allelic combinations occur more frequently in HLA haplotypes than predicted by random combination, a state referred to as linkage disequilibrium. Briefly, linkage disequilibrium is the difference between the frequency observed for a particular combination of alleles and that expected from the frequencies of the individual alleles. The expected frequency for the combination may be calculated by multiplying the frequencies of the two alleles. For example, if HLA-A1 occurs in 16% of individuals in a population (frequency = 0.16) and HLA-B8 in 9% of that group (frequency = 0.09) it is expected that about 1.4% of the group should have both alleles (0.16 X 0.09 = 0.014). However, the data show that HLA-A1 and HLA-B8 are found together in 8.8% of individuals studied. This difference is a measure of the linkage disequilibrium between these alleles of class I MHC genes.
Several explanations have been advanced to explain linkage disequilibrium. The simplest is that too few generations have elapsed to allow the number of crossovers necessary to reach equilibrium among the alleles present in founders of the population. The haplotypes that are over-represented in the population today would then reflect the combinations of alleles present in the founders. Alternatively, selective effects could also result in the higher frequency of certain allelic combinations. For example, certain combinations of alleles might produce resistance to certain diseases, causing them to be selected for and over-represented, or they might generate harmful effects, such as susceptibility to autoimmune disorders, and undergo negative selection. A third hypothesis is that crossovers are more frequent in certain DNA sequence regions, and the presence or absence of regions prone to crossover (hotspots) between alleles can dictate the frequency of allelic association. Data in support of this was found in mouse breeding studies that generated new recombinant H-2 types. The points of crossover in the new MHC haplotypes were not randomly distributed throughout the complex. Instead, the same regions of crossover were found in more than one recombinant haplotype. This suggests that hotspots of recombination do exist that would influence linkage disequilibrium in populations.
Despite linkage disequilibrium, there is still enormous polymorphism in the human MHC, and it remains very difficult to match donor and acceptor MHC types for successful organ transplants. The consequences of this major obstacle to the therapeutic use of transplantation are described in Chapter 21.
Sequence divergence among alleles of the MHC within a species is very high, as great as the divergence observed for the genes encoding some enzymes across species. Also of interest is that the sequence variation among MHC molecules is not randomly distributed along the entire polypeptide chain but instead is clustered in short stretches, largely within the membrane-distal a! and a2 domains of class I
molecules (Figure 7-14a). Similar patterns of diversity are observed in the a1 and (32 domains of class II molecules.
Progress has been made in locating the polymorphic residues within the three-dimensional structure of the membrane-distal domains in class I and class II MHC molecules and in relating allelic differences to functional differences (Figure 7-14b). For example, of 17 amino acids previously shown to display significant polymorphism in the HLA-A2 molecule, 15 were shown by x-ray crystallographic analysis to be in the peptide-binding cleft of this molecule. The location of so many polymorphic amino acids within the binding site for processed antigen strongly suggests that allelic differences contribute to the observed differences in the ability of MHC molecules to interact with a given antigenic peptide.
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