L

MHC molecules determine the specificity of peptide binding and T cell antigen recognition, which has led to the question of why MHC genes are polymorphic. The presence of multiple MHC alleles in the population will ensure that at least some individuals in a population will be able to recognize protein antigens produced by virtually any microbe, and thus reduce the likelihood that a single pathogen can evade host defenses in all the individuals in a given species.

Human and Mouse MHC Loci

In humans, the MHC is located on the short arm of chromosome 6 and occupies a large segment of DNA, extending about 3500 kilobases (kb). (For comparison, a large human gene may extend up to 50 to 100 kb, and the size of the entire genome of the bacterium Escherichia coli is approximately 4500 kb.) In classical genetic terms, the MHC locus extends about 4 centimorgans, meaning that crossovers within the MHC occur with a frequency of about 4% at each meiosis. A molecular map of the human MHC is shown in Figure 6-8.

The human class I HLA genes were first defined by serologic approaches (antibody binding). There are three class I MHC genes called HLA-A, HLA-B, and HLA-C, which encode three class I MHC molecules with the same names. Class II MHC genes were first identified by use of assays in which T cells from one individual would be activated by cells of another individual (called the mixed lymphocyte reaction; see Chapter 16).There are three class II HLA gene loci called HLA-DP, HLA-DQ, and HLA-DR. Each class II MHC molecule is composed of a het-erodimer of a and P polypeptides, and the DP, DQ, and DR loci each contain separate genes designated A or B, encoding a and P chains, respectively. More recently, DNA sequencing methods have been used to more precisely define MHC genes and their differences among individuals. The nomenclature of the HLA locus takes into account the enormous polymorphism (variation among individuals) identified by serologic and molecular methods. Thus, based on modern molecular typing, individual alleles may be called HLA-A*0201, referring to the 01 subtype of HLA-A2, or HLA-DRB1*0401, referring to the 01 subtype of the DR4 allele in the B1 gene, and so on.

The mouse MHC, located on chromosome 17, occupies about 2000 kb of DNA, and the genes are organized in an order slightly different from the human MHC gene. One of the mouse class I genes (H-2K) is centromeric to the class II region, but the other class I genes are telo-meric to the class II region. There are three mouse class I MHC genes called H-2K, H-2D, and H-2L, encoding three different class I MHC proteins, K, D, and L. These genes are homologous to the human HLA-A, B, and C genes. The MHC alleles of particular inbred strains of mice are designated by lowercase letters (e.g., a, b), named for the whole set of MHC genes of the mouse strain in which they were first identified. In the parlance of mouse geneticists, the allele of the H-2K gene in a strain with the k-type MHC is called Kk (pronounced K of k), whereas the allele of the H-2K gene in a strain with d-type MHC is called Kd (K of d). Similar terminology is used for H-2D and H-2L alleles. Mice have two class II MHC loci called I-A and I-E, which encode the I-A and I-E molecules, respectively. These are located in the A and E subregions of the Ir region of the MHC and were discovered to be the Ir genes discussed earlier. The mouse class II genes are homologous to human HLA-DP, DQ, and DR genes. The I-A allele found in the inbred mouse strain with the Kk and Dk alleles is called I-Ak (pronounced I A of k). Similar terminology is used for the I-E allele. As in humans, there are actually two different genes, designated A and B, in the I-A and I-E loci that encode the a and P chains of each class II MHC molecule.

The set of MHC alleles present on each chromosome is called an MHC haplotype. For instance, an HLA hap-lotype of an individual could be HLA-A2, HLA-B5, HLA-DR3, and so on. All heterozygous individuals, of course, have two HLA haplotypes. Inbred mice, being homozy-gous, have a single haplotype. Thus, the haplotype of an H-2d mouse is H-2Kd I-Ad I-Ed Dd Ld.

Class II MHC locus

"Class II MHC locus

Class I MHC locus

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