The major histocompatibility complex (MHC) plays key roles in controlling both adaptive and innate immune systems. In the adaptive immune system, both MHC class I and class II antigens recognize, bind and present peptides to cytotoxic and helper T-cells, respectively, and initiate cell-to-cell communication between antigen presenting cells and T-cells by forming immunological synapses and activating both subtypes of T-cells for both cellular and humoral immune systems. In addition, a number of gene clusters in this complex encode proteins which play important roles for antigen processing (proteosome subunit, LMP2 & 7, antigen transporter, TAP1 & 2, antigen loading for class I antigen, Tapasin, antigen loading for class II antigens, DM & DO molecules). In the innate immune system, both classical (HLA-A,-B,-C in human) and non-classical class I (HLA-E) antigens, plus class I-related molecules (MIC-A, -B) interact with natural killer (NK) receptors (Killer immunoglobulin-like receptor genes [KIR] and natural killer cell lectin-like receptors [NKG] antigens in human and Ly-49 and NKG antigens in mouse) and inhibit and activate NK-cell functions.? ? In addition to the immunological importance, the MHC provides important tools to study molecular evolution. Extremely polymorphic features of both class I and class II antigens identified in most vertebrates provide numerous numbers of peptide binding grooves for MHC class I and II antigens in order to adapt various pathogens. Natural and balancing selections play pivotal roles to generate and maintain these polymorphisms.? ? The nature of multigene clusters of the MHC genes also provides a number of theories to explain the genesis of the MHC. Also, paralogous chromosomal regions found in three other locations in human (chr. 6p21.3 for MHC, 9q33-34, 1, 19 for the others) and jawed vertebrates raises questions for the origin of the MHC.? ? A large-scale sequencing project for the HLA has been launched and completed for the 3.6 Mb of the classical class I, II, & III regions to reveal the molecular history of this important gene complex, and has identified 224 tightly linked genes, including 128 expressed genes, and 96 pseudogenes. More recently, the MHC expands to 4.6 Mb, including five subregions: 1) extended class II (280 kb); 2) class II (700 kb); 3) class III (1000 kb); 4) class I (1600 kb); and 5) extended class I (1000 kb). In contrast of this large complex structure in HLA, the chicken MHC B-locus presents a """"""""minimal essential MHC"""""""" disposition extending 92 kb and including 19 functional genes, raising questions about the structure of other MHC systems.? ? The feline MHC has been studied for an approach to comparative gene organization of this multigene cluster in mammals. DNA probes for 61 markers were designed from human MHC reference sequences and used to construct feline MHC BAC contig map spanning ARE1 in the class II region to the olfactory receptor complex in the extended class I region. Selected BAC clones were then used to identify feline-specific probes for the three regions of the mammalian MHC (class II-class III-class I) for radiation hybrid mapping and fluorescent in situ hybridization to refine the organization of the domestic cat MHC. The results not only confirmed that the p-arm of domestic cat B2 is inverted relative to human Chromosome 6, but also demonstrated that one inversion breakpoint localized to the distal segment of the MHC class I between TRIM39 and TRIM26. The inversion thus disjoined the approximately 2.85 Mb of MHC containing class II-class III-class I (proximal region) from the approximately 0.50 Mb of MHC class I/extended class I region, such that TRIM39 is adjacent to the Chromosome B2 centromere and TRIM26 is adjacent to the B2 telomere in the domestic cat.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
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