Your browser is too old
We can't provide a great video experience on old browserUpdate now
Detailed Genomic Map of MHC Genes
This Sqadia lecture establishes our concept towards major histocompatibility complex. The MHC spans some 2000 kb of mouse DNA and some 4000 kb of human DNA. The MIC family of class I genes has only 15%–30% sequence identity to classical class I, and those designated as MICA are highly polymorphic. The MIC gene products are expressed at low levels in epithelial cells and are induced by heat or other stimuli that influence heat shock proteins. The class III region of the MHC in humans and mice contains a heterogeneous collection of genes. These genes encode several complement components, two steroid 21-hydroxylases, two heat-shock proteins, and two cytokines.
Cellular Distribution of MHC Molecules
In general, the classical class I MHC molecules are expressed on most nucleated cells, but the level of expression differs among different cell types. In normal, healthy cells, the class I molecules will display self-peptides resulting from normal turnover of self-proteins. In cells infected by a virus, viral peptides, as well as self-peptides, will be displayed. Class II molecules are expressed constitutively only by antigen-presenting cells, primarily macrophages, dendritic cells, and B cells; thymic epithelial cells and some other cell types can be induced to express class II molecules and to function as antigen-presenting cells under certain conditions and under stimulation of some cytokines. The diversity generated by these mechanisms presumably increases the number of different antigenic peptides that can be presented and thus is advantageous to the organism.
Regulation of MHC Expression
Class I and class II MHC genes are flanked by 5´ promoter sequences, which bind sequence-specific transcription factors. The promoter motifs and transcription factors that bind to these motifs have been identified for a number of MHC genes. Transcriptional regulation of the MHC is mediated by both positive and negative elements. MHC expression is decreased by infection with certain viruses, including human cytomegalovirus (CMV), hepatitis B virus (HBV), and adenovirus 12 (Ad12). In some cases, reduced expression of class I MHC molecules on cell surfaces is due to decreased levels of a component needed for peptide transport or MHC class I assembly rather than in transcription. In cytomegalovirus infection, for example, a viral protein binds to microglobulin, preventing assembly of class I MHC molecules and their transport to the plasma membrane. Adenovirus 12 infection causes a pronounced decrease in transcription of the transporter genes (TAP1 and TAP2).
MHC and Immune Responsiveness
According to the determinant-selection model, different class II MHC molecules differ in their ability to bind processed antigen. According to the alternative holes-in-the-repertoire model, T cells bearing receptors that recognize foreign antigens closely resembling self-antigens may be eliminated during thymic processing. According to the alternative holes-in-the-repertoire model, T cells bearing receptors that recognize foreign antigens closely resembling self-antigens may be eliminated during thymic processing. Since the T-cell response to an antigen involves a trimolecular complex of the T cell’s receptor, an antigenic peptide, and an MHC molecule. This suggests that T cells recognizing this repressor peptide in association with IEd may have been eliminated by negative selection in the thymus, leaving a hole in the T-cell repertoire.
MHC and Disease Susceptibility
HLA alleles occur at a much higher frequency in those suffering from certain diseases than in the general population. The diseases associated with particular MHC alleles include autoimmune disorders, certain viral diseases, disorders of the complement system, some neurologic disorders, and several different allergies. The existence of an association between an MHC allele and a disease should not be interpreted to imply that the expression of the allele has caused the disease the relationship between MHC alleles and development of disease is complex. Some evidence suggests that a reduction in MHC polymorphism within a species may predispose that species to infectious disease. Cheetahs and certain other wild cats, such as Florida panthers, that have been shown to be highly susceptible to viral disease have very limited MHC polymorphism. It is postulated that the present cheetah population arose from a limited breeding stock, causing a loss of MHC diversity.