CLASS II MHC
Mouse [ I-A, I-E]
Human [DR, DQ, DP]
These proteins are found only on the surface of antigen presenting cells.
The Class II protein is a heterodimer, composed of 2 distinct polypeptide chains which are designated alpha and beta. Both chains are encoded by genes in the Class II MHC region and both are inserted into the membrane of the APC.
Please see figure of Class II MHC protein in the text.
Both polypeptide chains have 2 extracellular domains (designated alpha 1, alpha 2 & beta 1, beta 2),a short hydrophobic transmembrane section and a hydrophilic cytoplasmic domain inside the cell. The alpha 1 and beta 1 domains are highly variable between different allelic forms of the alpha and beta chain respectively. X-Ray crystallography (taking 10 years to complete) has proven that the alpha 1 and beta 1 domains together form the peptide binding cleft of the Class II MHC protein. The peptide binding cleft is very similar to the cleft observed for Class I MHC proteins (in fact, as you can see in the text the two clefts are actually superimposable). There are a few differences, however. The Class II MHC peptide binding cleft is open on both ends. Therefore, the processed peptide lays within the cleft somewhat like a hot dog in a bun. Rather than being anchored to the cleft at both ends (as in the Class I MHC cleft), the peptide is attached by various amino acid side chains along its length. The peptides which "fit" the cleft range in size from 13-18 amino acids in length.
*APCs possess both Class I and Class II MHC on their surface.
The sequence divergence among alleles of the MHC Class I and Class II molecules within a species are as great or greater than the divergence normally seen in proteins between species. This variability may be due to a high rate of gene conversion. Gene conversion occurs when short DNA sequences insert into recipient DNA sequences. Gene conversion often utilizes short sequences from pseudogenes and such pseudogenes are common within the MHC complex.
Even though Class I MHC proteins are found on the surface of almost all nucleated cells, the level of expression varies between different cell types. Lymphocytes probably express the highest levels of Class I while hepatocytes of the liver have only low level expression.
Class II MHC proteins are expressed only on a limited # of cell types.
Question that arises: How is the expression of MHC genes regulated?
At one level there are specific transcription factors which bind to promoter sequences 5' to each alpha and beta chain gene. When these transcription factors are present in high enough quantity, RNA polymerase is able to transcribe the gene.
Certain cytokines are known to impact the synthesis of these transcription factors. For instance, IFN gamma induces the synthesis of a specific transcription factor that binds to the promoter sequence flanking the class I genes. The binding of the transcription factor to the promoter sequence appears to coordinately up-regulate transcription of the genes encoding both the class I alpha chain and beta-2-microglobulin, Interestingly, the expression of Class II MHC molecules in B cells is down-regulated by IFN-gamma. This effect relates to the ability of IFN-gamma to function in down-regulation of the humoral (antibody) response.
Corticosteroids and prostaglandins have long been known to be immuno-suppressive. It turns out that both are able to decrease the expression of Class II MHC proteins.
Class I MHC protein expression is also influenced by various viruses. Specifically, CMV (cytomegalovirus), HBV (hepatitis B), and Ad12 (adenovirus 12) can decrease Class I MHC expression.
CMV
There is a viral peptide which binds to beta-2-microglobulin preventing Class I assembly and transport to the plasma membrane.
Ad12
Causes a pronounced decrease in the transcription of TAP1 and TAP2 which are required to transport processed peptides from the cytoplasm into the RER.
Of course the down regulation of Class I MHC proteins helps these viruses to evade the immune response since viral peptides are presented to CD8 Tc cells by Class I MHC proteins.
MHC haplotype has been shown to strongly influence immune responsiveness. This influence is strongest in the class II MHC region reflecting the central role of class II MHC molecules in presenting antigen to T helper lymphocytes.
There are two explanations which have been given for the variability observed in immune responsiveness between different haplotypes.
The Determinant Selection Model states that different Class II MHC molecules differ in their ability to bind processed antigen. In other words, individuals may simply lack MHC molecules for certain peptides.
The Holes in the Repertoire Model states that and individual may not have T cells with receptors that can recognize particular peptide-MHC complexes. This is entirely likely due to the phenomenon of negative selection which occurs during thymic education.
These two models are not mutually exclusive and both are probably correct.
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