CHARACTERIZATION OF POLYMORPHISM WITHIN THE H2-M MHC CLASS-II LOCI

The products of the class II-like H2-M genes of the major histocompati bility complex are required for class II antigen processing. We sequen ced H2-Ma and Mb from several mouse strains to determine whether these genes are polymorphic like the classical H2-A and E genes, or are oli gomorphic, Like H2-O. Both Mb loci appear to be transcribed and are di stinct from each other. Mb1 and Mb2 differ by about 11% at the nucleot ide level and are most dissimilar in their second exons (corresponding to the beta 1 domain). Relative to the published Mb/1(d) haplotype se quence, the products of the b, g7, f, and k2 alleles of Mb1 from Mus m usculus domesticus and the separate mouse species Mus spretus differ b y only one to four amino acids. The majority of the changes occurred i n the second exon of-Mb1, in contrast to HLA-DMB, the human orthologue . Little polymorphism was seen for Mb2, and Ma was invariant in all st rains tested. The similarity of the g7 allele to those from other hapl otypes makes it unlikely that the M class II genes play a role in the autoimmune diabetes of NOD strain mice. The M genes are regulated in a manner similar to classical class II genes, in that they are upregula ted by IFN-gamma in macrophages, and to a lesser extent by IL4 in B ce lls. When modeled on the crystal structure of the HLA-DR1 class II mol ecule, nearly all of the differences between M beta 1 and M beta 2 aff ect residues facing away from the putative peptide binding groove.