Structure and Polymorphism of Murine and Human Class II Major Histocompatibility Antigens

Abstract

The molecular analysis of the Class II region of the MHC of mice and of humans has to date led to some important conclusions. These regions encode sizeable families of related loci, at least 2 alpha and 6 beta in mice and 6 alpha and 7 beta in man. In addition to the sizeable number of potential molecules that could be expressed by the loci of this region, all the beta chains and both A alpha and DC alpha have extensive amounts of polymorphism. This polymorphism is strikingly similar at Class II loci in mouse and man. The majority of the variability is found in the first domain and consists of discrete regions of variability. These variable regions appear to be important functionally in presenting antigen, as evidenced by the bm12 mutant. The allotypy of these molecules is complex and is presumably generated by a combination of gene conversion and point mutation followed by selection. Final definition of the range of allelic variability and further insights into the mechanism by which it was generated are still to be resolved, as in a complete map of all the Class II loci in both mouse and man. The data available at present pose certain questions that now need to be addressed. The precise functional role of individual regions or residues of the Class II molecules can now be analyzed using the available sequence data and site specific mutagenesis. Fine structural analysis of these molecules is impossible at present using only sequence data, and X-ray crystallography will be required to answer fundamental questions about 3-dimensional structure. Finally, disease-specific sequences may be uncovered on particular haplotypes which permit the production of disease-specific probes. The molecular revelations of the last few years have resolved many questions about the polymorphisms of Class II products, but many new questions need to be resolved before these molecules and their extensive polymorphism can be properly understood.