The use of humanized MHC mouse strains for studies of rheumatic diseases

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The association between the expression of specific alleles of the major histocompatibility complex (MHC) and susceptibility to a number of autoimmune diseases has been recognized for many years. After the discovery that MHC molecules bind and present antigenic peptides, there were high hopes that the antigens that drive autoimmune responses would be identified and new treatments for these diseases devised. Despite the advances made in understanding the function of MHC molecules, little new information has been generated as to how these MHC molecules participate in the pathogenesis of these diseases. This is perhaps no better exemplified than by the rheumatic diseases, most of which appear to be autoimmune in nature. While most autoimmune rheumatic diseases have clear associations with the expression of specific human leukocyte antigens (HLA) Class I or Class II alleles, it is still unclear how possessing these HLA alleles predisposes an individual to developing these diseases. In an attempt to answer these questions, a number of investigators have developed humanized mouse models of rheumatic diseases in which the HLA alleles associated with susceptibility to these diseases have been established as a transgene (see Tab. 1). In this review, we examine a number of these HLA humanized models and discuss their overall contribution to advancing our understanding of rheumatic diseases. While none of these mouse models perfectly mimics its respective human disease, it is clear that these humanized models can be valuable tools in developing new information about the function of these HLA molecules and they have provided important new insights into the pathogenesis of autoimmunity.