Role of Major Histocompatibility Complex Genes in Murine Collagen-Induced Arthritis: A Model for Human Rheumatoid Arthritis

Collagen-induced arthritis is an animal model for rheumatoid arthritis that shares a number of clinical, hematologic, serologic, and radiographic features with human disease. Predisposition to rheumatoid arthritis has been associated with major histocompatibility complex (MHC) class II genes, HLA-DRB*0401/DQB1*0302 and resistance to DRB1*0402 and DQ6 genes. Animal models allow one to study the genetics and immunologic processes of individual genes involved in the complex human diseases. To study the interactions between class II molecules and to define their role in arthritis, the authors generated HLA-DR and -DQ transgenic mice. HLA transgenes are expressed on cell surface and can positively select CD4 cells. A peripheral tolerance is maintained to the transgenes even though an efficient T cell response to immunodominant antigens similar to human T cells is observed. Using HLA-DQ/DR double transgenic mice, the studies show that complementation between DQ and DR molecules contributes to predisposition to and severity of, or protection from, arthritis. Thus, these mice provide a powerful tool to understand the role of HLA molecules in the predisposition to and immunotherapy for human disease.