Investigating contributions of the accessory molecule HLA-DO to development of autoimmune diseases

Abstract

Abstract Used biochemical and biophysical studies, our laboratory has previously shown that HLA-DO (DO) enhances binding of DM-insensitive peptides, and reduces binding of DM-sensitive peptides to HLA-DR1 molecules. We hypothesized that these properties of DO might be important for ensuring proper presentation of immunodominant epitopes in the thymic medulla, a main DO expressing area; thereby ensuring proper negative selection. To test this hypothesis, we investigated the development of experimental autoimmune encephalomyelitis (EAE) in mice that were H2-O wild type (DO-WT), or knock-out (DO-KO). With this model, we found that DO-KO mice displayed faster disease onset in comparison to DO-WT mice. Accelerated disease onset correlated with increased recovery of MOG specific CD4 cells at all stages of disease in DO-KO mice. More recently, these observations were confirmed with a second autoimmune disease model, collagen induced arthritis (CIA), in transgenic HLA-DR1 expressing mouse. Using in vivo Near Infrared Fluorescence (NIRF) imaging, we found that DR1+DO-KO mice had increased levels of active collagen degradation relative to DR1+DO-WT mice. Diseased DR1+DO-KO mice were also found to have a greater accumulation of CD4 T cells in the affected areas. These observations suggest that DR1+DO-KO mice have larger pools of collagen specific CD4 T cells. Indeed, DR1+DO-KO mice immunized with the immunodominant collagen epitope showed an increased percentage of collagen specific CD4 T cells as compared to DR1+DO-WT mice. As a whole, data from both autoimmune models suggest that loss of DO function leads to an increased peripheral pool of autoreactive CD4 T cells, likely due to faulty negative selection.