A possible molecular mechanism of immunomodulatory activity of bilirubin

Bilirubin is an endogenous product of heme degradation in mammals. Bilirubin has long been considered as a cytotoxic waste product that needs to be excreted. However, increasing evidence suggests that bilirubin possesses multiple biological activities. In particular, recent studies have shown that bilirubin should be a protective factor for several autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. Since these autoimmune diseases are closely associated with specific types of human leukocyte antigens (HLAs), we have hypothesized that bilirubin might bind to the antigenic peptide-binding groove of the HLA molecules and exert its immunosuppressive actions. In order to evaluate the hypothesis, theoretical docking studies between bilirubin and the relevant HLA molecules have been undertaken. The in silico studies have clearly shown that bilirubin may bind to the antigenic peptide-binding groove of the HLA molecules relevant to the autoimmune diseases with significant affinity. The bound bilirubin may block the binding of antigenic peptides to be presented to T cell receptors and lead to suppression of the autoimmune responses. Based on this hypothesis new drug discovery research for autoimmune diseases will be conducted.