Dr. Holers research group performs both basic and translational research. A longstanding interest has been to decipher the roles of complement receptors and membrane regulatory proteins in the immune response, with a special emphasis on autoimmune diseases. Complement is a complex system of serum proteins which, upon activation, covalently bind targets (bacteria, viruses, immune complexes) and marks them as foreign. The interaction of complement with B cell receptors also results in substantial enhancement of humoral and cellular immunity. In addition to this role, excessive activation of complement is centrally involved in autoimmunity and the tissue damage that occurs in many inflammatory diseases involving organs such as the kidney. The Holers’ laboratory has developed human and mouse models in which to study these complement related biologic processes and to develop novel complement inhibitors. Candidate therapeutics derived from these studies have been advanced to clinical trials in humans.
With regard to translational research, Dr. Holers was a co-founder in 2001 of SERA (Studies of the Etiology of Rheumatoid Arthritis), which is focused on understanding the early pathogenesis and natural history of RA. In that regard, it is now known that autoimmune diseases such as RA begin years before clinical signs and symptoms are apparent, when at-risk individuals manifest highly predictive autoantibodies in their serum. By studying individuals in this period of time, SERA investigators have made novel findings suggesting that RA is initiated through a process linked to mucosal inflammation. This observation also suggests that additional therapeutic and/or prevention strategies could be considered for individuals in this at-risk but asymptomatic period. It is also relevant to determine how individuals transition from this autoantibody-positive, at-risk period to clinically active disease, and several studies are underway that are related to understanding these questions. Finally, the SERA investigator Dr. Kevin Deane has initiated the first RA prevention trial, designated StopRA, in asymptomatic individuals. The goal of this study is to prevent or delay the onset of arthritis in highly at-risk individuals.