HERV-K immunity, a trigger of citrullination in rheumatoid arthritis?

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Project Summary/Abstract The main purpose of our research is to elucidate the most proximal molecular mechanisms that initiate, and likely continue to perpetuate, rheumatoid arthritis (RA), a severe systemic autoimmune disorder affecting ~1% of the population world-wide. This R21 proposal will address the novel hypothesis that aberrant expression of proteins of an endogenous retrovirus, termed HERV-K, triggers a humoral and cellular immune response, which may be upstream of the increased protein citrullination and development of anti-citrullinated protein antibodies (ACPA) that are characteristic of RA. Shown here as Preliminary Data, we have made the exciting discovery that a high proportion of RA patients have autoantibodies against HERV-K envelope (Env) and/or Gag proteins, often with high titers. Based on this, we wish to address two fundamental questions about the potential role of HERV- K immunity in RA: What kind of immune response do RA patients mount against HERV-K and why? Is there a connection between anti-HERV-K immunity and protein citrullination and, hence, the development of ACPA? Our specific aims are: SPECIFIC AIM 1: To characterize anti-HERV-K immunity in RA. Here, we will establish what patient antibodies recognize, if they neutralize the ligand-binding properties of Env, if they recognize native Env better than denatured, and we will clone patient anti-Env mAbs. We will also ask if HERV-K specific T cells are present and where HERV-K is expressed. SPECIFIC AIM 2. Does HERV-K immunity lead to citrullination? In this Aim, we will ask if Env is citrullinated or if patient antibodies of T cells recognize citrullinated Env. We will also test if killing of Env-expressing neutrophils will trigger a citrullination reaction. Although HERV-K mRNA has been detected in RA blood and synovial fluid before, the possibilities raised by our findings are exciting and represent new territory in the exploration of RA pathogenesis. The high prevalence of anti-Env and anti-Gag (auto)antibodies in RA patients suggests that they may be related to RA pathogenesis. Hence, if our working models are even directionally correct, we may move the field forward in a significant manner. HERV-K involvement in RA may present new opportunities for the development of novel therapeutics for this disease. Unlike the currently approved therapies for RA, which are relatively non-specific immune suppressants, new drugs specifically targeted to the upstream pathogenic molecular mechanisms of RA may be more efficacious and have fewer safety liabilities.