Autoantibodies Against Unmodified and Citrullinated Human Endogenous Retrovirus K Envelope Protein in Patients With Rheumatoid Arthritis.

OBJECTIVE: Autoantibodies against proteins encoded by human endogenous retrovirus K (HERV-K) have been reported in patients with rheumatoid arthritis (RA), but their relevance, if any, has remained unresolved. We revisited this question and tested if such autoantibodies may react with citrullinated epitopes on the envelope (Env) protein of HERV-K. METHODS: Immunoblotting and ELISAs were conducted with unmodified Env protein and with Env citrullinated by protein arginine deiminase 4 (PAD4). Sera from 100 patients with RA, plasma from 32 patients with juvenile idiopathic arthritis (JIA), and healthy adult and pediatric controls were included. Antibody reactivity was evaluated for correlations with clinical and laboratory variables of the patients. RESULTS: We replicated and expanded upon published data suggesting that patients with RA or JIA have autoantibodies against HERV-K Env, some with high titers. Anti-HERV-K antibodies correlated with cigarette smoking and with circulating myeloperoxidase-DNA complexes indicative of nonapoptotic neutrophil cell death. Further, most of the patients with RA, but not those with JIA, had autoantibodies that reacted more strongly with Env that was citrullinated by PAD4. These anticitrullinated Env autoantibodies correlated with seropositivity and tended to be higher in patients with erosive disease. CONCLUSION: Our data suggest that anti-HERV-K immunity is elevated in RA and JIA and may have a connection with pathogenic protein citrullination in RA.

Autoantibodies against citrullinated serum albumin in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, potentially debilitating, inflammatory disease that primarily affects synovial joints. While the etiology of RA remains incompletely understood, it is clear that the disease is autoimmune in nature. A hallmark of RA is that the specific epitopes on self-antigens that are targeted by the immune system are often modified by arginine deimination, also referred to as citrullination. In fact, anti-citrullinated protein autoantibodies (ACPA) at high enough titers are diagnostic of RA and appear to have many different targets. Here, we report that RA patients have IgG autoantibodies that react with human serum albumin (HSA) when it had been citrullinated by protein arginine deiminase (PAD) 4, but not by PAD2. Unmodified albumin was not recognized by autoantibodies. In a cohort of 79 RA patients, 38% had anti-citrullinated HSA (anti-cit-HSA) reactivity above the cut-off of the average plus two standard deviations in a healthy subject cohort (n = 16). The titers of these autoantibodies correlated with ACPA status and seropositivity. There was also a trend toward correlation with the presence of radiographic joint erosions, but this did not reach statistical significance. Finally, patients with anti-cit-HSA were more frequently treated with biologics and combination regimens than patients without these autoantibodies. We conclude that ACPA directed against citrullinated albumin exist in a subset of RA patients. Because of the abundance of albumin, its modification by citrullination, as well as autoantibodies binding to it, may have deleterious consequences for the health of affected RA patients.