Background/Purpose: Rheumatoid arthritis is an autoimmune, destructive arthritis characterized by anti-citrullinated protein antibodies (ACPAs) and high levels of inflammatory cytokines like tumor necrosis factor alpha (TNFalpha). Citrullinated proteins may be a trigger for the development of rheumatoid arthritis since ACPA immune complexes can stimulate TNFalpha production, which promotes inflammation and arthritis. Inflammation appears to induce protein citrullination, but it is not known if TNFalpha can lead to citrullination with resultant ACPAs. We hypothesized that TNFalpha could augment ACPA production with a role for the citrullinating enzyme peptidyl arginine deiminase 4 (PAD4) as part of a feedback loop to accelerate arthritis development.

Methods: We measured ACPA levels by multiplex array in mice with chronic inflammatory arthritis due to overexpression of TNFalpha. We then crossed mice that overexpress TNFalpha with mice that lack PAD4. We compared ACPA levels by multiplex array, lymphocyte activation by flow cytometry, arthritis by clinical score, and systemic inflammation using microfluidics devices in TNF+PAD4+/+ versus TNF+PAD4-/- mice.

Results: Mice that overexpress TNFalpha have increased serum ACPAs, suggesting that high levels of TNFalpha, as is seen in human rheumatoid arthritis, can amplify ACPA production. Further, mice with TNFalpha induced arthritis that lack PAD4 have decreased ACPAs, reduced T cell activation, and less inflammation and arthritis, suggesting that PAD4 makes key contributions to TNFalpha driven, chronic inflammatory arthritis.

Conclusion: These data support a positive feedback loop in which ACPAs, TNFalpha, and PAD4 synergize to enhance inflammation and the development of rheumatoid arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tumor-necrosis-factor-alpha-induces-anti-citrullinated-protein-antibodies-and-arthritis-in-part-through-peptidyl-arginine-deiminase-4/