T cell proliferative response to a homocitrullinated peptide correlates with joint pathology in collagen induced...

Rheumatoid arthritis (RA) is characterized by autoimmune responses against citrullinated and homocitrullinated proteins/peptides (CitP and HomoCitP respectively), resulting in joint pain, inflammation, and damage. Although the collagen induced arthritis (CIA) model shares pathological features with RA, it remains unclear whether this model is suitable for studying RA-specific immune responses. Therefore, we investigated whether immune responses to CitP and HomoCitP influence arthritis severity in CIA. Male DBA/1J mice were immunized with bovine type II collagen (CII) (N = 58) or PBS (N = 14) in adjuvant. Arthritis was assessed by clinical arthritis score, caliper measurements of joint swelling, von Frey pain testing, micro-CT, histopathology, and immunofluorescence. Splenocyte proliferation was measured using flow cytometry and serum antibodies via ELISAs. Although anti-bovine and anti-mouse CII IgG developed in all bovine CII-immunized mice, only 31 % developed clinical arthritis. Arthritis closely resembled RA pathology, including joint pain, reduced bone mineral density, and histopathological damage. Immunofluorescence showed higher CitP and HomoCitP in joints from arthritic vs. PBS-injected mice. At day 49 post primary immunization, HomoCitP, but not CitP, stimulation induced higher proliferation in splenic T cells from arthritic mice compared to controls and strongly correlated with joint swelling, pain, and histopathology, as well as with serum anti-CII IgG. Anti-HomoCitP IgG were rare, and anti-CitP IgG were undetected, in arthritic mice. This study identifies RA-specific antigens and immune responses to HomoCitP as potentially relevant in CIA. These results support the use of CIA to study RA-specific immunopathogenic mechanisms and highlight HomoCitP-specific T cells as potential contributors to disease.