The role of IgM anti-acetylated protein antibodies and B cells in the origin of anti-modified protein autoimmunity in rheumatoid arthritis.

Abstract

Rheumatoid arthritis (RA) is characterized by anti-modified protein antibodies (AMPAs), including anti-citrullinated (ACPA), anti-carbamylated (anti-CarP), and anti-acetylated (AAPA) protein antibodies. In contrast to other AMPAs, AAPA IgM is found in healthy individuals, raising questions about its role in early immune responses. We investigated whether AAPA IgM serves as a precursor for other AMPAs, marking the initial breach of tolerance in RA. AAPA IgM levels were measured in cord blood and serum of children up to three years old to assess whether it represents a natural (auto)antibody. To evaluate whether AAPA IgM presence precedes other AMPAs, we longitudinally measured AAPA and ACPA IgM in individuals before RA onset. To assess whether AAPA IgM-expressing B cells display a naïve phenotype and carry germline-encoded BCRs, single cells were sorted and sequenced. AAPA IgM was not detected in early life, but before RA onset significantly more individuals were AAPA IgM-positive (27.3%) compared to ACPA IgM-positive (11.7%). Towards disease onset, ACPA IgM positivity increased to 51.2%, while AAPA IgM positivity remained stable. Furthermore, AMPAs developed in individuals who were AAPA IgM-negative. Regarding B cell characteristics, germline-encoded BCRs were identified among both AAPA- and ACPA-expressing B cells in RA patients. AMPA responses in RA do not appear to arise solely from AAPA IgM, as suggested by the lack of association between pre-disease AMPA IgM positivity and later AMPA evolution. This is further supported by the presence of germline-configured ACPA BCRs, suggesting multiple possible starting points for AMPA responses.