Antibodies to native and citrullinated RA33 (hnRNP A2/B1) challenge citrullination as the inciting principle underlying loss of tolerance in rheumatoid arthritis

Abstract

These data suggest that native and citrullinated proteins targeted by autoantibodies in RA may be part of a single antibody system and challenge the paradigm of citrullination as the unifying principle underlying loss of tolerance in RA.

Antibody Responses to Citrullinated and Noncitrullinated Antigens in the Sputum of Subjects With Rheumatoid Arthritis and Subjects at Risk for Development of Rheumatoid Arthritis

“…This finding suggests that broad antibody reactivity to both non-cit and cit antigens occurs in the lung of these subjects, but that more cit specific reactivity is generated toward certain antigens and is more prevalent in subjects with RA. These findings support the hypothesis that early localized autoimmunity may be directed to native proteins, with evolution to cit epitopes occurring through epitope spreading(4–6, 45). However, it is also possible that tolerance is initially broken to cit proteins, and that the autoimmune responses to epitopes intramolecularly spreads to native epitopes on the same proteins.…”

“…In addition to anti-cit antibodies, antibodies to non-cit/native proteins have been identified in the serum of preclinical and early classified RA subjects(4–9). These data suggest that early autoimmunity may be to native proteins initially, with evolution to cit epitopes over time through epitope spreading.…”

Aggregatibacter actinomycetemcomitans –induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis

“…5C, lower panels). This may represent recognition of neutrophil antigens targeted as native (unmodified) proteins in RA (9). Given the time to complete neutrophil lysis, hypercitrullinated cellular proteins were released together with neutrophil chromatin, as detected by immunofluorescence staining and in micrococcal nuclease digests (Fig.…”

“… Anti-LtxA, anti-leukotoxin A antibodies; ACPA, anti-citrullinated protein antibodies, † any positivity by multiplex assay as previously defined (23); ACPA fine specificity was expressed as median fluorescence intensity (IQR) (63); antibodies against citrullinated RA33 (citRA33) were quantified by full-protein ELISA using citrullinated heterogeneous nuclear ribonucleoprotein B1b (hnRNP B1b) as previously described (9). …”

Immune checkpoint inhibitor–induced inflammatory arthritis as a model of autoimmune arthritis

“…Another well‐described target in RA is a nuclear antigen known as RA33. Initially defined by Western blot as a 33‐kDa protein in nuclear extracts from HeLa cells that was recognized by sera from RA patients, RA33 was later identified as hnRNP A2/B1, a protein of the spliceosome that can be targeted by autoantibodies in its citrullinated or non‐citrullinated form …”