Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a Disease-Specific CD8+T Lymphocyte Signature

Rheumatoid arthritis (RA) is a complex autoimmune disease targeting synovial joints. Traditionally, RA is divided into seropositive (SP) and seronegative (SN) disease forms, the latter consisting of an array of unrelated diseases with joint involvement. Recently, we described a severe form of SN-RA that associates with characteristic joint destruction. Here, we sought biological characteristics to differentiate this rare but aggressive anti-citrullinated peptide antibody-negative destructive RA (CND-RA) from early seropositive (SP-RA) and seronegative rheumatoid arthritis (SN-RA). We also aimed to study cytotoxic CD8+ lymphocytes in autoimmune arthritis. CND-RA, SP-RA and SN-RA were compared to healthy controls to reveal differences in T-cell receptor beta (TCR beta) repertoire, cytokine levels and autoantibody repertoires. Whole-exome sequencing (WES) followed by single-cell RNA-sequencing (sc-RNA-seq) was performed to study somatic mutations in a clonally expanded CD8+ lymphocyte population in an index patient. A unique TCR beta signature was detected in CND-RA patients. In addition, CND-RA patients expressed higher levels of the bone destruction-associated TNFSF14 cytokine. Blood IgG repertoire from CND-RA patients recognized fewer endogenous proteins than SP-RA patients repertoires. Using WES, we detected a stable mutation profile in the clonally expanded CD8+ T-cell population characterized by cytotoxic gene expression signature discovered by sc-RNA-sequencing. Our results identify CND-RA as an independent RA subset and reveal a CND-RA specific TCR signature in the CD8+ lymphocytes. Improved classification of seronegative RA patients underlines the heterogeneity of RA and also, facilitates development of improved therapeutic options for the treatment resistant patients.
Funding Agencies|European Research CouncilEuropean Research Council (ERC) [M-IMM 647355, STRATIFY 862011, DynaOmics 677943]; Academy of Finland Heal-Art consortium [314442]; ERA PerMed (JAKSTAT-TARGET consortium); Finnish Medical foundation; Instrumentarium Science foundation; Biomedicum Helsinki foundation; Orion research foundation; Juhani Aho foundation; K. Albin Johansson foundation; Paulo foundation; Region Ostergotland (ALF grants); European UnionEuropean Union (EU) [675395]; Tekes the Finnish Funding Agency for InnovationFinnish Funding Agency for Technology & Innovation (TEKES) [1877/31/2016]; Sigrid Juselius FoundationSigrid Juselius Foundation; Finska Lakaresallskapet; Liv ochHalsa Foundation; Maire Lisko foundation