The human bone marrow plasma cell compartment in rheumatoid arthritis - Clonal relationships and anti-citrulline autoantibody producing cells. Issue 136 (April 2023)

• Record Type: Journal Article
• Authors: Hensvold, Aase; Horuluoglu, Begum; Sahlström, Peter; Thyagarajan, Radha; Diaz Boada, Juan Sebastian; Hansson, Monika; Mathsson-Alm, Linda; Gerstner, Christina; Sippl, Natalie; Israelsson, Lena; Wedin, Rikard; Steen, Johanna; Klareskog, Lars; Réthi, Bence; Catrina, Anca I.; Diaz-Gallo, Lina-Marcela; Malmström, Vivianne; Grönwall, Caroline
• Is Part Of: Journal of autoimmunity. Issue 136(2023)
• Publication Date: 2023-04
• Subjects: Bone marrow -- Plasma cells -- Rheumatoid arthritis -- Antibody repertoires -- Anti-Citrullinated protein autoantibodies (ACPA) -- Anti-CCP -- Receptor revision -- Clonal convergence -- Ig repertoire; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2023.103022
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: A majority of circulating IgG is produced by plasma cells residing in the bone marrow (BM). Long-lived BM plasma cells constitute our humoral immune memory and are essential for infection-specific immunity. They may also provide a reservoir of potentially pathogenic autoantibodies, including rheumatoid arthritis (RA)-associated anti-citrullinated protein autoantibodies (ACPA). Here we investigated paired human BM plasma cell and peripheral blood (PB) B-cell repertoires in seropositive RA, four ACPA+ RA patients and one ACPA− using two different single-cell approaches, flow cytometry sorting, and transcriptomics, followed by recombinant antibody generation. Immunoglobulin (Ig) analysis of >900 paired heavy-light chains from BM plasma cells identified by either surface CD138 expression or transcriptome profiles (including gene expression of MZB1, JCHAIN and XBP1 ) demonstrated differences in IgG/A repertoires and N-linked glycosylation between patients. For three patients, we identified clonotypes shared between BM plasma cells and PB memory B cells. Notably, four individuals displayed plasma cells with identical heavy chains but different light chains, which may indicate receptor revision or clonal convergence. ACPA-producing BM plasma cells were identified in two ACPA+ patients. Three of 44 recombinantly expressed monoclonal antibodies from ACPA+ RA BM plasma cells were CCP2+, specifically binding to citrullinated peptides. Out of these, two clones reacted with citrullinated histone-4 and activated neutrophils. In conclusion, single-cell investigation of B-cell repertoires in RA bone marrow provided new understanding of human plasma cells clonal relationships and demonstrated pathogenically relevant disease-associated autoantibody expression in long-lived plasma cells. Highlights: Paired heavy-light chain repertoires reveal plasma cell clonal relationships. Shared blood memory and bone marrow plasma cell clonotypes were identified. N-linked glycosylation sites were common in the RA IgG + plasma cells. RA patients demonstrated differences in plasma cell IgA/IgG ratio and IgG4 usage. Different single-cell methods identified RA ACPA-producing bone marrow plasma cells.