Autoreactive B cells against malondialdehyde-induced protein cross-links are present in the joint, lung, and bone marrow of rheumatoid arthritis patients

• Published in: The Journal of biological chemistry 2023-11, Vol.299 (11), p.105320-105320, Article 105320
• Main Authors: Sahlström, Peter, Joshua, Vijay, Valkovskaia, Viktoriia, Biese, Charlotte, Stålesen, Ragnhild, Israelsson, Lena, Végvári, Ákos, Scheel-Toellner, Dagmar, Klareskog, Lars, Hansson, Monika, Hensvold, Aase, Malmström, Vivianne, Grönwall, Caroline
• Format: Article
• Language: English
• Subjects: Acetaldehyde - metabolism; anti-modified protein autoantibodies (AMPA); Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - pathology; Autoantibodies; Autoimmunity; autoreactive B cells; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Bone Marrow - metabolism; Humans; Immunoglobulin G - metabolism; Lung - metabolism; Lysine - metabolism; Malondialdehyde - metabolism; malondialdehyde acetaldehyde (MAA); post-translational modifications; protein cross-linking; rheumatoid arthritis (RA)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2023.105320

Autoantibodies to malondialdehyde (MDA) proteins constitute a subset of antimodified protein autoantibodies in rheumatoid arthritis (RA), which is distinct from citrulline reactivity. Serum anti-MDA immunoglobulin (Ig) G levels are commonly elevated in RA and correlate with DAS28, CRP, IL6, and TNF-α. MDA is an oxidation-associated reactive aldehyde that together with acetaldehyde mediates formation of various immunogenic amino acid adducts including linear MDA-lysine, fluorescent malondialdehyde acetaldehyde (MAA)-lysine, and intramolecular cross-linking. We used single-cell cloning, generation of recombinant antibodies (n = 356 from 25 donors), and antigen-screening to investigate and compare the presence of class-switched MDA/MAA+ B cells in RA synovium, bone marrow, and bronchoalveolar lavage. Anti-MDA/MAA+ B cells were found in bone marrow plasma cells of late disease and in the lung of both early disease and risk-individuals and in different B cell subsets (memory, double negative B cells). These could be compared with previously identified anti-MDA/MAA from synovial memory and plasma cells. Seven out of the eight clones carried somatic hypermutations and all bound MDA/MAA-lysine independently of protein backbone. However, clones with somatic hypermutations targeted MAA cross-linked structures rather than MDA- or MAA-hapten, while the germline-encoded synovial clone instead bound linear MDA-lysine in proteins and peptides. Binding patterns were maintained in germline converted clones. Affinity purification of polyclonal anti-MDA/MAA from patient serum revealed higher proportion of anti-MAA versus anti-MDA compared to healthy controls. In conclusion, IgG anti-MDA/MAA show distinct targeting of different molecular structures. Anti-MAA IgG has been shown to promote bone loss and osteoclastogenesis in vivo and may contribute to RA pathogenesis.