The Sjögren’s syndrome‐associated autoantigen Ro52/TRIM21 modulates follicular B cell homeostasis and immunoglobulin production

• Published in: Clinical and experimental immunology Vol. 194; no. 3; pp. 315 - 326
• Main Authors: Brauner, S., Ivanchenko, M., Thorlacius, G. E., Ambrosi, A., Wahren‐Herlenius, M.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-12-2018; John Wiley and Sons Inc
• Subjects: Activation; Antigens; Autoantibodies; Autoimmune diseases; B cell; B-cell receptor; CD40 antigen; Cell activation; Cell differentiation; Cell proliferation; Chronic conditions; Differentiation (biology); Gene regulation; Glomerulonephritis; Homeostasis; Immunization; immunoglobulin; Lymphocytes B; Medicin och hälsovetenskap; Mice; Original; Pathogenesis; Phenotypes; Rheumatic diseases; Ro52; Sjogren's syndrome; Sjögren’s syndrome; Spleen; Systemic lupus erythematosus; Thymus; TRIM21; B cell; Sjögren’s syndrome; immunoglobulin; Ro52; TRIM21
• ISSN: 0009-9104; 1365-2249; 1365-2249
• DOI: 10.1111/cei.13211

Summary
Systemic rheumatic diseases are characterized by abnormal B cell activation with autoantibody production and hypergammaglobulinaemia. Ro52/SSA, also denoted tripartite motif (TRIM)21, is a major autoantigen in Sjögren’s syndrome and systemic lupus erythematosus. Interestingly, TRIM21‐deficient mice develop systemic autoimmunity with B cell‐driven manifestations such as autoantibodies, hypergammaglobulinaemia and glomerulonephritis following tissue injury. The mechanisms by which TRIM21‐deficiency leads to enhanced B cell activation and antibody production are, however, not well understood, and to further elucidate the role of TRIM21 in systemic autoimmunity, we investigated the B cell phenotype and antibody responses of Trim21–/– mice following immunization with thymus‐dependent (TD) and thymus‐independent (TI) antigens. We found that TRIM21‐deficient mice developed significantly higher specific antibody titres than their wild‐type counterparts upon B cell receptor (BCR) engagement by TD and TI type II antigens, and this was accompanied by an altered B cell phenotype. Furthermore, BCR cross‐linking, but not anti‐CD40 stimulation, in vitro resulted in a significantly higher proliferation of Trim21–/– cells. We also observed that splenic follicular B cells were expanded not only in immunized mice but also already in young, unmanipulated Trim21–/– mice, and transcriptomic analysis of these cells revealed an up‐regulation of genes associated with B cell differentiation, indicating a role for TRIM21 in their regulation. In conclusion, in this study we describe a link between the rheumatic autoantigen Ro52/TRIM21 and increased antibody production associated with follicular B cell expansion, implicating a potential role for Ro52/TRIM21 in the pathogenesis of systemic autoimmune diseases.
“The rheumatic autoantigen Ro52/TRIM21 regulates B cell homeostasis in a B cell receptor‐dependent manner. Loss of TRIM21 results in increased B cell proliferation, antibody production, and follicular B cell differentiation. The role of TRIM21 in B cells offers a link between autoantigen and disease.”