Background/Purpose: Systemic rheumatic diseases are characterized by abnormal B cell activation with autoantibody production and hypergammaglobulinemia. The autoantigen Ro52/SSA, also denoted TRIM21, is a major autoantigen in Sjögren’s syndrome and systemic lupus erythematosus. Interestingly, Trim21-deficient mice develop systemic autoimmunity with B cell-related features such as autoantibodies, hypergammaglobulinemia and glomerulonephritis following tissue injury. The mechanisms by which Trim21 deficiency leads to enhanced B cell activation and antibody production are not well understood, and to further elucidate the role of Trim21 in systemic autoimmunity we investigated the B cell phenotype of Trim21^-/- mice.

Methods: Littermate C57BL/6J Trim21^+/+ and Trim21^-/- mice were immunized with antigens eliciting thymus-dependent or thymus-independent B cell responses: nitrophenol-coupled ovalbumin (NP-OVA), lipopolysaccharide (NP-LPS) and ficoll (NP-ficoll). Anti-NP-IgM and IgG antibody titers were measured by ELISA, and B cell subpopulations were assessed by flow cytometry. CD19⁺ splenic cells from naïve mice were sorted and stimulated with anti-IgM antibodies, and proliferation was estimated by H³-thymidine incorporation and Ki67 expression. CD19⁺CD21⁺CD23^high follicular B cells were isolated from naïve mice and subjected to RNA extraction and microarray analysis.

Results: Higher specific IgG and IgM antibody titers were detected in Trim21^-/- mice compared to wild-type littermates upon immunization with NP-OVA and NP-ficoll. Consistent with these observations, NP-OVA-immunized Trim21^-/- mice had higher frequencies of splenic follicular (CD19⁺CD21⁺CD23^high) cells and bone marrow plasma (CD19^–CD138⁺) cells. B cell receptor-specific stimulation of naïve splenic B cells in vitro resulted in significantly higher proliferation of Trim21^-/- cells. We also observed that splenic follicular B cells were more frequent already in naïve Trim21^-/- mice. Transcriptome analysis of these cells revealed differential regulation of genes associated with B cell differentiation, proliferation and metabolism.

Conclusion: Our findings reveal a link between the rheumatic autoantigen Ro52/Trim21 and increased antibody production associated with expansion of follicular B cells, suggesting a potential role for this autoantigen in the pathogenesis of systemic autoimmunity.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/ro52-trim21-influences-follicular-b-cell-homeostasis-and-immunoglobulin-production/