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

Abstract

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.

TRIM21 Dysfunction Enhances Aberrant B-Cell Differentiation in Autoimmune Pathogenesis

“…During the preparation of this paper, Brauner et al have reported that follicular B cells and Ab production were significantly increased by immunization of Trim21-deficient C57BL/6 mice with ovalbumin (65). Although the paper does not show an effect of TRIM21 deficiency on phenotype in disease model and the mechanism of B cell increase has not been investigated, their data are well-consistent with our results.…”

Proteomic and histopathological characterisation of sicca subjects and primary Sjögren’s syndrome patients reveals promising tear, saliva and extracellular vesicle disease biomarkers

“…Moreover, the three most upregulated proteins identified in tear fluid of pSS patients were similar, when compared to both non-SS subjects and healthy controls, namely LMO7, HUWE1 and TPD52 (Table 4, Additional file 1: Figure S1). Here, LMO7 and HUWE1 are both involved in the post-translational modification processes of ubiquitination [47, 48], similar to the SS autoantigen Ro52 [49], also known as E3 ubiquitin ligase. Meanwhile, TPD52 plays a central role in adaptive immunity by regulating B cell differentiation [50].…”

Clinical manifestations in anti-Ro52/SS-A antibody-seropositive patients with Sjögren's syndrome

“…The presence of anti-Ro/SS-A antibody is a critical item in the 2002 American-European Consensus Group (AECG) [4] classification criteria, the 2016 American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) classification criteria [5], and the 1999 revised Japanese Ministry of Health criteria [6] for primary SS. Anti-Ro/ SS-A antibody (anti-Ro) is not specific for SS [it is also detected in sera from patients with systemic lupus erythematosus (SLE)], and Ro/SS-A antigen has two distinct subtypes: Ro52 (which was identified as TRIM21) and Ro60 [7]. Robbins et al examined the frequency of anti-Ro52 and anti-Ro60 in SS and reported that 32.6% of anti-Ro52-positive patients were both anti-Ro60 and anti-Ro52 positive [8].…”