Background/Purpose: TRIM21 is a member of the tripartite motif family proteins and is one of the autoantigens which react with anti-SS-A antibody (Ab) present in sera of patients with systemic lupus erythematosus (SLE) and Sjögren’s syndrome. Although TRIM21 has been thought to play a role in B-cell proliferation and apoptosis, the role of TRIM21 in SLE pathogenesis is still unknown. Previous studies have shown the data strongly suggesting that TRIM21 can act as a suppressor for autoimmune and inflammatory response and that its dysfunction can cause the pathological state of SLE. Here we examined the pathological role of TRIM21 in SLE using Trim21-deficient lupus model mice and B cells from SLE patients.

Methods: Trim21-deficient MRL/lpr mice were generated by backcrossing Trim21-deficient C57BL/6 mice to MRL/lpr mice. Urine albumin/creatinine ratio was measured as the urine protein level. Anti-dsDNA and anti-TRIM21 Abs were measured by enzyme-linked immunosorbent assay. CD43-negative resting B cells were isolated from mouse spleens or peripheral blood of SLE patients by magnetic-activated cell sorting and stimulated with several Toll-like receptor (TLR) ligands. The abilities to differentiate into plasmablasts and to product Ab were examined by flow cytometry and bead-based immunoassay, respectively.

Results: The levels of urine protein and serum anti-dsDNA Ab at 28 weeks of age were significantly higher in Trim21-deficient MRL/lpr mice as compared to wild-type MRL/lpr mice (p = 0.029 and 0.003, respectively). When we stimulated resting B cells from these mice with TLR ligands for 24 hours, B cells from Trim21-deficient MRL/lpr mice showed significantly higher abilities to differentiate into plasmablasts (Figure 1) and to produce Ab (Figure 2) as compared to wild-type MRL/lpr mice. Due to the reduction of TRIM21-mediated ubiquitylation, IRF5 protein expression was increased in Trim21-deficient MRL/lpr mice (p = 0.021), which correlated with increased plasmablasts generation. B cells from SLE patients with anti-TRIM21 Ab seropositivity also indicated significantly higher ability to differentiate into plasmablasts and to produce Ab as compared with SLE patients without anti-TRIM21 Ab seropositivity or healthy controls (Figure 3).

Conclusion: TRIM21 dysfunction promotes aberrant B-cell differentiation and Ab production in SLE. Anti- TRIM21 Ab may be related to the TRIM21 dysfunction in human SLE pathogenesis. These findings suggest that TRIM21 and anti-TRIM21 Ab can be promising targets for SLE treatment.

Figure 1

Figure 2

Figure 3

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dysfunction-of-trim21-promotes-aberrant-plasmablast-differentiation-in-systemic-lupus-erythematosus-due-to-the-reduction-of-trim21-mediated-ubiquitylation-of-irf5/