TRIM21 Dysfunction Enhances Aberrant B-Cell Differentiation in Autoimmune Pathogenesis

Frontiers in Immunology

Yumiko Sugiyama¹  Ryusuke Yoshimi²  Reikou Kamiyama²  Yohei Kirino²  Koji Yoshida²  Takaaki Komiya²  Yosuke Kunishita²  Natsuki Sakurai²  Hideaki Nakajima²  Daiga Kishimoto²  Eijin Hashimoto²  Keiko Ozato³ 

[1] Center for Rheumatic Diseases, Yokohama City University Medical Center, Yokohama, Japan;Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan;Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD, United States;

关键词: TRIM21;    systemic lupus erythematosus;    B cell;    immunoglobulin;    lupus model mouse;   

DOI  :  10.3389/fimmu.2020.00098

来源: DOAJ

【 摘 要 】

TRIM21 is one of the autoantigens that reacts with an anti-SS-A antibody (Ab) present in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome. TRIM21 is thought to play a role in B-cell proliferation and apoptosis, among other activities. Here we examined a pathological role of TRIM21 in SLE. Trim21-deficient MRL/lpr mice were generated by backcrossing Trim21-deficient C57BL/6 mice to MRL/lpr mice. The levels of serum anti-dsDNA Ab and urine protein 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). Resting B cells from Trim21-deficient mice showed significantly higher abilities to differentiate into plasmablasts and to produce Ab as compared with control 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 plasmablast generation and immunoglobulin production. B cells from SLE patients with anti-TRIM21 Ab seropositivity also showed a significantly higher ability to differentiate into plasmablasts as compared with those without anti-TRIM21 Ab or healthy controls. These results suggest that TRIM21 dysfunction contributes to SLE pathogenesis by promoting B-cell differentiation, for which anti-TRIM21 Ab may be partly responsible.

【 授权许可】

Unknown