TRIM21 Dysfunction Enhances Aberrant B-Cell Differentiation in Autoimmune Pathogenesis

Front Immunol. 2020 Feb 7;11:98. doi: 10.3389/fimmu.2020.00098. eCollection 2020.

Abstract

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.

Keywords: B cell; TRIM21; immunoglobulin; lupus model mouse; systemic lupus erythematosus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Autoantibodies / immunology
  • Autoantigens / immunology*
  • Autoimmunity / immunology*
  • B-Lymphocytes / immunology*
  • Cell Differentiation / immunology*
  • Female
  • Humans
  • Lupus Erythematosus, Systemic / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Mice, Knockout
  • Ribonucleoproteins / immunology*

Substances

  • Autoantibodies
  • Autoantigens
  • Ribonucleoproteins
  • SS-A antigen