AUTHOR=Kunishita Yosuke , Yoshimi Ryusuke , Kamiyama Reikou , Kishimoto Daiga , Yoshida Koji , Hashimoto Eijin , Komiya Takaaki , Sakurai Natsuki , Sugiyama Yumiko , Kirino Yohei , Ozato Keiko , Nakajima Hideaki 

TITLE=TRIM21 Dysfunction Enhances Aberrant B-Cell Differentiation in Autoimmune Pathogenesis

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00098

DOI=10.3389/fimmu.2020.00098

ISSN=1664-3224

ABSTRACT=<p>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. <italic>Trim21</italic>-deficient MRL/<italic>lpr</italic> mice were generated by backcrossing <italic>Trim21</italic>-deficient C57BL/6 mice to MRL/<italic>lpr</italic> mice. The levels of serum anti-dsDNA Ab and urine protein at 28 weeks of age were significantly higher in <italic>Trim21</italic>-deficient MRL/<italic>lpr</italic> mice as compared to wild-type MRL/<italic>lpr</italic> mice (<italic>p</italic> = 0.029 and 0.003, respectively). Resting B cells from <italic>Trim21</italic>-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 <italic>Trim21</italic>-deficient MRL/<italic>lpr</italic> mice (<italic>p</italic> = 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.</p>