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- Title
Fn14-Fc suppresses germinal center formation and pathogenic B cells in a lupus mouse model via inhibition of the TWEAK/Fn14 Pathway.
- Authors
Hong-Ki Min; Sung-Min Kim; Jin-Sil Park; Jae-Kyeong Byun; Jennifer Lee; Seung-Ki Kwok; Young-Woo Park; Mi-La Cho; Sung-Hwan Park; Min, Hong-Ki; Kim, Sung-Min; Park, Jin-Sil; Byun, Jae-Kyeong; Lee, Jennifer; Kwok, Seung-Ki; Park, Young-Woo; Cho, Mi-La; Park, Sung-Hwan
- Abstract
<bold>Background: </bold>Systemic lupus erythematosus (SLE) is an autoimmune-mediated chronic inflammatory disease. Half of patients with SLE suffer from lupus nephritis, which is major cause of death in SLE. TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) interactions mediate inflammatory responses that are linked to the pathogenesis of lupus nephritis. Blocking of the TWEAK/Fn14 pathway by Fn14-Fc was performed in a SLE mouse model and the likely therapeutic mechanisms were investigated.<bold>Methods: </bold>To investigate the impact of TWEAK on B cell differentiation in SLE, the levels of AID, Blimp-1, and IRF4 messenger RNA were measured in CD19(+) B cells extracted from the spleens of sanroque mice and cultured with TWEAK. To identify the therapeutic effects of Fn14-Fc in SLE, sanroque mice were treated with Fn14-Fc or a control-Fc for 3 weeks. Immunoglobulin (Ig) G, IgG1, IgG2a, and anti-dsDNA antibody (Ab) levels were measured in the sera of each group. Spleens from each group were stained with antibodies against CD4, B220, GL-7, CD138, and PD-1. Kidneys were stained with hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS).<bold>Results: </bold>Administration of TWEAK increased the mRNA levels of AID, Blimp-1, and IRF4. Treatment with Fn14-Fc suppressed levels of IgG, IgG1, IgG2a, and anti-dsDNA Ab in sera and reduced numbers of B, plasma, and follicular helper T (Tfh) cells in spleens of sanroque mice. In addition, renal protective effects of Fn14-Fc were shown.<bold>Conclusion: </bold>Fn14-Fc had beneficial effects in a SLE mouse model by repressing B cells, plasma cells, Tfh, and renal damage. This suggested that Fn14-Fc represents a potential therapeutic agent for SLE.
- Subjects
GERMINAL centers; LYMPHOID tissue; B cells; SYSTEMIC lupus erythematosus; MESSENGER RNA; ANIMAL experimentation; BIOLOGICAL models; CELL differentiation; CELL receptors; CELLULAR signal transduction; IMMUNOGLOBULINS; MICE; T cells; TUMOR necrosis factors
- Publication
Journal of Translational Medicine, 2016, Vol 14, p1
- ISSN
1479-5876
- Publication type
journal article
- DOI
10.1186/s12967-016-0846-4