Fn14-Fc suppresses germinal center formation and pathogenic B cells in a lupus mouse model via inhibition of the TWEAK/Fn14 Pathway.

Hong-Ki Min,Sung-Min Kim,Jennifer Lee,Sung-Hwan Park,Jae-Kyeong Byun,Jin-Sil Park,Seung-Ki Kwok,Young-Woo Park,Mi-La Cho

doi:10.1186/s12967-016-0846-4

Abstract

BackgroundSystemic 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.MethodsTo 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).ResultsAdministration 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.ConclusionFn14-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.

Highlights

Systemic lupus erythematosus (SLE) is an autoimmune-mediated chronic inflammatory disease
In the TNF-like weak inducer of apoptosis (TWEAK)-administrated group, expression levels of B cell maturation and differentiation-associated genes, including activation-induced deaminase (AID), B lymphocyte-induced maturation protein-1 (Blimp-1), and interferon regulatory factor-4 (IRF4) were significantly higher than in the control group (Fig. 1a). These results showed that TWEAK promoted B cell differentiation in SLE mouse models and that TWEAK could play an important role in aberrant humoral immunity in SLE
The results of this study showed that blocking the TWEAK/factor-inducible 14 (Fn14) pathway using Fn14-Fc showed therapeutic effects in a SLE mouse model

Summary

Introduction

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. Aberrant immune reactions in SLE are mediated by autoantibodies (autoAbs), immune complexes and autoreactive inflammatory cells, which result in organ damage. Autoantibodies and immune complexes play a crucial role in tissue damage and inflammatory responses in SLE. In the GC, follicular helper T (Tfh) cells play an important role in B cell selection and differentiation toward plasma cells [3]. In SLE patients, dysregulation of Tfh in the GC plays a crucial role in the expansion of self-reactive B cells and the production of autoAbs [4].

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