Context-dependent induction of autoimmunity by TNF signaling deficiency.

Tam D Quach,Martin L Lesser,Roshawn Johnson,Anne Davidson,Chirag Raparia,Chaim O Jacob,Catherine M.M Diadhiou,Çagla Tükel,Tung Ming Leung,Peta Gay Ricketts,Stefania Gallucci,Weiqing Huang,Susan Malkiel,Yong-Rui Zou,Ranjit Sahu

doi:10.1172/jci.insight.149094

Abstract

TNF inhibitors are widely used to treat inflammatory diseases; however, 30%–50% of treated patients develop new autoantibodies, and 0.5%–1% develop secondary autoimmune diseases, including lupus. TNF is required for formation of germinal centers (GCs), the site where high-affinity autoantibodies are often made. We found that TNF deficiency in Sle1 mice induced TH17 T cells and enhanced the production of germline encoded, T-dependent IgG anti-cardiolipin antibodies but did not induce GC formation or precipitate clinical disease. We then asked whether a second hit could restore GC formation or induce pathogenic autoimmunity in TNF-deficient mice. By using a range of immune stimuli, we found that somatically mutated autoantibodies and clinical disease can arise in the setting of TNF deficiency via extrafollicular pathways or via atypical GC-like pathways. This breach of tolerance may be due to defects in regulatory signals that modulate the negative selection of pathogenic autoreactive B cells.

Highlights

Tumor necrosis factor (TNF) is a potent inflammatory cytokine with pleiotropic effects on both cell survival and death
Sle1, and Sle1.TNFR2-/- mice formed spontaneous germinal centers by 6 months of age but these were absent in Sle1.TNF-/, TNFR1-/- and TNFR1&2 double deficient mice (Figures 1B-H), with no differences between males and females
By using bone marrow chimeras in which bone marrow cells from Sle1 mice were transplanted into lethally irradiated Sle1.TNFR1-/- mice, we showed that contrary to what has previously been reported, these CD21/35+ cells are CD45+ B cells and not stromal

Summary

INTRODUCTION

Tumor necrosis factor (TNF) is a potent inflammatory cytokine with pleiotropic effects on both cell survival and death. TNF inhibition affects B cell homeostasis and selection via disorganization of the B cell follicle and disruption of the follicular dendritic cell (FDC) network [30, 31] This is due to the absence of the interaction of TNFR1 on the FDCs with soluble TNF provided by B cells [30, 32, 33] and is associated with decreased expression of CXCL13 that compromises the recruitment of CXCR5 expressing B cells and TFH cells to GCs. Loss of germinal centers occurs in both mice and human treated with TNF inhibitors [33, 34].

RESULTS

DISCUSSION

FIGURES AND LEGENDS