Role of Tumor Necrosis Factor Superfamily in Neuroinflammation and Autoimmunity.

Sandip Sonar

doi:10.3389/fimmu.2015.00364

Abstract

Tumor necrosis factor superfamily (TNFSF) molecules play an important role in the activation, proliferation, differentiation, and migration of immune cells into the central nervous system (CNS). Several TNF superfamily molecules are known to control alloimmunity, autoimmunity, and immunity. Development of transgenic and gene knockout animals, and monoclonal antibodies against TNFSF molecules have increased our understanding of individual receptor–ligand interactions, and their intracellular signaling during homeostasis and neuroinflammation. A strong clinical association has been observed between TNFSF members and CNS autoimmunity such as multiple sclerosis and also in its animal model experimental autoimmune encephalomyelitis. Therefore, they are promising targets for alternative therapeutic options to control autoimmunity. Although, TNFSF ligands are widely distributed and have diverse functions, we have restricted the discussions in this review to TNFSF receptor–ligand interactions and their role in the pathogenesis of neuroinflammation and CNS autoimmunity.

Highlights

CD4+ T cells are one of the key adaptive immune cells that play an important role in several autoimmune diseases like multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), inflammatory bowel disease (IBD), and collagen-induced arthritis (CIA)
About 19 Tumor necrosis factor superfamily (TNFSF) ligands have been identified, which include tumor necrosis factor (TNF)-α, TNF-β [ known as lymphotoxin alpha (LTα)], lymphotoxin-β (LT-β), CD27L, CD30L, CD40L, FasL, 4-1BBL, OX40L, TNF-related apoptosis-inducing ligand (TRAIL), LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes), receptor activator of NF-κB ligand (RANKL), TNF-related weak inducer of apoptosis (TWEAK), a proliferation-inducing ligand (APRIL), B-cell activating factor (BAFF), vascular endothelial cell-growth inhibitor (VEGI), ectodysplasin A (EDA-A1, EDAA2), and glucocorticoid-induced TNF receptor (TNFR) family-related gene ligand (GITRL) (Figure 1)
While expressions of TNFSF ligands are induced largely on professional antigen-presenting cells (APCs; dendritic cells, B cells, macrophages), their expression is reported on T cells, NK cells, mast cells, eosinophils, basophils, endothelial cells, thymic epithelial cells, and smooth muscle cells [5]

Summary

Frontiers in Immunology

Tumor necrosis factor superfamily (TNFSF) molecules play an important role in the activation, proliferation, differentiation, and migration of immune cells into the central nervous system (CNS). Several TNF superfamily molecules are known to control alloimmunity, autoimmunity, and immunity. A strong clinical association has been observed between TNFSF members and CNS autoimmunity such as multiple sclerosis and in its animal model experimental autoimmune encephalomyelitis. They are promising targets for alternative therapeutic options to control autoimmunity. TNFSF ligands are widely distributed and have diverse functions, we have restricted the discussions in this review to TNFSF receptor–ligand interactions and their role in the pathogenesis of neuroinflammation and CNS autoimmunity

Introduction

GITRL TRAIL

Effect on neuroinflammation in EAE or MS

Mild EAE Mild EAE

Future Perspective