TNF superfamily is one of oldest family of molecules and earliest to be successfully targeted for immunotherapy. This family of molecules is large with more than 18 receptor/ligand pairs. The most prominent members of the Family are TNF?, the prototypical proinflammatory cytokine and Fas ligand (FasL), the prototypical death-inducing ligand. In addition, it includes CD40L, April and BAFF, which are prominent regulators of B cells, including control of immunoglobulin class switching and homeostasis. On the other hand, light and lymphotoxin regulate lymphogenesis. Besides these physiological functions, preclinical studies have identified both protective and pathogenic roles for the members of this family against organ- and systemic autoimmune diseases and cancers. These findings have been applied in the clinic. In fact, TNF? inhibitors are among the earliest blockbuster drugs for the treatment of a variety of chronic inflammatory diseases. However, therapeutic potential of promising preclinical findings are yet to be translated to humans. Based on studies in animal models of multiple sclerosis and type 1 diabetes and other organ specific autoimmune diseases, the Fas pathway seems particularly ripen for translational application. A major obstacle is the absence of mechanistic understanding why blocking e.g. FasL or Fas prevents these disease. The biology of the Fas pathway is perplexing. Despite clear understanding of structures and apoptotic cascade induced by Fas/FasL interactions, the phenotypic changes caused by loss-of-function mutations of Fas (lpr) and FasL (gld) are poorly understood. It is also paradoxical that inactivation of the Fas pathway prevents autoimmune diabetes, multiple sclerosis, silicosis, while at the same time causes lymphoproliferation in both mice and humans (autoimmune lymphoproliferation). Why the lymphoproliferation caused by inactivation of the Fas pathway, unlike that caused by mutations in Foxp3, CTLA-4, Bcl2, is predominated by double negative (DN) apha/beta T cells whose origin is still a mystery. In cancer, earlier studies implicates FasL expression in immune privilege, whereas recent studies implicate FasL in protection from tumors by removal of Treg cells. Articles pertinent to this research topic are expected to contribute to better understanding of the biological functions of members of TNF superfamily and to clarify when they serve as friends and when they snap as foes and potential therapeutic targets.
TNF superfamily is one of oldest family of molecules and earliest to be successfully targeted for immunotherapy. This family of molecules is large with more than 18 receptor/ligand pairs. The most prominent members of the Family are TNF?, the prototypical proinflammatory cytokine and Fas ligand (FasL), the prototypical death-inducing ligand. In addition, it includes CD40L, April and BAFF, which are prominent regulators of B cells, including control of immunoglobulin class switching and homeostasis. On the other hand, light and lymphotoxin regulate lymphogenesis. Besides these physiological functions, preclinical studies have identified both protective and pathogenic roles for the members of this family against organ- and systemic autoimmune diseases and cancers. These findings have been applied in the clinic. In fact, TNF? inhibitors are among the earliest blockbuster drugs for the treatment of a variety of chronic inflammatory diseases. However, therapeutic potential of promising preclinical findings are yet to be translated to humans. Based on studies in animal models of multiple sclerosis and type 1 diabetes and other organ specific autoimmune diseases, the Fas pathway seems particularly ripen for translational application. A major obstacle is the absence of mechanistic understanding why blocking e.g. FasL or Fas prevents these disease. The biology of the Fas pathway is perplexing. Despite clear understanding of structures and apoptotic cascade induced by Fas/FasL interactions, the phenotypic changes caused by loss-of-function mutations of Fas (lpr) and FasL (gld) are poorly understood. It is also paradoxical that inactivation of the Fas pathway prevents autoimmune diabetes, multiple sclerosis, silicosis, while at the same time causes lymphoproliferation in both mice and humans (autoimmune lymphoproliferation). Why the lymphoproliferation caused by inactivation of the Fas pathway, unlike that caused by mutations in Foxp3, CTLA-4, Bcl2, is predominated by double negative (DN) apha/beta T cells whose origin is still a mystery. In cancer, earlier studies implicates FasL expression in immune privilege, whereas recent studies implicate FasL in protection from tumors by removal of Treg cells. Articles pertinent to this research topic are expected to contribute to better understanding of the biological functions of members of TNF superfamily and to clarify when they serve as friends and when they snap as foes and potential therapeutic targets.
