title: A clinical conundrum: the detrimental effect of TNF antagonists in multiple sclerosis.
abstract: Although TNF antagonists are efficacious in treating a range of autoimmune conditions, they exacerbate or even promote multiple sclerosis (MS)--a clinical finding that has been a conundrum for over a decade and has been a source of debate regarding the role of these drugs and of TNF signaling in the development of demyelinating disease. Recent work investigating the functional consequences of MS-associated genetic variation in the gene encoding TNFR1 has demonstrated that genetic risk drives the production of a novel, endogenous TNF antagonist. This mirrors the clinical experience with the drugs and indicates that the net effect of TNF function in MS development is a protective one, warranting a re-evaluation of the studies that have contributed to our understanding of TNF signaling in inflammation, immunoregulation and neuroprotection, to determine how future research can be directed towards targeting this pathway for therapeutic benefit.
authors.affiliation: Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, UK.
authors.forename: Calliope A
authors.initials: CA
authors.lastname: Dendrou
authors.forename: John I
authors.initials: JI
authors.lastname: Bell
authors.forename: Lars
authors.initials: L
authors.lastname: Fugger
mesh_terms: D055106:Genome-Wide Association Study; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D058990:Molecular Targeted Therapy; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha