title: TNFα in the regulation of Treg and Th17 cells in rheumatoid arthritis and other autoimmune inflammatory diseases.
abstract: TNFα is a principal pro-inflammatory cytokine vital for immunity to infections. However, its excessive production is involved in chronic inflammation and disease pathology in autoimmune diseases. Evidence for its pathogenic role is validated by the fact that its neutralisation by therapeutic agents in vivo is beneficial in ameliorating disease and controlling symptoms. Paradoxically, however, treatment with TNFα inhibitors can either have no clinical effects, or even exacerbate disease in some patients. The explanation for such contradictory outcomes may lay in how and which downstream signalling pathways are activated and drive disease. TNFα causes its effects by binding to either or both of two membrane-bound receptors, TNFR1 and TNFR2. Engagement of the receptors can induce cell death or cell proliferation. T cells both produce and respond to TNFα and depending on whether the cytokine is membrane-bound or soluble and the level of expression of its two receptors, the biological outcome can be distinct. In addition, polymorphisms in genes encoding TNFα and T cell signalling proteins can significantly impact the outcome of TNFα receptor engagement. Early studies revealed that effector T cells in patients with rheumatoid arthritis (RA) are hyporesponsive due to chronic exposure to TNFα. However, recent evidence indicates that the relationship between TNFα and T cell responses is complex and, at times, can be paradoxical. In addition, there is controversy as to the specific effects of TNFα on different T cell subsets. This review will summarise knowledge on how TNFα modulates T cell responses and the effect of engaging either of its two receptors. Furthermore, we discuss how such interactions can dictate the outcome of treatment with TNFα inhibitors.
authors.affiliation: Experimental Medicine and Rheumtology, William Harvey Research Institute, Queen Mary University of London, London, UK. Electronic address: j.bystrom@qmul.ac.uk.
authors.forename: Jonas
authors.initials: J
authors.lastname: Bystrom
authors.affiliation: Kennedy Institute of Rheumatology, Oxford University, Oxford, UK.
authors.forename: F I
authors.initials: FI
authors.lastname: Clanchy
authors.affiliation: Experimental Medicine and Rheumtology, William Harvey Research Institute, Queen Mary University of London, London, UK.
authors.forename: Taher E
authors.initials: TE
authors.lastname: Taher
authors.affiliation: Department of Rheumatology, Royal Free Hospital, NHS Foundation Trust, London, UK.
authors.forename: Pam
authors.initials: P
authors.lastname: Mangat
authors.affiliation: Experimental Medicine and Rheumtology, William Harvey Research Institute, Queen Mary University of London, London, UK.
authors.forename: Ali S
authors.initials: AS
authors.lastname: Jawad
authors.affiliation: Kennedy Institute of Rheumatology, Oxford University, Oxford, UK.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Williams
authors.affiliation: Experimental Medicine and Rheumtology, William Harvey Research Institute, Queen Mary University of London, London, UK.
authors.forename: Rizgar A
authors.initials: RA
authors.lastname: Mageed
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D011110:Polymorphism, Genetic; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology
chemical_list: D018501:Antirheumatic Agents; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha
keywords: Anti-TNF; Interleukin-17; Regulatory T cells; TNFα; Th17 cells