title: Avenues to autoimmune arthritis triggered by diverse remote inflammatory challenges.
abstract: Environmental factors contribute to development of autoimmune diseases. For instance, human autoimmune arthritis can associate with intestinal inflammation, cigarette smoking, periodontal disease, and various infections. The cellular and, molecular pathways whereby such remote challenges might precipitate arthritis or flares remain unclear. Here, we used a transfer model of self-reactive arthritis-inducing CD4(+) cells from KRNtg mice that, upon transfer, induce a very mild form of autoinflammatory arthritis in recipient animals. This model enabled us to identify external factors that greatly aggravated disease. We show that several distinct challenges precipitated full-blown arthritis, including intestinal inflammation through DSS-induced colitis, and bronchial stress through Influenza infection. Both triggers induced strong IL-17 expression primarily in self-reactive CD4(+) cells in lymph nodes draining the site of inflammation. Moreover, treatment of mice with IL-1β greatly exacerbated arthritis, while transfer of KRNtg CD4(+) cells lacking IL-1R significantly reduced disease and IL-17 expression. Thus, IL-1β enhances the autoaggressive potential of self-reactive CD4(+) cells, through increased Th17 differentiation, and this influences inflammatory events in the joints. We propose that diverse challenges that cause remote inflammation (lung infection or colitis, etc.) result in IL-1β-driven Th17 differentiation, and this precipitates arthritis in genetically susceptible individuals. Thus the etiology of autoimmune inflammatory arthritis likely relates to diverse triggers that converge to a common pathway involving IL-1β production and Th17 cell distribution.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Medical Center, University of Freiburg, Germany, 79106 Freiburg, Germany; Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, 3800 VIC, Australia; Immunology Department, Garvan Institute of Medical Research, 2010 Sydney, Australia. Electronic address: nina.chevalier@uniklinik-freiburg.de.
authors.forename: Nina
authors.initials: N
authors.lastname: Chevalier
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, 3800 VIC, Australia.
authors.forename: Jian K
authors.initials: JK
authors.lastname: Tan
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, 3800 VIC, Australia.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Mason
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, 3800 VIC, Australia.
authors.forename: Remy
authors.initials: R
authors.lastname: Robert
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, 3800 VIC, Australia.
authors.forename: Craig I
authors.initials: CI
authors.lastname: McKenzie
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, 3800 VIC, Australia.
authors.forename: Florence
authors.initials: F
authors.lastname: Lim
authors.affiliation: Center for Inflammatory Disease, Monash University, 3800 Melbourne, Australia.
authors.forename: Connie H
authors.initials: CH
authors.lastname: Wong
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, 3800 VIC, Australia; School of Medical Sciences, The University of Sydney, 2006 Sydney, Australia; Department of Physiology, School of Medical Sciences, Charles Perkins Centre, The University of Sydney, 2006 Sydney, Australia.
authors.forename: Laurence
authors.initials: L
authors.lastname: Macia
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, 3800 VIC, Australia.
authors.forename: Alison N
authors.initials: AN
authors.lastname: Thorburn
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, 3010 Melbourne, Australia.
authors.forename: Brendan E
authors.initials: BE
authors.lastname: Russ
authors.affiliation: Division of Inflammation, The Walter and Eliza Hall Institute of Medical Research, 3052 Melbourne, Australia.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, 3800 VIC, Australia. Electronic address: charles.mackay@monash.edu.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Mackay
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D003092:Colitis / Q000139:chemically induced / Q000276:immunology; D016264:Dextran Sulfate / Q000633:toxicity; D020022:Genetic Predisposition to Disease; D009980:Influenza A virus / Q000276:immunology; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D007596:Joints / Q000276:immunology; D007711:Klebsiella pneumoniae / Q000276:immunology; D008171:Lung Diseases / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000821:virology; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000382:microbiology; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D025241:Spondylarthritis / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: C587672:IL1B protein, mouse; D020381:Interleukin-17; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D016264:Dextran Sulfate
keywords: Arthritis; Autoimmunity; IL-1β; Infection; Inflammation; Th17