title: High Chlamydia Burden Promotes Tumor Necrosis Factor-Dependent Reactive Arthritis in SKG Mice.
abstract: OBJECTIVE
  Chlamydia trachomatis is a sexually transmitted obligate intracellular pathogen that causes inflammatory reactive arthritis, spondylitis, psoriasiform dermatitis, and conjunctivitis in some individuals after genital infection. The immunologic basis for this inflammatory response in susceptible hosts is poorly understood. As ZAP-70(W163C) -mutant BALB/c (SKG) mice are susceptible to spondylo-arthritis after systemic exposure to microbial β-glucan, we undertook the present study to compare responses to infection with Chlamydia muridarum in SKG mice and BALB/c mice.
  
  
  METHODS
  After genital or respiratory infection with C muridarum, conjunctivitis and arthritis were assessed clinically, and eye, skin, and joint specimens were analyzed histologically. Chlamydial major outer membrane protein antigen-specific responses were assessed in splenocytes. Treg cells were depleted from FoxP3-DTR BALB/c or SKG mice, and chlamydial DNA was quantified by polymerase chain reaction.
  
  
  RESULTS
  Five weeks after vaginal infection with live C muridarum, arthritis, spondylitis, and psoriasiform dermatitis developed in female SKG mice, but not in BALB/c mice. Inflammatory bowel disease did not occur in mice of either strain. The severity of inflammatory disease was correlated with C muridarum inoculum size and vaginal burden postinoculation. Treatment with combination antibiotics starting 1 day postinoculation prevented disease. Chlamydial antigen was present in macrophages and spread from the infection site to lymphoid organs and peripheral tissue. In response to chlamydial antigen, production of interferon-γ and interleukin-17 was impaired in T cells from SKG mice but tumor necrosis factor (TNF) responses were exaggerated, compared to findings in T cells from BALB/c mice. Unlike previous observations in arthritis triggered by β-glucan, no autoantibodies developed. Accelerated disease triggered by depletion of Treg cells was TNF dependent.
  
  
  CONCLUSIONS
  In the susceptible SKG strain, Chlamydia-induced reactive arthritis develops as a result of deficient intracellular pathogen control, with antigen-specific TNF production upon dissemination of antigen, and TNF-dependent inflammatory disease.
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute and Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Athan C
authors.initials: AC
authors.lastname: Baillet
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute and Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Rehaume
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute and Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Benham
authors.affiliation: Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Connor P
authors.initials: CP
authors.lastname: O'Meara
authors.affiliation: Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Armitage
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute and Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Roland
authors.initials: R
authors.lastname: Ruscher
authors.affiliation: Lions Eye Institute, Nedlands, West Australia, Australia.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Brizard
authors.affiliation: Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Marina C G
authors.initials: MC
authors.lastname: Harvie
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute and Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Jared
authors.initials: J
authors.lastname: Velasco
authors.affiliation: Hunter Medical Research Institute and University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Hansbro
authors.affiliation: Lions Eye Institute, Nedlands, West Australia, Australia, and University of Aberdeen Medical School, Aberdeen, Scotland.
authors.forename: John V
authors.initials: JV
authors.lastname: Forrester
authors.affiliation: Lions Eye Institute, Nedlands, West Australia, Australia, and University of West Australia, Crawley, West Australia, Australia.
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
authors.affiliation: Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Beagley
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute and Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology*; D016918:Arthritis, Reactive / Q000276:immunology*; D002690:Chlamydia Infections / Q000276:immunology*; D023502:Chlamydia muridarum / Q000276:immunology*; D005260:Female; D015212:Inflammatory Bowel Diseases / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D011565:Psoriasis / Q000276:immunology; D060737:Reproductive Tract Infections / Q000276:immunology*; D012141:Respiratory Tract Infections / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D016585:Vaginosis, Bacterial
chemical_list: D000907:Antibodies, Bacterial; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma