{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T07:53:00Z","timestamp":1793087580049,"version":"4.5.0"},"reference-count":69,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2008,12,1]],"date-time":"2008-12-01T00:00:00Z","timestamp":1228089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Gene expression analysis previously revealed a robust IFN-responsive gene induction profile that was selectively up-regulated in Borrelia burgdorferi-infected C3H mice at 1 wk postinfection. This profile was correlated with arthritis development, as it was absent from infected, mildly arthritic C57BL\/6 mice. In this report we now demonstrate that profile induction in infected C3H scid mice occurs independently of B or T lymphocyte infiltration in the joint tissue. Additionally, type I IFN receptor-blocking Abs, but not anti-IFN-\u03b3 Abs, dramatically reduced arthritis, revealing a critical but previously unappreciated role for type I IFN in Lyme arthritis development. Certain examined IFN-inducible transcripts were also significantly diminished within joint tissue of mice treated with anti-IFNAR1, whereas expression of other IFN-responsive genes was more markedly altered by anti-IFN-\u03b3 treatment. These data indicate that induction of the entire IFN profile is not necessary for arthritis development. These findings further tie early type I IFN induction to Lyme arthritis development, a connection not previously made. Bone marrow-derived macrophages readily induced IFN-responsive genes following B. burgdorferi stimulation, and this expression required a functional type I IFN receptor. Strikingly, induction of these genes was independent of TLRs 2,4, and 9 and of the adapter molecule MyD88. These data demonstrate that the extracellular pathogen B. burgdorferi uses a previously unidentified receptor and a pathway traditionally associated with viruses and intracellular bacteria to initiate transcription of type I IFN and IFN-responsive genes and to initiate arthritis development.<\/jats:p>","DOI":"10.4049\/jimmunol.181.12.8492","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T23:24:21Z","timestamp":1397863461000},"page":"8492-8503","source":"Crossref","is-referenced-by-count":90,"title":["A Critical Role for Type I IFN in Arthritis Development following <i>Borrelia burgdorferi<\/i> Infection of Mice"],"prefix":"10.1093","volume":"181","author":[{"given":"Jennifer C","family":"Miller","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Utah , Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Utah , Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiantao","family":"Bian","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Utah , Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen C F","family":"Sheehan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine , St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James F","family":"Zachary","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, University of Illinois at Urbana-Champaign , Urbana, IL 61802"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H","family":"Weis","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Utah , Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert D","family":"Schreiber","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine , St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janis J","family":"Weis","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Utah , Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2008,12,15]]},"reference":[{"key":"2025032719415978500_R1","first-page":"1317","article-title":"Lyme disease: a tick-borne spirochetosis?","volume-title":"Science","year":"1982"},{"key":"2025032719415978500_R2","first-page":"143","article-title":"Elucidation of Lyme arthritis","volume-title":"Nat. Rev. Immunol.","year":"2004"},{"key":"2025032719415978500_R3","first-page":"69","article-title":"Lyme disease","volume-title":"Adv. Intern. Med.","year":"1995"},{"key":"2025032719415978500_R4","first-page":"725","article-title":"The clinical evolution of Lyme arthritis","volume-title":"Ann. Intern. Med.","year":"1987"},{"key":"2025032719415978500_R5","first-page":"133","article-title":"Lyme borreliosis in selected strains and ages of laboratory mice","volume-title":"J. Infect. Dis.","year":"1990"},{"key":"2025032719415978500_R6","first-page":"263","article-title":"Kinetics of Borrelia burgdorferi dissemination and evolution of disease after intradermal inoculation of mice","volume-title":"Am. J. Pathol.","year":"1991"},{"key":"2025032719415978500_R7","first-page":"161","article-title":"Distinct characteristics of resistance to Borrelia burgdorferi-induced arthritis in C57BL\/6N mice","volume-title":"Infect. Immun.","year":"1998"},{"key":"2025032719415978500_R8","first-page":"1967","article-title":"Genetic control of experimental Lyme arthritis in the absence of specific immunity","volume-title":"Infect. Immun.","year":"1999"},{"key":"2025032719415978500_R9","first-page":"605","article-title":"Lyme borreliosis in genetically resistant and susceptible mice with severe combined immunodeficiency","volume-title":"Am. J. Trop. Med. Hyg.","year":"1992"},{"key":"2025032719415978500_R10","first-page":"274","article-title":"Host-pathogen interactions promoting inflammatory Lyme arthritis: use of mouse models for dissection of disease processes","volume-title":"Curr. Opin. Microbiol.","year":"2001"},{"key":"2025032719415978500_R11","first-page":"348","article-title":"Toll-like receptor 2 is required for innate, but not acquired, host defense to Borrelia burgdorferi","volume-title":"J. Immunol.","year":"2002"},{"key":"2025032719415978500_R12","first-page":"2003","article-title":"MyD88 plays a unique role in host defense but not arthritis development in Lyme disease","volume-title":"J. Immunol.","year":"2004"},{"key":"2025032719415978500_R13","first-page":"3195","article-title":"Myeloid differentiation antigen 88 deficiency impairs pathogen clearance but does not alter inflammation in Borrelia burgdorferi-infected mice","volume-title":"Infect. Immun.","year":"2004"},{"key":"2025032719415978500_R14","first-page":"1462","article-title":"MyD88 deficiency results in tissue-specific changes in cytokine induction and inflammation in interleukin-18-independent mice infected with Borrelia burgdorferi","volume-title":"Infect. Immun.","year":"2006"},{"key":"2025032719415978500_R15","first-page":"7930","article-title":"Gene expression profiling reveals unique pathways associated with differential severity of Lyme arthritis","volume-title":"J. Immunol.","year":"2006"},{"key":"2025032719415978500_R16","first-page":"124","article-title":"T cell infiltration is associated with increased Lyme arthritis in TLR2\u2212\/\u2212 mice","volume-title":"FEMS Immunol. Med. Microbiol.","year":"2008"},{"key":"2025032719415978500_R17","first-page":"3329","article-title":"Experimental Lyme arthritis in the absence of interleukin-4 or gamma interferon","volume-title":"Infect. Immun.","year":"1999"},{"key":"2025032719415978500_R18","first-page":"163","article-title":"Autoimmune disease complicating antiviral therapy for hepatitis C virus infection","volume-title":"Semin. Arthritis Rheum.","year":"2002"},{"key":"2025032719415978500_R19","first-page":"485","article-title":"Arthritis and bursitis in multiple sclerosis patients treated with interferon-\u03b2","volume-title":"Scand. J. Rheumatol.","year":"2005"},{"key":"2025032719415978500_R20","first-page":"481","article-title":"Microarray analysis of interferon-regulated genes in SLE","volume-title":"Autoimmunity","year":"2003"},{"key":"2025032719415978500_R21","first-page":"1540","article-title":"Induction of dendritic cell differentiation by IFN-\u03b1 in systemic lupus erythematosus","volume-title":"Science","year":"2001"},{"key":"2025032719415978500_R22","first-page":"2499","article-title":"IFN-\u03b1 induces early lethal lupus in preautoimmune (New Zealand Black \u00d7 New Zealand White) F1 but not in BALB\/c mice","volume-title":"J. Immunol.","year":"2005"},{"key":"2025032719415978500_R23","first-page":"777","article-title":"Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice","volume-title":"J. Exp. Med.","year":"2003"},{"key":"2025032719415978500_R24","first-page":"657","article-title":"Distinct expression pattern of IFN\u03b1 and TNF\u03b1 in juvenile idiopathic arthritis synovial tissue","volume-title":"Rheumatology","year":"2007"},{"key":"2025032719415978500_R25","first-page":"2660","article-title":"Coevolution of markers of innate and adaptive immunity in skin and peripheral blood of patients with erythema migrans","volume-title":"J. Immunol.","year":"2003"},{"key":"2025032719415978500_R26","first-page":"346","article-title":"Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism","volume-title":"Nat. Immunol.","year":"2001"},{"key":"2025032719415978500_R27","first-page":"143","article-title":"Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function","volume-title":"Immunity","year":"1998"},{"key":"2025032719415978500_R28","first-page":"521","article-title":"Isolation and cultivation of Lyme disease spirochetes","volume-title":"Yale J. Biol. Med.","year":"1984"},{"key":"2025032719415978500_R29","first-page":"492","article-title":"Heritable susceptibility to severe Borrelia burgdorferi-induced arthritis is dominant and is associated with persistence of large numbers of spirochetes in tissues","volume-title":"Infect. Immun.","year":"1994"},{"key":"2025032719415978500_R30","first-page":"804","article-title":"Blocking monoclonal antibodies specific for mouse IFN-\u03b1\/\u03b2 receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection","volume-title":"J. Interferon Cytokine Res.","year":"2006"},{"key":"2025032719415978500_R31","first-page":"4231","article-title":"Generation and characterization of monoclonal antibodies specific for the human IFN-\u03b3 receptor","volume-title":"J. Immunol.","year":"1988"},{"key":"2025032719415978500_R32","first-page":"1609","article-title":"Monoclonal antibodies to murine \u03b3-interferon which differentially modulate macrophage activation and antiviral activity","volume-title":"J. Immunol.","year":"1985"},{"key":"2025032719415978500_R33","first-page":"34","article-title":"In vivo effects of anti-asialo GM1 I: reduction of NK activity and enhancement of transplanted tumor growth in nude mice","volume-title":"J. Immunol.","year":"1981"},{"key":"2025032719415978500_R34","first-page":"5294","article-title":"Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease","volume-title":"Biochemistry","year":"1979"},{"key":"2025032719415978500_R35","first-page":"954","article-title":"Quantification of low-copy transcripts by continuous SYBR Green I monitoring during amplification","volume-title":"BioTechniques","year":"1998"},{"key":"2025032719415978500_R36","first-page":"1459","article-title":"The importance of IL-1\u03b2 and TNF-\u03b1, and the noninvolvement of IL-6, in the development of monoclonal antibody-induced arthritis","volume-title":"J. Immunol.","year":"2002"},{"key":"2025032719415978500_R37","first-page":"103","article-title":"A reverse transcriptase-polymerase chain reaction assay of Borrelia burgdorferi 16S rRNA for highly sensitive quantification of pathogen load in a vector","volume-title":"Vector Borne Zoonotic Dis.","year":"2006"},{"key":"2025032719415978500_R38","first-page":"987","article-title":"Rapid and sensitive quantification of Borrelia burgdorferi-infected mouse tissues by continuous fluorescent monitoring of PCR","volume-title":"J. Clin. Microbiol.","year":"1999"},{"key":"2025032719415978500_R39","first-page":"213","article-title":"Studies on the activation of mouse bone marrow-derived macrophages by the macrophage cytotoxicity factor (MCF)","volume-title":"Eur. J. Immunol.","year":"1976"},{"key":"2025032719415978500_R40","first-page":"107","article-title":"CpG DNA functions as an effective adjuvant for the induction of immune responses in aged mice","volume-title":"Exp. Gerontol.","year":"2001"},{"key":"2025032719415978500_R41","first-page":"795","article-title":"Lyme disease spirochetes and ixodid tick spirochetes share a common surface antigenic determinant defined by a monoclonal antibody","volume-title":"Infect. Immun.","year":"1983"},{"key":"2025032719415978500_R42","first-page":"2645","article-title":"In vivo manipulation of dendritic cells overcomes tolerance to unmodified tumor-associated self antigens and induces potent antitumor immunity","volume-title":"J. Immunol.","year":"2005"},{"key":"2025032719415978500_R43","first-page":"7162","article-title":"Early induction of gamma interferon and interleukin-10 production in draining lymph nodes from mice infected with Borrelia burgdorferi","volume-title":"Infect. Immun.","year":"2000"},{"key":"2025032719415978500_R44","first-page":"3460","article-title":"CD19+ cells produce IFN-\u03b3 in mice infected with Borrelia burgdorferi","volume-title":"Eur. J. Immunol.","year":"2001"},{"key":"2025032719415978500_R45","first-page":"266","article-title":"Modulation of murine Lyme borreliosis by interruption of the B7\/CD28 T-cell costimulatory pathway","volume-title":"Infect. Immun.","year":"1998"},{"key":"2025032719415978500_R46","first-page":"6051","article-title":"Inflammatory cytokine production predominates in early Lyme disease in patients with erythema migrans","volume-title":"Infect. Immun.","year":"2003"},{"key":"2025032719415978500_R47","first-page":"e6","article-title":"Distinct TLR- and NLR-mediated transcriptional responses to an intracellular pathogen","volume-title":"PLoS Pathog.","year":"2008"},{"key":"2025032719415978500_R48","first-page":"1122","article-title":"Identification of genes selectively regulated by IFNs in endothelial cells","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032719415978500_R49","first-page":"601","article-title":"IFN-inducible GTPases and immunity to intracellular pathogens","volume-title":"Trends Immunol.","year":"2004"},{"key":"2025032719415978500_R50","first-page":"2020","article-title":"Role of IL-4 and IFN-\u03b3 in modulation of immunity to Borrelia burgdorferi in mice","volume-title":"J. Immunol.","year":"1995"},{"key":"2025032719415978500_R51","first-page":"1251","article-title":"T helper phenotype and genetic susceptibility in experimental Lyme disease","volume-title":"J. Exp. Med.","year":"1995"},{"key":"2025032719415978500_R52","first-page":"1219","article-title":"Plasmacytoid dendritic cells in immunity","volume-title":"Nat. Immunol.","year":"2004"},{"key":"2025032719415978500_R53","first-page":"134","article-title":"IRF family proteins and type I interferon induction in dendritic cells","volume-title":"Cell Res.","year":"2006"},{"key":"2025032719415978500_R54","first-page":"2085","article-title":"Defective LPS signaling in C3H\/HeJ and C57BL\/10ScCr mice: mutations in the Tlr4 gene","volume-title":"Science","year":"1998"},{"key":"2025032719415978500_R55","first-page":"2046","article-title":"Phagocytosis of Borrelia burgdorferi and Treponema pallidum potentiates innate immune activation and induces gamma interferon production","volume-title":"Infect. Immun.","year":"2007"},{"key":"2025032719415978500_R56","first-page":"5208","article-title":"Activation of natural killer cells in arthritis-susceptible but not arthritis-resistant mouse strains following Borrelia burgdorferi infection","volume-title":"Infect. Immun.","year":"1998"},{"key":"2025032719415978500_R57","first-page":"388","article-title":"Genetic control of susceptibility to experimental Lyme arthritis is polygenic and exhibits consistent linkage to multiple loci on chromosome 5 in four independent mouse crosses","volume-title":"Genes Immun.","year":"2001"},{"key":"2025032719415978500_R58","first-page":"948","article-title":"Identification of quantitative trait loci governing arthritis severity and humoral responses in the murine model of Lyme disease","volume-title":"J. Immunol.","year":"1999"},{"key":"2025032719415978500_R59","first-page":"3737","article-title":"Gamma interferon is not required for arthritis resistance in the murine Lyme disease model","volume-title":"Infect. Immun.","year":"2001"},{"key":"2025032719415978500_R60","first-page":"907","article-title":"Interferon signalling network in innate defence","volume-title":"Cell. Microbiol.","year":"2006"},{"key":"2025032719415978500_R61","first-page":"6680","article-title":"Biologic consequences of Stat1-independent IFN signaling","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2001"},{"key":"2025032719415978500_R62","first-page":"6674","article-title":"Stat1-independent regulation of gene expression in response to IFN-\u03b3","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2001"},{"key":"2025032719415978500_R63","first-page":"163","article-title":"Interferon-\u03b3: an overview of signals, mechanisms and functions","volume-title":"J. Leukocyte Biol.","year":"2004"},{"key":"2025032719415978500_R64","first-page":"375","article-title":"Mechanisms of type-I- and type-II-interferon-mediated signalling","volume-title":"Nat. Rev. Immunol.","year":"2005"},{"key":"2025032719415978500_R65","first-page":"390","article-title":"Stat1 deficiency exacerbates carditis but not arthritis during experimental Lyme borreliosis","volume-title":"J. Interferon Cytokine Res.","year":"2006"},{"key":"2025032719415978500_R66","first-page":"783","article-title":"Pathogen recognition and innate immunity","volume-title":"Cell","year":"2006"},{"key":"2025032719415978500_R67","first-page":"3064","article-title":"A crucial role for macrophages in the pathology of K\/B X N serum-induced arthritis","volume-title":"Eur. J. Immunol.","year":"2005"},{"key":"2025032719415978500_R68","first-page":"2341","article-title":"Distinct roles for MyD88 and Toll-like receptors 2, 5, and 9 in phagocytosis of Borrelia burgdorferi and cytokine induction","volume-title":"Infect. Immun.","year":"2008"},{"key":"2025032719415978500_R69","first-page":"19879","article-title":"Group A Streptococcus activates type I interferon production and MyD88-dependent signaling without involvement of TLR2, TLR4, and TLR9","volume-title":"J. Biol. Chem.","year":"2008"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/12\/8492\/62577439\/8235.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/12\/8492\/62577439\/8235.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T19:13:24Z","timestamp":1743362004000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/181\/12\/8492\/8004692"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,12]]},"references-count":69,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2008,12,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.181.12.8492","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2008,12]]},"published":{"date-parts":[[2008,12]]}}}