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* Department of Pathology, University of Utah, Salt Lake City, UT 84112;
Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL 61802; and
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
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-
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- 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.
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1 This work was supported by Public Health Services Grants AI-32223 and AI-43521 (to J.J.W.), AI-24158 (to J.H.W.), CA-43059 (to R.D.S.), and 5T32-AI-055434 (Training Program in Microbial Pathogenesis) and an Arthritis Foundation Award (to J.C.M.).
2 Address correspondence and reprint requests to Dr. Janis J. Weis, Department of Pathology, University of Utah, 15 North Medical Drive East, Room 2100, Salt Lake City, UT 84112-5650. E-mail address: janis.weis{at}path.utah.edu
3 Abbreviations used in this paper: qPCR, quantitative PCR; BMM
, bone marrow-derived macrophage; cDC, conventional dendritic cell; IFNAR1, IFN-
/β receptor subunit 1; IRF, IFN-regulatory factor; pDC, plasmacytoid dendritic cell; PDCA-1, pDC Ag-1.
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  Y. Ma, J. C. Miller, H. Crandall, E. T. Larsen, D. M. Dunn, R. B. Weiss, M. Subramanian, J. H. Weis, J. F. Zachary, C. Teuscher, et al. Interval-Specific Congenic Lines Reveal Quantitative Trait Loci with Penetrant Lyme Arthritis Phenotypes on Chromosomes 5, 11, and 12 Infect. Immun., August 1, 2009; 77(8): 3302 - 3311. [Abstract] [Full Text] [PDF]
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