Characterization of the source and function of interleukin-10 during lyme arthritis development

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Title Characterization of the source and function of interleukin-10 during lyme arthritis development
Publication Type dissertation
School or College School of Medicine
Department Pathology
Author Sonderegger, F. Lynn
Date 2011-12
Description IL-10 is a non-redundant inflammatory modulator that suppresses the development of arthritis in Borrelia burgdorferi infected mice. Previous microarray studies of infected B6 and C3H joint tissue found IL-10 to be induced only in B6 mice, leading to the hypothesis that the inability to produce IL-10 was a factor in arthritis development in C3H mice. Expression of IL-10 was robust in the skin from around the ankle joint in both B6 and C3H mice, suggesting that arthritis in C3H mice develops through pathways not regulated by IL-10. B6 IL-10-/- mice were previously found to have a robust and sustained interferoninducible response in joint tissues, and the current study identified high concentrations of IFN-γ in sera. Infection of IL-10 reporter mice demonstrated that macrophages and CD4+ T cells were the primary sources of IL-10 in the infected joint and skin tissues, which suggested that early local production of IL-10 dampened the pro-arthritic interferon response. In fact, treatment of IL-10-/- mice with anti-IFN-γ reduced arthritis severity and suppressed interferon-inducible transcripts to wild type levels, thereby linking dysregulation of IFN-γ to disease in the IL-10-/- mouse. Arthritis in IL-10 deficient mice was associated with elevated numbers of NK cell, NKT cell, α/β T cell, and macrophage infiltration of the infected joint. FACS lineage sorting revealed NK cells and CD4+ T cells as sources of IFN-γ in the joint tissue of IL-10-/- mice. These findings suggest the presence of a positive feedback loop in the joint tissue of infected IL-10-/- mice, where iv production of inflammatory chemokines, infiltration of IFN-γ producing cells, and additional production of inflammatory cytokines result in arthritis. This mechanism of arthritis is in contrast to that seen in C3H mice, where arthritis development is linked to transient production of Type I interferon, and develops independently of IFN-γ. Due to the sustained interferon response driven by NK cells and T cells, we propose the IL-10-/- mouse as a potential model to study the prolonged symptoms observed in some human Lyme disease patients.
Type Text
Publisher University of Utah
Subject MESH Borrelia burgdorferi; Lyme Disease; Autoimmune Diseases; Interferon-gamma; Interleukin-10; Inflammation; Erythema Chronicum Migrans; Cell Polarity; T-Lymphocytes; Gene Expression; Lyme Arthritis; Macrophages; Chemokines
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital reproduction of Characterization of the Source and Function of Interleukin-10 During Lyme Arthritis Development. Print version available at the J. Willard Marriott Library Special Collections.
Rights Management Copyright© F. Lynn Sonderegger 2011
Format application/pdf
Format Medium application/pdf
Format Extent 3,827,099 bytes
Source Original in Marriott Library Special Collections,
ARK ark:/87278/s6vt519w
Setname ir_etd
ID 196407
Reference URL https://collections.lib.utah.edu/ark:/87278/s6vt519w
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