Lyme arthritis is caused by infection with the tick-borne spirochete Borrelia burgdorferi and in humans is responsible for a number of symptoms involving the heart, joints, central and peripheral nervous system, and skin. A self-limiting, acute arthritis developing one to several months following infection is reported in 60% of patients not treated at the time of the tick bite. Genetic regulation of disease severity is evident in B. burgdorferi-infected mice as C3H mice display severe arthritis while C57BL/6 (B6) mice develop mild to moderate arthritis. Localized induction of Type I IFN has been associated with severe Lyme arthritis development in C3H mice. B. burgdorferi arthritis associated (Bbaa) Quantitative Trait Loci (QTL) on five chromosomes were previously identified, and reciprocal interval specific congenic lines (ISCL) of mice have been generated and tested for penetrant arthritis phenotypes. ISCL encompassing Bbaa2Bbaa3 on chromosome 5 and Bbaa4 on chromosome 11 transferred arthritis phenotypes in both directions. Interval specific recombinant congenic lines (ISRCL) have been generated within Bbaa2Bbaa3 resulting in significantly delimiting the physical boundaries encompassing the relevant loci. Two loci have been identified with enhanced influence on arthritis phenotype;Bbaa2a at 119.18-125.31Mbp and Bbaa2b at 127.40-137.53Mbp. A third region, Bbaa2c at 125.31-127.40Mbp, suppresses phenotypes attributed to Bbaa2b. ISRCL across the Bbaa4 interval on chromosome 11 have also been generated and physical mapping of the relevant locus is anticipated. The exciting finding of increased phenotype in the narrowed ISRCL is a major advance towards the ultimate goal of identifying the allelic genes responsible for the difference in arthritis severity in B6 and C3H mice following infection with B. burgdorferi. Four approaches that incorporate genetics, molecular biology, and biological characterization are proposed for the identification of these genes: 1) high resolution congenic mapping of Bbaa2a, Bbaa2b, and Bbaa4;2) identification of positional candidates by comparative sequence and expression analysis;3) determine the contribution of Type I IFN to arthritis in each ISRCL;and 4) using RNA silencing to assess candidate genes for modulation of B. burgdorferi signaling in macrophages.
Lyme arthritis is a consequence of infection with the tick borne spirochete Borrelia burgdorferi, and the severity of disease is genetically regulated by the host. Identification of the genes that regulate disease severity will provide insight into the mechanism of arthritis development and may be extended to other inflammatory pathologies.
|Paquette, Jackie K; Ma, Ying; Fisher, Colleen et al. (2017) Genetic Control of Lyme Arthritis by Borrelia burgdorferi Arthritis-Associated Locus 1 Is Dependent on Localized Differential Production of IFN-? and Requires Upregulation of Myostatin. J Immunol 199:3525-3534|
|Pioli, Peter D; Whiteside, Sarah K; Weis, Janis J et al. (2016) Snai2 and Snai3 transcriptionally regulate cellular fitness and functionality of T cell lineages through distinct gene programs. Immunobiology 221:618-33|
|Lochhead, Robert B; Zachary, James F; Dalla Rosa, Luciana et al. (2015) Antagonistic Interplay between MicroRNA-155 and IL-10 during Lyme Carditis and Arthritis. PLoS One 10:e0135142|
|Pioli, Peter D; Chen, Xinjian; Weis, Janis J et al. (2015) Fatal autoimmunity results from the conditional deletion of Snai2 and Snai3. Cell Immunol 295:1-18|
|Bramwell, Kenneth K C; Mock, Kelton; Ma, Ying et al. (2015) ?-Glucuronidase, a Regulator of Lyme Arthritis Severity, Modulates Lysosomal Trafficking and MMP-9 Secretion in Response to Inflammatory Stimuli. J Immunol 195:1647-56|
|Ma, Ying; Bramwell, Kenneth K C; Lochhead, Robert B et al. (2014) Borrelia burgdorferi arthritis-associated locus Bbaa1 regulates Lyme arthritis and K/B×N serum transfer arthritis through intrinsic control of type I IFN production. J Immunol 193:6050-60|
|Bramwell, Kenneth K C; Teuscher, Cory; Weis, Janis J (2014) Forward genetic approaches for elucidation of novel regulators of Lyme arthritis severity. Front Cell Infect Microbiol 4:76|
|Lochhead, Robert B; Ma, Ying; Zachary, James F et al. (2014) MicroRNA-146a provides feedback regulation of lyme arthritis but not carditis during infection with Borrelia burgdorferi. PLoS Pathog 10:e1004212|
|Bramwell, Kenneth K C; Ma, Ying; Weis, John H et al. (2014) Lysosomal ?-glucuronidase regulates Lyme and rheumatoid arthritis severity. J Clin Invest 124:311-20|
|Debnath, Irina; Roundy, Kirstin M; Pioli, Peter D et al. (2013) Bone marrow-induced Mef2c deficiency delays B-cell development and alters the expression of key B-cell regulatory proteins. Int Immunol 25:99-115|
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