Molecular Genetics of Lyme Arthritis Susceptibility

描述（由申请人提供）：莱姆关节炎是由蜱传螺旋体伯氏疏螺旋体感染引起的，在人类中引起涉及心脏、关节、中枢和外周神经系统以及皮肤的许多症状。据报道，在被蜱叮咬时未接受治疗的患者中，有60%在感染后1至数月发生自限性急性关节炎。疾病严重程度的遗传调节在B中是明显的。感染伯氏螺旋体的小鼠如C3 H小鼠表现出严重的关节炎，而C57 BL/6（B6）小鼠发展为轻度至中度关节炎。I型IFN的局部诱导与C3 H小鼠中严重莱姆病关节炎的发展相关。B。先前鉴定了5条染色体上的与伯氏关节炎相关（Bbaa）的数量性状基因座（QTL），并且已经产生了小鼠的相互间隔特异性同源系（ISCL）并测试了渗透性关节炎表型。包含5号染色体上的Bbaa 2Bbaa 3和11号染色体上的Bbaa 4的ISCL在两个方向上转移关节炎表型。区间特异性重组同源系（ISRCL）已在Bbaa 2Bbaa 3内产生，从而显著界定了包含相关基因座的物理边界。已经鉴定出两个对关节炎表型具有增强影响的位点; Bbaa 2a在119.18-125.31Mbp处，Bbaa 2b在127.40-137.53Mbp处。第三个区域，Bbaa 2c在125.31-127.40Mbp，抑制归因于Bbaa 2b的表型。还产生了跨越11号染色体上Bbaa 4间隔的ISRCL，并预期对相关基因座进行物理作图。在狭窄ISRCL中增加表型的令人兴奋的发现是朝向鉴定导致B感染后B6和C3 H小鼠关节炎严重程度差异的等位基因的最终目标的重大进展。burgdorferi。本文提出了四种结合遗传学、分子生物学和生物学特性的方法来鉴定这些基因：1）Bbaa 2a、Bbaa 2b和Bbaa 4的高分辨率同源基因定位; 2）通过比较序列和表达分析来鉴定位置候选者; 3）确定I型IFN对每个ISRCL中关节炎的贡献;和4）使用RNA沉默来评估用于调节B的候选基因。巨噬细胞中的burgdorferi信号传导。公共卫生相关性莱姆病关节炎是由蜱传螺旋体伯氏疏螺旋体感染的结果，疾病的严重程度由宿主遗传调节。鉴定调节疾病严重程度的基因将提供对关节炎发展机制的深入了解，并可能扩展到其他炎症病理。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.