Molecular Genetics of Lyme Arthritis Susceptibility

描述（由申请人提供）：莱姆病关节炎是由蜱传螺旋体伯氏疏螺旋体感染引起的，在人类中会引起一系列症状，包括心脏、关节、中枢和周围神经系统以及皮肤。据报道，60%在蜱虫叮咬时未接受治疗的患者在感染后一至几个月出现自限性急性关节炎。在感染伯氏疏螺旋体的小鼠中，疾病严重程度的遗传调控很明显，C3H小鼠表现为严重关节炎，而C57BL/6 （B6）小鼠表现为轻度至中度关节炎。在C3H小鼠中，I型IFN的局部诱导与严重莱姆病关节炎的发展有关。先前已鉴定出5条染色体上的B. burgdorferi arthritis associated (Bbaa) Quantitative Trait Loci (QTL)，并生成了小鼠的互易区间特异性同源系（ISCL），并对其进行了渗透性关节炎表型检测。包括5号染色体上的Bbaa2Bbaa3和11号染色体上的Bbaa4的ISCL在两个方向上转移关节炎表型。间隔特异性重组基因系（ISRCL）在Bbaa2Bbaa3中产生，从而显著划定了相关位点的物理边界。两个基因座已被确定与关节炎表型增强的影响；Bbaa2a位于119.18-125.31Mbp， Bbaa2b位于127.40-137.53Mbp。第三个区域，位于125.31-127.40Mbp的Bbaa2c，抑制归因于Bbaa2b的表型。11号染色体上横跨Bbaa4区间的ISRCL也已生成，相关位点的物理定位有望实现。令人兴奋的是，在狭窄的ISRCL中增加表型的发现是在确定B6和C3H小鼠感染伯氏疏螺旋体后关节炎严重程度差异的等位基因的最终目标方面取得的重大进展。本文提出了四种结合遗传学、分子生物学和生物学表征的方法来鉴定这些基因：1)Bbaa2a、Bbaa2b和Bbaa4的高分辨率同源定位；2)通过比较序列和表达分析确定候选位置；3)确定I型IFN在各ISRCL中对关节炎的贡献；4)利用RNA沉默技术评估巨噬细胞中调节伯氏疏螺旋体信号传导的候选基因。莱姆病关节炎是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基因调控。确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.