Molecular genetics of Lyme arthritis susceptibility

描述（由申请人提供）：莱姆病是由蜱传播的伯氏疏螺旋体感染引起的。在被蜱虫叮咬时未接受治疗的人群中，约60%的人受到感染可导致炎症性关节炎，在一小部分易感人群中，这可能发展为慢性疾病。感染相关性关节炎可在小鼠中进行研究；强有力的证据表明，伯氏疏螺旋体引起的关节炎的严重程度是由宿主的遗传调节的。通过将患有严重莱姆病（C3H）的近交系与患有轻度关节炎（C57BL/6）的近交系杂交而成的小鼠群体，我们发现了6个调节关节炎严重程度的数量性状位点（QTL）。这些QTL具有高度显著性，其LOD得分在3.5-10.2之间。基因系已被开发出来，通过回交7代与互亲本分离出与QTL相关的单个染色体间隔。已经产生了几个具有高渗透性莱姆病表型的间隔特异性基因系。本申请的目标是：1)完成C3H x C57BL/6基因系的鉴定，并开发间隔特异性重组系，以缩小与每个QTL相关的物理区域，使其适合定位克隆；2)确定吞噬细胞NADPH氧化酶的组成部分Ncf1是否为5号染色体高度显著QTL定位（Bb2）的候选者；3)确定活性氧中间体抑制伯氏疏螺旋体诱导的小鼠关节炎的机制。这些研究将提供有关莱姆病关节炎遗传调控的信息，最终目标是确定导致小鼠和人类严重程度差异的多态性基因。具有强候选基因Ncf1的研究进一步揭示了炎症调节的一个意想不到的范式，表明活性氧中间体可能在莱姆病中发挥调节作用。

DESCRIPTION (provided by applicant): Lyme disease is caused by infection with the tick-transmitted spirochete Borrelia burgdorferi. Infection in humans can cause inflammatory arthritis in approximately 60% of those not treated at the time of the tick bite, and this can progress to chronic disease in a small percentage of susceptible individuals. The infection-associated arthritis can be studied in mice; with strong evidence suggesting that the severity of B. burgdorferi induced arthritis is regulated by the genetics of the host. Using intercross populations of mice developed by crossing inbred strains that develop severe Lyme arthritis (C3H) with those that display milder arthritis (C57BL/6), we have identified six Quantitative Trait Loci (QTL) that regulate arthritis severity. These QTL are highly significant, with LOD scores ranging from 3.5-10.2. Congenic lines have been developed to isolate individual chromosomal intervals associated with QTL by backcrossing seven generations to the reciprocal parent. Several interval specific congenic lines with highly penetrant Lyme arthritis phenotypes have been generated. The goals of this application are to 1) complete the characterization of the C3H x C57BL/6 congenic lines and develop interval specific recombinant lines to narrow the physical region associated with each QTL to that amenable to positional cloning; 2) determine if Ncf1, a component of the phagocyte NADPH oxidase, is a candidate for a highly significant QTL mapping to chromosome 5 (Bb2); and 3) determine the mechanism by which reactive oxygen intermediates suppress B. burgdorferi-induced arthritis in mice. These studies will provide information on the genetic regulation of Lyme arthritis, with the ultimate goal being the identification of polymorphic genes responsible for differences in severity in mice and humans. Studies with a strong candidate gene, Ncf1, have further revealed an unexpected paradigm in inflammatory regulation, suggesting that reactive oxygen intermediates may play a regulatory role in Lyme arthritis.