Defining Microbial and Host Factors in Innate Immune Responses in Lyme Arthritis

描述（由申请人提供）：莱姆病已达到流行病的程度，并继续在美国东北部的某些地区传播。该地区受到一种特别具有炎症性的B的影响。burgdorferi基因型，RST 1（OspC A型），其已显示在蜱中具有高传播频率，并且可能是导致世纪后期在美国东北部以流行形式出现莱姆病的主要原因。然而，B。伯氏螺旋体不含任何已知的引起毒性的毒素。相反，感染后引发的疾病与由螺旋体刺激的炎症免疫反应类型有关，并且通过TLR1（1805GG）基因中的单核苷酸多态性进一步增强，TLR1（1805GG）基因存在于约一半的欧洲高加索人中。为了评估这些微生物和宿主因素在莱姆关节炎先天免疫反应中的作用，我们提出：1。比较巨噬细胞中的细胞因子和趋化因子反应，巨噬细胞是一种单细胞类型，来自具有或不具有1805GG多态性的正常供体，使用基于珠粒的Luminex测定法，用高度炎症性RST1（OspC A型）菌株或较低炎症性RST2（OspC K型）菌株刺激，2.通过使用全基因组微阵列测量细胞基因的激活，鉴定巨噬细胞用于感知和响应OspC A型或K型菌株的信号转导网络，并评估1805GG TLR1多态性如何改变这些网络，以及3.通过使用RNA干扰试剂抑制候选基因的基因微阵列识别的途径的功能后果，TLR1 1805GG多态性通过所述候选基因改变我们的巨噬细胞培养系统中的炎症反应。抗生素难治性莱姆病关节炎可能是，至少部分是一种涉及微生物和宿主遗传学的不适当的巨噬细胞活化综合征。巨噬细胞也参与其他风湿性疾病的发病机制，包括RA，其中滑膜病变与难治性莱姆关节炎患者相似。因此，它很可能是有针对性的方法，在这里开发，描绘机制不适当的巨噬细胞激活在难治性莱姆病关节炎，将是有价值的了解如何先天免疫炎症反应可能导致自身免疫的发展，在其他炎症和风湿性疾病，包括RA关节。

DESCRIPTION (provided by applicant): Lyme disease has reached epidemic proportions and continues to spread in certain locations in the northeastern U.S. This region is affected by an especially inflammatory B. burgdorferi genotype, RST1 (OspC Type A) which has been shown to have a high transmission frequency among ticks, and may be primarily responsible for the emergence of Lyme disease in epidemic form in the northeastern U.S. in the late 20th century. However, B. burgdorferi spirochetes do not contain any known toxins that cause virulence. Rather, the disease that ensues following infection is related to the type of inflammatory immune responses that are stimulated by the spirochetes, and that are further augmented by a single nucleotide polymorphism in the TLR1 (1805GG) gene which is present in about half of the European Caucasians. To assess the role of these microbial and host factors in innate immune responses in Lyme arthritis we propose: 1. to compare cytokine and chemokine responses in macrophages, a single cell type, from normal donors with or without the 1805GG polymorphism, stimulated with a highly inflammatory RST1 (OspC type A) strain or a less inflammatory RST2 (OspC type K) strain, using bead-based Luminex assays, 2. to identify the signal transduction networks used by macrophages to sense and respond to OspC type A or K strains and to assess how the 1805GG TLR1 polymorphism alters these networks, by measuring the activation of cellular genes using genome-wide microarrays, and 3. to discern the functional consequences of pathways identified by gene microarrays using RNA interference reagents to inhibit candidate genes by which the TLR1 1805GG polymorphism alters the inflammatory response in our macrophage culture system. Antibiotic-refractory Lyme arthritis may be, at least in part, a syndrome of inappropriate macrophage activation involving both microbial and host genetics. Macrophages are also implicated in the pathogenesis of other rheumatic diseases including RA in which the synovial lesions are similar to those in patients with antibiotic-refractory Lyme arthritis. Thus, it is likely that the targeted approach developed here, to delineate mechanisms underlying inappropriate macrophage activation in antibiotic-refractory Lyme arthritis, will be valuable in understanding how innate immune inflammatory responses may lead to development of autoimmunity in the joint in other inflammatory and rheumatic diseases, including RA.