OspA and autoimmunity in chronic Lyme disease

描述（由申请人提供）：莱姆病螺旋体伯氏疏螺旋体感染可累及多个组织。神经系统并发症以中枢和外周神经系统为目标，通常对抗生素治疗有反应。然而，一些患者，尽管治疗和没有明显的感染，有持续的神经功能缺损，这表明自身免疫在慢性莱姆病的发病机制中可能发挥作用。最近关于接种B疫苗后发生类似神经系统综合征的报告。在某些患者中检测到的伯氏螺旋体外表面蛋白A（OspA）为自身免疫假说提供了支持，并指出OspA是可能的罪魁祸首。在我们的初步研究中，我们发现针对对应于人脑cDNA序列的OspA肽产生的抗体强烈免疫染色人脑锥体神经元、脊髓运动神经元和背根神经节感觉神经元。此外，发现来自在接种OspA疫苗后不久开始出现神经系统症状的6名患者中的3名患者的血清，而不是来自6名对照受试者的血清，具有针对相同肽的升高的抗体滴度。我们现在建议鉴定交叉反应蛋白，并确定对其的免疫反应是否与莱姆病的慢性神经系统后遗症有关。该项目的具体目标是：1）鉴定和表征假定的交叉反应性神经蛋白，2）确定交叉反应性神经抗原抗体的存在是否与慢性莱姆病的神经功能缺损相关，3）确定抗生素耐药慢性莱姆病和神经功能缺损患者是否表现出对肽或蛋白的T细胞反应性。如果这项研究的结果支持自身免疫在慢性神经疏螺旋体病中的作用，那么它将为神经系统并发症的发病机制提供新的线索，并为在这组患者中使用免疫调节剂的临床试验提供依据。对自身抗原的特异性免疫反应性的鉴定也可能用作诊断标志物和监测受影响患者的疾病活动。

DESCRIPTION (provided by applicant): Infection with the Lyme disease spirochete Borrelia burgdorferi can involve multiple tissues. The neurologic complications target the central and peripheral nervous systems and usually respond to antibiotic treatment. Some patients, however, have persistent neurologic deficits despite treatment and in the absence of obvious infection, suggesting a possible role for autoimmunity in the pathogenesis of chronic Lyme disease. Recent reports of occurrence of similar neurologic syndromes following vaccination with the B. burgdorferi outer surface protein A (OspA) in some patients provide support for the autoimmune hypothesis, and point to OspA as a possible culprit. In our preliminary studies, we found that antibodies generated against an OspA peptide, corresponding to a human brain cDNA sequence, to strongly immunostain human brain pyramidal neurons, spinal cord motor neurons, and dorsal root ganglia sensory neurons. In addition, sera from 3 of 6 patients whose neurologic symptoms began shortly after vaccination with OspA, but not from 6 control subjects, were found to have elevated antibody titers against the same peptide. We now propose to identify the cross-reactive protein and to determine if immune reactivity to it is associated with the chronic neurologic sequelae in Lyme disease. The specific aims of this project are: 1) to identify and characterize the putative cross-reactive neural protein, 2) to determine whether the presence of antibodies to the cross-reactive neural antigen is associated with neurologic deficits in chronic Lyme disease, and 3) to determine whether patients with antibiotic resistant chronic Lyme disease and neurological deficits exhibit T-cell reactivity to the peptide or protein. If the findings of the study support a role for autoimmunity in chronic neuroborreliosis, it would shed new light on the pathogenesis of the neurological complications and provide a rationale for clinical trials using immunomodulatory agents in this group of patients. Identification of specific immune reactivity to an autoantigen might also be useful as a diagnostic marker and for monitoring of disease activity in affected patients.