Pathogen-specific T cell responses in patients with SLE

描述（由申请人提供）： 这是一个K 08指导临床科学家发展奖的申请，来自一位经过临床训练的风湿病学家，他现在寻求扩大自己的职业生涯，成为一名独立的医生科学家。系统性红斑狼疮（SLE）患者中EB-巴尔病毒（EBV）感染比对照组更常见，表明该病毒在疾病中起病因作用和/或狼疮患者具有受损的EBV特异性免疫应答。该建议的初步研究结果表明，SLE患者在控制潜伏性EBV感染方面存在缺陷，与健康对照相比，EBV病毒载量增加和EBV特异性T细胞应答改变证明了这一点。值得关注的是，研究报告了由于SLE患者水痘带状疱疹病毒（VZV）的再活化导致带状疱疹的频率增加，以及类风湿性关节炎（RA）患者外周血中EBV病毒载量增加。这些发现提出了几个问题：1）控制潜伏性EBV感染的缺陷是否是SLE的独特发现，还是慢性免疫介导疾病（如RA）的全球现象; 2）SLE中的这种缺陷是否仅限于EBV或与其他潜伏性病毒感染（如VZV和巨细胞病毒（CMV））相关。接下来的问题是这种缺陷的机制及其临床意义。为解决这些问题，计划实现三个具体目标。首先，将寻找SLE患者与健康和患病（RA）对照之间EBV和VZV特异性T细胞的数量和功能差异。在此，将使用MHC I类四聚体、短期体外刺激后的流式细胞术和细胞毒性试验分析外周血中的EBV和VZV特异性CD 4+和CD 8 + T细胞。将使用实时PCR测量外周血中的EBV病毒载量。第二，为了发现缺陷是否继发于免疫抑制药物和/或免疫激活，将使用相同的测定来确定新发SLE患者中的EBV和VZV特异性T细胞应答和EBV病毒载量。第三，将通过连续测量免疫抑制治疗前后EB病毒和VZV特异性T细胞以及EB病毒载量的频率和功能来评估免疫抑制治疗对SLE中EB病毒和VZV特异性T细胞以及EB病毒载量的影响。

DESCRIPTION (provided by applicant): This is an application for a K08 Mentored Clinical Scientist Development Award from a clinically trained rheumatologist who now seeks to expand his career to become an independent physician scientist. Epstein- Barr virus (EBV) infection is more common in patients with systemic lupus erythematosus (SLE) than control subjects, suggesting that this virus plays an etiologic role in disease and/or that patients with lupus have impaired EBV-specific immune responses. The results of preliminary study of this proposal has demonstrated that patients with SLE have a defect in controlling latent EBV infection as evidenced by the increased EBV viral loads and altered EBV-specific T cell responses compared to healthy controls. Of interest, studies reported an increased frequency of herpes zoster due to reactivation of varicella zoster virus (VZV) in patients with SLE and increased EBV viral loads in peripheral blood of patients with rheumatoid arthritis (RA). These findings raise several questions: 1) whether the defect in controlling latent EBV infection is a unique finding in SLE or a global phenomenon in chronic immune-mediated diseases such as RA; and 2) whether this defect in SLE is limited to EBV or relavent to other latent viral infections such as VZV and cytomegalovirus (CMV). Next issues are the mechanisms for this defect and its clinical significance. To address these questions, three specific aims are planned. First, numerical and functional differences in EBV- and VZV-specific T cells between patients with SLE and healthy and diseased (RA) controls will be sought. Here, EBV- and VZV-specific CD4+ and CD8+ T cells in peripheral blood will be analyzed using MHC class I tetramers, flow cytometry following short-term in vitro stimulation and cytotoxic assay. EBV viral loads in peripherla blood will be measured using real-time PCR. Second, to find if the defect is secondary to immunosuppressive drugs and/or immune activation, EBV- and VZV- specific T cell responses and EBV viral loads in patients with new onset SLE will be determined using the same assays. Third, the effects of immunosuppressive therapies on EBV- and VZV-specific T cells and EBV viral loads in SLE will be assessed by serially measuring the frequency and function of EBV- and VZV-specific T cells and EBV viral loads before and after immunosuppressive therapies.