Pathogen-specific T cell responses in patients with SLE

描述(由申请人提供)： 这是一位临床训练有素的风湿病专家申请K08临床科学家发展奖，他现在正寻求扩大自己的职业生涯，成为一名独立的内科科学家。EB病毒(EBV)感染在系统性红斑狼疮(SLE)患者中比对照组更常见，提示该病毒在疾病中起病因学作用和/或狼疮患者EBV特异性免疫反应受损。这项建议的初步研究结果表明，与健康对照组相比，SLE患者在控制潜伏的EBV感染方面存在缺陷，EBV病毒载量增加和EBV特异性T细胞反应改变就是明证。有趣的是，研究报告称，由于系统性红斑狼疮患者水痘带状疱疹病毒(VZV)的重新激活以及类风湿关节炎(RA)患者外周血中EBV病毒载量的增加，带状疱疹的频率增加。这些发现提出了几个问题：1)控制潜伏性EBV感染的缺陷是SLE的独特发现，还是在诸如RA等慢性免疫介导性疾病中的全球现象；以及2)SLE的这种缺陷是仅限于EBV还是与其他潜伏性病毒感染有关，如VZV和巨细胞病毒(CMV)。下一个问题是这种缺陷的机制及其临床意义。为了解决这些问题，计划了三个具体目标。首先，将寻求SLE患者与健康和疾病(RA)对照组之间EBV和VZV特异性T细胞在数量和功能上的差异。在这里，外周血中EBV和VZV特异性的CD4+和CD8+T细胞将使用MHC I类四聚体、短期体外刺激后的流式细胞术和细胞毒试验进行分析。外周血液中的EBV病毒载量将使用实时聚合酶链式反应进行测量。其次，为了确定缺陷是否继发于免疫抑制药物和/或免疫激活，将使用相同的检测方法来确定新发SLE患者中EBV和VZV特异性T细胞反应和EBV病毒载量。第三，免疫抑制治疗对系统性红斑狼疮中EBV和VZV特异性T细胞和EBV病毒载量的影响将通过连续测量免疫抑制治疗前后EBV和VZV特异性T细胞和EBV病毒载量的频率和功能来评估。

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.