Infections, Microbiome and HLA-DR in the Induction of Lupus Related Auto-antibodies

摘要 系统性红斑狼疮(SLE)是一种全身性自身免疫性疾病的原型，主要影响 年轻的雌性。它会导致严重的发病率和死亡率。无明显副作用的有效疗法 因为诱导缓解和预防复发是不够的。我们的新假说将人类白细胞抗原-D 系统性红斑狼疮的发病机制是自身抗体和自身反应性T细胞由 T细胞与自身抗原(自身抗原)和环境抗原(如细菌)的交叉反应 人类白细胞抗原-DR限制性方式。在一段时间内，自身反应性T细胞的积累导致产生 复杂的自身抗体，在合适的宿主中导致临床疾病。缓解发生在自动减退- 反应性T细胞和自身抗体的特异性。复发发生在分子模拟的重复刺激下 主持人。最初的临床表现和复发取决于刺激的性质 分子模拟。我们已经广泛地定位了狼疮相关抗原SMD中的T细胞表位。这款Auto-Ag有 分子内和分子间T细胞表位的交叉反应。分子内交叉反应T细胞的存在 表位是它们成为SLE靶点的原因。多个交叉反应T细胞表位的存在 其中SNRNP的多肽为我们提供了对B细胞表位扩散机制的了解 SLE。在SMD中发现了多个T细胞抗原区。每个区域似乎都能诱导出独特的 自身抗体的特异性模式。多个T细胞受体(TCR)用于免疫应答 SMD。从指令区系中鉴定出几种微生物模拟物，它们能够诱导不同的 自身抗体的表达方式与亲本多肽相似。在模拟物之间存在交叉反应的B细胞表位 和亲本SMD多肽。破伤风类毒素(TT)T细胞表位与SMD表位的交叉反应 都已被记录在案。这些结果和其他初步数据为目前的提议提供了基础 我们希望更好地了解环境银在SLE相关自身抗体诱导中的作用。三个具体目标 建议：具体目标1：将我们在DR3转基因模型中观察到的结果转化为正常个体 和SLE患者，并将SLE相关抗体的诱导与微生物区系和破伤风类毒素联系起来；具体目标2： 证明消耗或调节肠道微生物区系的抗生素治疗将调节自身抗体 (NZM2328xNOD)F1、NZM2328和(NZM2328) NZM2328.DR3；以及特定目标3：从NZM2328和NZM2328.DR3获得无菌小鼠，以展示 狼疮性肾炎和狼疮相关自身抗体不会在无菌或有生菌的环境中发展， 支持微生物区系在系统性红斑狼疮相关自身抗体的发展中起关键作用的论点。论 在基础水平上，预期的结果将为SLE中自动抗体的来源提供洞察，并将提供证据 T细胞和B细胞在SLE发病中均起重要作用。他们还将支持将微生物区系作为一种新的方法 治疗和预防系统性红斑狼疮的发展。

ABSTRACT Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune disorder that affects mostly young females. It causes significant morbidity and mortality. Effective therapies without significant side effects for induction of remission and prevention of relapses are wanting. Our novel hypothesis that links the HLA-D region to the pathogenesis of SLE is that autoantibodies (auto-Ab) and auto-reactive T cells are generated by the activation of T cells cross-reactive with autoantigens (auto-Ag) and enviromental (such as bacterial) Ag in the HLA-DR restricted manner. Over a period of time accumulation of auto-reactive T cells leads to the production of complex auto-Ab, resulting in clinical disease in suitable hosts. Remission occurs with reduction of auto- reactive T cells and of auto-Ab specificities. Relapses occur with repeated stimulation by molecular mimics in the host. The initial clinical presentation and the relapses depend on the nature of the stimulation by the molecular mimics. We have extensively mapped the T cell epitopes in a lupus-related Ag, SmD. This auto-Ag has cross reactive intra- and inter-molecular T cell epitopes. The presence of intra-molecular cross-reactive T cell epitopes is the reason why they are targeted in SLE. The presence of multiple cross-reactive T cell epitopes among polypeptides of snRNP provides us the understanding of the mechanism of B cell epitope spreading in SLE. Multiple T cell antigenic regions have been identified in SmD. Each region appears to induce unique patterns of auto-Ab specificity. Multiple T cell receptors (TCR) are utilized in responses to immunization with SmD. Several microbial mimics from commansal flora were identified with the capability of inducing diverse auto-Ab in a similar manner as the parental peptide. There are cross reactive B cell epitopes between the mimics and the parental SmD peptides. Cross reactivity between tetenus toxoid (TT) T cell epitopes and those of SmD have been documented. These results and other preliminary data provide the basis for the current proposal for us to understand better the role of environmental Ag in the induction of SLE-related auto-Ab. Three specific aims are proposed: Specific Aim 1: To translate our observations in our DR3 transgenic model to normal individuals and SLE patients and to relate SLE-related Ab induction to microbiota and tetanus toxoid; Specific Aim 2: To demonstrate that antibiotic treatments that deplete or modulate the gut microbiota will modulate autoantibody production and/or disease course with prolonged survival in (NZM2328xNOD)F1, NZM2328 and NZM2328.DR3; and Specific Aim 3: To derive germ-free mice from NZM2328 and NZM2328.DR3 to show that lupus nephritis and lupus related auto-Ab will not develop in a germ-free or gnotobiotic environment, supporting the thesis that microbiota play a crucial role in the development of SLE-related auto-Abs. On the basic level, the expected results will provide insight to the origin of auto-Ab in SLE and will provide evidence that both T and B cells play important roles in SLE. They will also support targeting microbiota as a novel approach to treating and preventing the development of SLE.