Mechanisms of IL-6 mediated T cell pathogenesis in autoimmunity

项目摘要 IL-6信号通路在自身免疫中失调，部分是通过增加IL-6受体的表达， 膜结合IL-6 R（mbIL-6 R）。这些研究的中心假设是mbIL-6 R升高， 表达导致改变的T细胞命运和功能，导致由于变化而导致的致病性自身反应性T细胞 STAT 1和STAT 3磷酸化的大小和平衡。以下三个具体目标将 解决这个假设。目的1研究mbIL-6 R在T细胞中的表达调控， 1例糖尿病（T1 D）、复发缓解型多发性硬化症（RRMS）和类风湿性关节炎（RA）受试者， 遗传、转录、翻译和翻译后水平，重点关注 IL 6 RAsp 358 Ala变体和ADAM 17介导的脱落。目的2研究将确定如何增加mbIL-6 R 改变STAT 1和STAT 3磷酸化的幅度和平衡，以及这些变化如何影响 关于谱系定型、归巢和对调节的反应的T细胞反应。这些研究将 利用具有遗传确定的mbIL-6 R表达水平的健康受试者队列。目标3 研究将确定mbIL-6 R表达升高对总T细胞和自身反应性T细胞的影响 在T1 D、RRMS和RA中。主要终点将是T细胞谱系定型、转录谱和免疫原性。 回应监管。该目的还将确定mbIL-6 R表达升高对胰岛细胞的影响。 T1 D患者对托珠单抗的特异性T细胞应答。本申请中提出的研究适用于 “高优先免疫学资助（R 01）”机制，因为它是研究免疫学 自身免疫性疾病发病机制使用明确的人类队列，高分辨率 免疫表型和系统免疫学。这些研究将使我们进一步了解 IL-6信号传导的改变有助于自身免疫的发展和增强。

PROJECT ABSTRACT The IL-6 signaling pathway is dysregulated in autoimmunity in part through increased expression of the membrane bound IL-6R (mbIL-6R). The central hypothesis for the proposed studies is that elevated mbIL-6R expression leads to altered T cell fate and function resulting in pathogenic autoreactive T cells due to changes in the magnitude and balance of STAT1 and STAT3 phosphorylation. The following three Specific Aims will address this hypothesis. Aim 1 studies will determine the regulation of mbIL-6R expression in T cells from type 1 diabetes (T1D), relapsing remitting multiple sclerosis (RRMS) and rheumatoid arthritis (RA) subjects at the genetic, transcriptional, translational and post-translation level, focusing on the contribution of the IL6RAsp358Ala variant and ADAM17 mediated shedding. Aim 2 studies will determine how increased mbIL-6R alters the magnitude and balance of STAT1 and STAT3 phosphorylation and how these changes influence the T cell response with respect to lineage commitment, homing and response to regulation. These studies will take advantage of a cohort of healthy subjects with genetically determined mbIL-6R expression levels. Aim 3 studies will determine the impact of elevated mbIL-6R expression on both total T cells and autoreactive T cells in T1D, RRMS and RA. The primary endpoints will be T cell lineage commitment, transcriptional profile, and response to regulation. This aim will also determine the effect of elevated mbIL-6R expression on the islet specific T cell response to tocilizumab in T1D. The studies proposed in this application are appropriate for the “High Priority Immunology Grant (R01)” mechanism as it is research investigating the immunological mechanisms of autoimmune disease pathogenesis using well-defined human cohorts, high resolution immunophenotyping and systems immunology. These studies will advance our understanding of how subtle alterations in IL-6 signaling, contribute to the development and potentiation of autoimmunity.