Role of type 2 Innate Lymphoid Cells (ILC2s) in optic neuritis

所提出的研究的主要目的是测试一种新的假设性视神经炎模型， 总体目标是精确定位药物治疗靶点。视神经炎是一种涉及原发性 视神经的炎症。急性时，它与视力丧失或复视有关， 多发性硬化症的表现几条证据表明，这是一个多因素，自身免疫性 一种涉及T细胞介导的视神经脱髓鞘的疾病，但已被证明难以区分 旁观者效应的因果反应。提供一个框架，用于识别 在多因素相互作用的背景下，我们已经开发了联合收割机 HSV-1感染通过眼部感染引起白细胞介素-2（IL-2）的组成性过表达 重组HSV-IL-2病毒或使用Alzet渗透微型泵将IL-2递送到小鼠脑中， 野生型HSV-1的眼部感染。CD 4+和CD 8 + T细胞均参与HSV-1/IL-2诱导的视神经细胞凋亡。 神经和CNS病理学，并且病理学类似于MOG 35 -55 EAE模型。现款车型 然而，它们是不同的，因为它们证明，在病毒感染的情况下，IL-2可以驱动视神经， 和CNS脱髓鞘。IL-2驱动的病理学所需的相互作用的初步分析， 敲除、耗尽、过继转移和/或阻断方法提供了新的见解， IL-2和IL-2 r γ（而不是IL-2 r α或IL-2 r β）亚基之间相互作用的潜在要求，以及 IL-2的单个氨基酸突变与发病机制阻断的关联;一个潜在的要求 对于2型先天淋巴（ILC 2）细胞，ILC 1或ILC 3不起作用;以及潜在的需要 通过ILC 2细胞产生IL-17 A。IL-17 RA或IL-17 RC受体在TH 17细胞上的结合 似乎会导致中枢神经系统脱髓鞘巨噬细胞和IL-12 p70似乎在该模型中起保护作用。 总的来说，这些数据提示了一个假设模型，其中在病毒感染的背景下IL-2的升高 驱动自身攻击性TH 17反应，通过产生 产生IL-17的ILC 2。我们将通过定义细胞因子/受体相互作用来检验这一假设， 在这些模型中ILC亚型对以下的反应：（1）确定ILC 2的存在是否是视神经病变所必需的。 （2）确定IL-17 A的ILC 2-产生是否有助于视神经/CNS病理学; （3）确定ILC 2细胞应答和ILC 2细胞应答之间的相互作用， 脱髓鞘中巨噬细胞产生IL-12 p70。临床相关性：视神经炎是典型的 炎症性自身免疫性疾病与MS密切相关。 一个假设的模型将有广泛的影响，在促进理解的相互作用， 环境信号和宿主易感性因素，产生自身免疫反应，并将提供 设计更有效的治疗靶向以解决和/或阻断 视神经炎在某些病人与这种情况。

The primary objective of the proposed studies is to test a novel hypothetical model of optical neuritis with the overall goal of pinpointing druggable therapeutic targets. Optic neuritis is a condition involving primary inflammation of the optic nerve. Acutely it is associated with loss of vision or double vision and is often the first presentation of multiple sclerosis. Several lines of evidence indicate that it is a multifactorial, autoimmune condition involving T-cell mediated demyelination of the optic nerve, but it has proven difficult to distinguish causative responses from bystander effects. To provide a framework for identification of causative responses in the context of multifactorial interactions, we have developed mouse models of optic neuritis that combine constitutive overexpression of interleukin-2 (IL-2) with HSV-1 infection through ocular infection with recombinant HSV-IL-2 virus or delivery of IL-2 into the brains of mice using Alzet osmotic mini-pumps prior to ocular infection with wild-type HSV-1. Both CD4+ and CD8+ T cells contribute to the HSV-1/IL-2-induced optic nerve and CNS pathology and the pathology resembles that of the MOG35–55 EAE model. The current models are distinct, however, in that they demonstrate that, in the context of viral infection, IL-2 can drive optic nerve and CNS demyelination. Preliminary analysis of the interactions required for the IL-2-driven pathology using knockout, depletion, adoptive transfer and/or blocking approaches have provided novel insights pinpointing a potential requirement for interactions between IL-2 and the IL-2rγ (but not IL-2rα or IL-2rβ) subunit as well as the association of a single amino acid mutation of IL-2 with blockade of pathogenesis; a potential requirement for type 2 innate lymphoid (ILC2) cells, with ILC1 or ILC3 playing no role; and a potential requirement for production of IL-17A by the ILC2 cells. Engagement of either the IL-17RA or IL-17RC receptor on TH17 cells appears to drive CNS demyelination. Macrophages and IL-12p70 appear to play protective roles in this model. Collectively, these data suggest a hypothetical model in which elevation of IL-2 in the context of viral infection drives an autoaggressive TH17 response that causes optic neuritis and CNS pathology through generation of IL-17-producing ILC2s. We will test this hypothesis by defining the cytokine/receptor interactions and responses of ILC subtypes in these models to: (1) Determine whether the presence of ILC2 is required for optic nerve/CNS pathology; (2) Determine whether ILC2-production of IL-17A contributes to optic nerve/CNS pathology by promoting a TH17 response; and (3) Determine the interplay between ILC2 cell responses and macrophage production of IL-12p70 in demyelination. CLINICAL RELEVANCE: Optic neuritis is a prototypic inflammatory autoimmune disease that is closely associated with MS. Confirmation of the proposed hypothetical model will have broad implications in terms of advancing the understanding of the interactions of environmental signals and host susceptibility factors that generate autoimmune responses and will provide a conceptual framework for the design of more effective therapeutic targeting for resolution and/or blocking of optic neuritis in some patients with this condition.