Environmentally-Induced Ocular Surface Inflammation Mimicking Sjogren's Syndrome

环境引起的眼表炎症模仿干燥综合征

基本信息

批准号：
7525584
负责人：
Stephen C Pflugfelder
金额：
$ 39.82万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7525584
关键词：
Adoptive Transfer Affect American Antigens Autoantibodies Autoantigens Autoimmune Process CD4 Positive T Lymphocytes CD8B1 gene Cells Cessation of life Cytosol Development Epithelial Epithelium Epitopes Eye diseases Functional disorder Goblet Cells Human Immune Immune response Infiltration Inflammation Inflammatory Inflammatory Response Keratoconjunctivitis Lacrimal gland structure Lead Liquid substance Location Mediating Membrane Modeling Mus Nude Mice Pathology Production Proteins Reflex action Role Secretory Cell Self Tolerance Serum Severities Sjogren&apos s Syndrome Spleen Stress Superficial Cervical Lymph Node Surface Surface Antigens Syndrome T-Lymphocyte Testing Tissues base cell transformation chemokine cytokine eye dryness intraepithelial lacrimal molecular size ocular surface prevent public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): Sj"gren's syndrome causes profound dysfunction of the lacrimal functional unit (LFU) that results in decreased secretion of tear fluid and ocular surface supportive factors by the lacrimal glands, loss of reflex tearing and loss of conjunctival goblet cells. These changes lead to a poorly wettable and irregular ocular surface. Immunopathological changes including immune/inflammatory cell infiltration and increased production of inflammatory cytokines and chemokines have been detected in the dysfunctional lacrimal glands and ocular surface tissues in Sj"gren's syndrome. The mechanisms responsible for this autoimmune lacrimal keratoconjunctivitis, as well as the specific role of inflammation in the LFU dysfunction in Sj"gren's syndrome remain to be determined. We have developed murine models with features mimicking the autoimmune lacrimal keratoconjunctivitis (ALKC) in human Sj"gren's syndrome that appear relevant to answer these unresolved questions. We have observed that exposure of the ocular surface to desiccating environmental stress exposes an autoantigen in the surface epithelia that induces a cellular and cytokine-mediated immune response that causes specific components of this pathology. We have demonstrated the pivotal role of this immune response by inducing Sj"gren's syndrome-like ALKC in na¿ve T cell deficient (nude) mice following adoptive transfer of CD4+ T cells isolated from the spleens or superficial cervical lymph nodes of mice exposed to desiccating environmental stress. We have found that regulatory T cells protect against the development of ALKC. These models will allow us to elucidate the mechanism of the immune based dysfunction of the LFU in Sj"gren's syndrome. Our central hypothesis is that desiccating ocular surface stress reveals autoantigens in the ocular surface epithelia that initiate a tissue specific T cell response which causes dysfunction and death of the critical secretory cells in the LFU. We further propose that the severity of this ALKC is worsened by defective self tolerance mechanisms. PUBLIC HEALTH RELEVANCE Our central hypothesis is that desiccating ocular surface stress reveals autoantigens in the ocular surface epithelia that initiate a tissue specific T cell response which causes dysfunction and death of the critical secretory cells in the LFU. We further propose that the severity of this ALKC is worsened by defective self tolerance mechanisms.

描述（由申请人提供）：干燥综合征导致泪腺功能单位（LFU）严重功能障碍，导致泪腺分泌泪液和眼表面支持因子减少、泪液反射丧失和结膜杯状细胞丧失这些变化导致眼表面润湿性差和不规则，包括免疫/炎症细胞浸润以及炎症细胞因子和趋化因子的产生增加。在干燥综合征的功能障碍的泪腺和眼表组织中检测到。导致这种自身免疫性泪腺角结膜炎的机制，以及炎症在干燥综合征的 LFU 功能障碍中的具体作用仍有待确定。具有模仿人类干燥综合征自身免疫性泪道角结膜炎 (ALKC) 特征的小鼠模型，这些模型似乎与回答这些问题相关我们观察到，眼表暴露于干燥的环境压力会暴露表面上皮细胞中的自身抗原，从而诱导细胞和细胞因子介导的免疫反应，从而导致这种病理学的特定组成部分。通过在 na¿ 中诱导类似干燥综合征的 ALKC 来做出反应过继转移从暴露于干燥环境应激的小鼠的脾脏或颈浅淋巴结中分离出的 CD4+ T 细胞后，我们发现调节性 T 细胞可以防止 ALKC 的发展。我们的目的是阐明干燥综合征中基于免疫的 LFU 功能障碍的机制。我们的中心假设是干燥的眼表应激揭示了眼表上皮细胞中的自身抗原，启动组织特异性 T 细胞反应，导致 LFU 中关键分泌细胞功能障碍和死亡。我们进一步提出，自我耐受机制缺陷会加剧这种 ALKC 的严重程度。我们的中心假设是眼表压力干燥。揭示了眼表上皮细胞中的自身抗原启动组织特异性 T 细胞反应，导致 LFU 中关键分泌细胞功能障碍和死亡。有缺陷的自我容忍机制。