Molecular Mechanisms of Squamous Metaplasia in Dry Eye

干眼症鳞状上皮化生的分子机制

• 批准号: 8186306
• 负责人: Nancy A McNamara
• 金额: $ 34.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8186306
• 关键词: Ablation; Anabolism; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Biological Markers; Biological Models; Blindness; CCL2 gene; CD4 Positive T Lymphocytes; Cells; Characteristics; Chronic; Clinical; Collaborations; Cornea; Couples; Cytology; Data; Development; Dichloromethylene Diphosphonate; Disease; Down-Regulation; Early Diagnosis; Effector Cell; Epithelial Cells; Epithelium; Event; Eye diseases; Fibrosis; Gene Chips; Genes; Genetic; Glycoconjugates; Goals; Goblet Cells; Histologic; Human; Immune; Immunosuppressive Agents; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Keratin; Keratoconjunctivitis Sicca; Keratopathy; Lacrimal gland structure; Left; Ligands; Link; Liposomes; Mediating; Mediator of activation protein; Molecular; Molecular Profiling; Monitor; Mononuclear; Morbidity - disease rate; Mucins; Mus; Nuclear; Ocular cicatricial pemphigoid; Organ; Pathogenesis; Pathological Staging; Patients; Phenotype; Polysaccharides; Process; Production; Proteins; Publishing; Research; Role; Severities; Severity of illness; Signal Transduction; Sjogren' s Syndrome; Skin; Specimen; Squamous Metaplasia; Staging; Stevens-Johnson Syndrome; Syndrome; Systemic disease; Testing; Vision; Work; aqueous; autoimmune exocrinopathy; base; chemokine receptor; corneal epithelium; cytokine; eye dryness; glycosylation; immunopathology; impression; in vivo; keratinization; mRNA Expression; macrophage; monocyte; mouse model; novel; ocular surface; palliative; prevent; proline-rich proteins; systemic autoimmune disease; transdifferentiation; treatment strategy

DESCRIPTION (provided by applicant): In systemic autoimmune diseases like Sj"gren's syndrome (SS), exocrinopathy of the lacrimal gland leads to an aqueous-deficient dry eye that is among the most common and debilitating clinical manifestations. As dry eye disease progresses, it initiates a multi-step, immune-mediated process that includes two pathological characteristics (1) transdifferentiation a nonkeratinized, mucosal ocular surface to a keratinized, "skin-like" epithelium; and (2) disruption of ocular surface and goblet cell mucins. This process, known as squamous metaplasia (SQM), is a devastating, end-stage consequence of dry eye disease that can cause considerable morbidity as advanced keratinzation couples with subepithelial fibrosis to cause corneal opacification and blindness. While immune-mediated inflammation has been implicated in the pathogenesis of SQM, little is known about the precise immunopathogenic mechanisms, leaving us with treatment strategies that are limited, costly and largely palliative. The goal of our research is to decipher how autoimmune-mediated inflammation provokes vision-threatening SQM. Using three model systems, (i) human patients with SS; (ii) a validated mouse model of spontaneous autoimmune exocrinopathy and keratopathy that mimics the clinical characteristics of SS; and (iii) in vitro studies of cultured corneal epithelial cells, our previous work demonstrated an essential role for autoreactive CD4+ T cells and their interplay with the proinflammatory cytokine IL-1 in the pathogenesis of SQM. Yet, the specific mechanism whereby CD4+ T cells and IL-1 promote SQM in autoimmune dry eye remains unknown. To deepen our understanding of the molecular and cellular pathogenic mechanism of immune-mediated SQM, and to identify possible targets for treatment, we seek to (i) determine how CD4+ cells work together with IL-1 to provoke SQM; and (ii) how IL-1 promotes transdifferentiation of the ocular surface epithelium to one that is mucin-depleted and pathologically keratinized. We hypothesize that autoantigen-primed CD4+ T cells work in collaboration with infiltrating monocytes to promote the local release of proinflammatory mediators (e.g., IL-1) that establish and sustain a chronic inflammatory state at the ocular surface. Once established, the local inflammatory response causes ocular surface damage and promotes SQM by disrupting, PAX6, the master regulator of ocular mucosal phenotype and altering the glycosylation and expression of ocular mucins. To test this hypothesis we will (Aim 1) explore infiltrating mononuclear cells as potential cellular intermediate linking antigen-primed CD4+ T cells to the local production of IL-1; (Aim 2) define how IL-1 directs the early stages of pathological keratinization, by studying its effects on the master gene controlling corneal phenotype, Pax6; and (Aim 3) characterize the mechanisms whereby IL-1 alters ocular mucins by identifying key genes regulating glycoconjugate biosynthesis. The overall impact of this work will include a better understanding of the immunopathology of SQM in autoimmune disease that is likely to uncover key events that aid in its early diagnosis and/or treatment. PUBLIC HEALTH RELEVANCE: Autoimmune diseases like Sj"gren's syndrome cause a severe dry eye that is highly recalcitrant to treatment. Despite powerful immunosuppressive and immunomodulatory therapy, autoimmune dry eye can progress to complete corneal opacification and blindness through a process known as squamous metaplasia. Little is known about the pathogenesis of squamous metaplasia and there is no cure. A better understanding of the underlying disease process would open the possibility of developing novel treatments to prevent corneal blindness.

描述（由申请人提供）：在SJ“ Gren's综合征（SS）等全身性自身免疫性疾病中，泪腺的外分泌性疾病会导致缺陷的干眼眼，这是最常见的，令人衰弱的临床表现。它启动了一个多步，免疫介导的过程，其中包括两个病理特征（1）转变的非乳头，粘膜眼表面到角质化的“皮肤样”上皮；这个过程被称为鳞状变质（SQM），是干眼症的毁灭性，终点，可能引起相当大的发病率，因为伴有上皮纤维化的晚期角化夫妇会导致角膜粘附和盲目性。在SQM的发病机理中，对精确的免疫致病机制知之甚少，这给我们带来了有限，昂贵且在很大程度上姑息治疗的治疗策略。我们研究的目的是破译自身免疫性介导的炎症如何激发威胁性的SQM。使用三个模型系统，（i）SS的人类患者； （ii）一种自发性自身免疫性外分病和角膜病的经过验证的小鼠模型，该模型模仿了SS的临床特征； （iii）对培养的角膜上皮细胞的体外研究，我们以前的工作表明了自动反应性CD4+ T细胞以及它们与促炎性细胞因子IL-1相互作用在SQM发病机理中的重要作用。然而，CD4+ T细胞和IL-1在自身免疫性眼睛中促进SQM的特定机制仍然未知。为了加深我们对免疫介导的SQM的分子和细胞致病机制的理解，并确定可能的治疗靶标，我们寻求（i）确定CD4+细胞与IL-1一起工作以引起SQM； （ii）IL-1如何促进眼表上皮转变为粘蛋白缺乏并在病理上角膜生素化的上皮。我们假设自动抗原启动的CD4+ T细胞与浸润的单核细胞合作起作用，以促进促炎性介质（例如IL-1）的局部释放，这些介体（例如IL-1）在眼部表面建立和维持慢性炎症状态。建立后，局部炎症反应会导致眼部表面损伤，并通过破坏眼粘膜表型的主要调节剂PAX6来促进SQM，并改变眼粘蛋白的糖基化和表达。为了检验这一假设，我们将（AIM 1）探索浸润的单核细胞，作为潜在的细胞中间体，将抗原引发的CD4+ T细胞与IL-1的局部产生联系起来。 （AIM 2）通过研究其对控制角膜表型的主基因PAX6的影响，定义IL-1如何指导病理角化的早期阶段； （AIM 3）表征IL-1通过鉴定调节糖缀合物生物合成的关键基因来改变眼粘蛋白的机制。这项工作的总体影响将包括对自身免疫性疾病中SQM的免疫病理学的更好理解，这可能会发现有助于早期诊断和/或治疗的关键事件。 公共卫生相关性：像SJ“ Gren's综合征”这样的自身免疫性疾病会导致严重的干眼，尽管具有强大的免疫抑制和免疫调节疗法，但具有高度顽固性的干眼症。自身免疫性的干眼可以发展到完全的角膜无序和盲目的过程中，这是一种称为鳞状化的鳞状质量。关于鳞状化生的发病机理已知，对潜在的疾病过程没有更好的理解。