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Defining the Immune Cell Roles in Meibomian Gland Dysfunction in the Context of Ocular Surface Immune Diseases

定义眼表免疫疾病背景下睑板腺功能障碍中免疫细胞的作用

基本信息

批准号：
10707387
负责人：
Daniel Raphael Saban
金额：
$ 39.88万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707387
关键词：
Ablation Aging Allergic Atlases Automobile Driving Benign Mucous Membrane Pemphigoid Bioinformatics Blood Caring Cells Chronic Clinical Color Complex Cutaneous Data Data Set Diagnosis Disease Disease model Dry Eye Syndromes Duct (organ) structure Epithelium Eye Eye diseases Eyelid structure FDA approved Film Flow Cytometry Funding Future Genes Genetic Genetic Models Gland Grant Human Hypersensitivity Image Immune Immune System Diseases Immune response Immunodiagnostics Immunologic Markers Individual Inflammation Kinetics Knowledge Link Lipids Literature Maps Mediating Medicine Metadata Microscopy Mind Modeling Mucous Membrane Mus Mutagenesis Neutrophil Infiltration Obstruction Ocular cicatricial pemphigoid Oils Outcome Study Pathogenesis Pathogenicity Pathologic Pathologic Processes Pathology Patients Phenotype Play Prevalence Process Risk Factors Role Sampling Sebaceous Glands Severities Sjogren&apos s Syndrome Skin Stevens-Johnson Syndrome Surface Tissues Toxic Epidermal Necrolysis Translating Work Zinc Fingers atopy chemokine receptor conjunctiva diagnostic biomarker evaporation eye dryness genome wide association study graft vs host disease human disease in vivo meibomian gland dysfunction mouse model neutrophil new therapeutic target novel novel therapeutic intervention ocular surface ocular surface disease overexpression pharmacologic programs single-cell RNA sequencing tool tv watching

项目摘要

ABSTRACT Inflammation is a vastly underappreciated player in meibomian gland dysfunction – a common pathological condition of eyelid sebaceous glands responsible for producing tear film lipids. Pathologic blockage of the gland orifice and central duct, referred to as “obstructive” meibomian gland dysfunction, is regularly accompanied by ocular surface inflammation in patients. Moreover, this type of obstruction is ubiquitous, and even more aggressive, in patients with ocular surface immune disease. The latter is defined here as ocular surface pathology associated with systemic immune disorders, such as atopy (allergy), Stevens-Johnson syndrome/toxic epidermal necrolysis, Sjogren’s syndrome, graft versus host disease, cicatricial pemphigoid, and others. Still, the exact immune mechanisms involved in meibomian gland dysfunction remain elusive. As no pharmacological agents are indicated for meibomian gland dysfunction, there is a critical need for uncovering the pertinent immune responses of this pathobiology in patients with ocular surface immune disease. In the last funding cycle, we showed a direct role for neutrophils in meibomian gland dysfunction in our model of chronic-like allergic eye disease. Based on this work and the current literature, our central hypothesis is that neutrophils play a role in driving meibomian gland dysfunction across different forms of ocular surface immune diseases. In the current proposal, we will: i) elucidate the pathogenic neutrophil mechanisms that drive meibomian gland dysfunction in our established model of chronic-like allergic eye disease; ii) decipher the role of neutrophils in meibomian gland dysfunction in a novel and spontaneous genetic mouse model of ocular surface immune disease; and iii) map the tear immune cell landscape of meibomian gland dysfunction in patients with different ocular surface immune disease entities. In addition to mouse models, we will leverage our unpublished single cell RNA-seq dataset of immune cells from blood, conjunctiva, and tears from our allergic eye disease mouse model, paired with computational, genetic, and pharmacologic tools to pinpoint the pathogenic neutrophil mechanisms. For human samples, we established a 36-color flow cytometry panel for deep immune profiling of patient tears and have incorporated clinical expertise for the annotation of each individual with detailed clinical metadata. The rationale for this project is that identifying the critical immune cell subsets and associated pathogenic cellular programs that drive meibomian gland dysfunction will offer a strong scientific framework by which to delineate the role of inflammation in human meibomian gland dysfunction, as well as identify novel therapeutic targets and diagnostic immune markers to support efforts in the clinical space. Completion of these studies is therefore expected to have a significant impact by expanding the breadth and depth of knowledge regarding the role of inflammation, specifically neutrophils, in meibomian gland dysfunction, ultimately providing new opportunities to treat and diagnose this pervasive condition.

摘要炎症是眉毛腺功能障碍--一种常见的病理--的一个被严重低估的因素负责产生泪膜脂质的眼皮皮脂腺的状况。腺体病理性阻塞开口和中央导管，被称为“梗阻性”眉板腺功能障碍，常伴有患者眼表炎症。此外，这种类型的障碍无处不在，甚至更多侵袭性，在眼表免疫性疾病患者中。后者在这里被定义为眼表与全身免疫紊乱相关的病理学，如特应性(过敏)、史蒂文斯-约翰逊综合征/毒性表皮坏死松解症、干燥综合征、移植物抗宿主病、瘢痕性类天疱疮等。不过，有关眉板腺功能障碍的确切免疫机制仍不清楚。因为没有药理作用药物是眉毛腺功能障碍的适应症，迫切需要揭示相关的眼表免疫性疾病患者的免疫反应。在上一个资金周期中，在我们的慢性类过敏性眼睛模型中，我们显示了中性粒细胞在眉板腺功能障碍中的直接作用。疾病。基于这项工作和目前的文献，我们的中心假设是中性粒细胞在在不同形式的眼表免疫性疾病中驱动眉板腺功能障碍。在当前建议，我们将：i)阐明致病性中性粒细胞导致眉板腺功能障碍的机制。我们建立的慢性类过敏性眼病模型；ii)破译中性粒细胞在眉板腺中的作用一种新的自发遗传小鼠眼表免疫病模型的功能障碍；以及iii)MAP 不同眼表免疫力患者泪腺功能障碍的泪液免疫细胞图谱疾病实体。除了小鼠模型，我们还将利用我们未发表的单细胞rna-seq数据集来自血液、结膜和泪液的免疫细胞来自我们的过敏性眼病小鼠模型，与计算、遗传和药理学工具，以确定致病中性粒细胞的机制。对于人类来说样本，我们建立了一个36色流式细胞仪小组，用于深度免疫分析患者泪液和结合临床专业知识，使用详细的临床元数据对每个个体进行注释。其基本原理是对于这个项目来说，识别关键的免疫细胞亚群和相关的致病细胞程序这将提供一个强有力的科学框架来描述脑膜腺的功能人类眉板腺功能障碍中的炎症，以及确定新的治疗靶点和诊断免疫标记物支持临床领域的努力。因此，预计这些研究将于通过扩大关于炎症作用的知识的广度和深度，产生重大影响，特别是中性粒细胞，在眉毛腺功能障碍中，最终提供了新的治疗和治疗机会。诊断这种普遍存在的情况。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ocular allergy modulation to hi-dose antigen sensitization is a Treg-dependent process.

DOI：
10.1371/journal.pone.0075769
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Lee HS;Schlereth S;Khandelwal P;Saban DR
通讯作者：
Saban DR

Linking immune responses with fibrosis in allergic eye disease.

DOI：
10.1097/aci.0000000000000197
发表时间：
2015-10
期刊：
Current opinion in allergy and clinical immunology
影响因子：
2.8
作者：
Dale SB;Saban DR
通讯作者：
Saban DR

The chemokine receptor CCR7 expressed by dendritic cells: a key player in corneal and ocular surface inflammation.

DOI：
10.1016/j.jtos.2013.10.007
发表时间：
2014-04
期刊：
The ocular surface
影响因子：
0
作者：
Saban DR
通讯作者：
Saban DR

Ocular mucosal CD11b+ and CD103+ mouse dendritic cells under normal conditions and in allergic immune responses.

DOI：
10.1371/journal.pone.0064193
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Khandelwal P;Blanco-Mezquita T;Emami P;Lee HS;Reyes NJ;Mathew R;Huang R;Saban DR
通讯作者：
Saban DR

Disease-Specific Expression of Conjunctiva Associated Lymphoid Tissue (CALT) in Mouse Models of Dry Eye Disease and Ocular Allergy.

在干眼症和眼过敏的小鼠模型中，结膜相关淋巴组织（CALT）的疾病特异性表达。