Interaction of environment and genetics in the predisposition to inflammatory art

环境和遗传学的相互作用导致炎症艺术的易感性

• 批准号: 8633790
• 负责人: HOLLY Lallman ROSENZWEIG
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633790
• 关键词: Address; Affect; Age; Agonist; American; Arthritis; Arts; Base Pairing; Biological Process; C Type Lectin Receptors; CD4 Positive T Lymphocytes; Chronic; Clinical; Collaborations; Complex; Data; Dependency; Development; Discipline; Disease; Disease model; Dose; Environment; Etiology; Event; Exposure to; Eye; Family; Genes; Genetic; Genetic Predisposition to Disease; Host Defense; Immune; Immune System Diseases; Immune system; Immunologic Receptors; In Situ; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Investigation; Joints; Kinetics; Knowledge; Mediating; Microbe; Mission; Molecular Profiling; Mouse Strains; Mus; Mutate; Mutation; Mycobacterium Infections; Mycoses; Natural Immunity; Pain; Pathogenesis; Pathway interactions; Patient Care; Patients; Pattern recognition receptor; Penetrance; Point Mutation; Population; Predisposition; Prevalence; Production; Receptor Signaling; Regulation; Research; Rheumatoid Arthritis; Rheumatology; Role; Severities; Signal Transduction; Skin; Syndrome; T cell differentiation; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Toll-like receptors; arm; autoreactive T cell; base; chemokine; curdlan; cytokine; dectin 1; design; disability; human disease; in vivo; insight; joint destruction; mRNA Expression; microbial; novel; novel therapeutics; pathogen; public health relevance; receptor; response; sensor; theories; therapy development

DESCRIPTION (provided by applicant): Inflammatory arthritis is a highly debilitating and chronic immunological disease that results in pain and progressive destruction of the joints. Most arthritic syndromes are presumed polygenetic diseases with unknown etiologies. A prevailing theory is that in the context of genetic predisposition, environmental microbes trigger innate immunity in order to induce inflammatory disease. The preponderance of research to date has focused on adaptive and T cell responses in arthritis, with little being understood of what innate signals precede the activation of arthritis-causing T cells in the induction of disease. A recently identified gene NOD has unveiled important insight into the genetics involved in arthritis. A single base-pair change i NOD2 results in 100% penetrance of a disease called Blau syndrome wherein patients develop arthritis that is accompanied by inflammation of the eyes and skin. NOD2 belongs to the NOD-like receptor (NLR) family of pattern recognition receptors (PRRs) and is an important aspect of host defense against microbial pathogens, thereby suggesting an intriguing connection between microbial sensing and chronic inflammatory disease. To explore the role of NOD2 in arthritis, we chose to use disease modeled in the genetically susceptible SKG mouse strain because they develop a chronic, T cell-mediated arthritis that is induced by exposure to microbial triggers. In SKG mice, a spontaneous point mutation that perturbs T cell receptor signaling results in impaired positive and negative selection and enhanced production of autoreactive T cells. While arthritis in SKG mice is related to aberrant T cell responses, its initiation depends on innate immune mechanisms that activate the C- type lectin receptors (CLR), a class of PRRs known to be involved in host defense against fungal and mycobacterial infections. We crossed the NOD2 KO mice to the SKG mice and discovered that SKG mice deficient in NOD2 expression developed an exacerbated form of arthritis triggered by curdlan, which activates the CLR, Dectin-1. The three aims proposed relate to the hypothesis central of this application: NOD2 is an important determinant of arthritis susceptibility through regulation of immunological responses triggered by microbial activation of CLRs. We will: 1) Define how NOD2 expression influences the onset and development of arthritis triggered by curdlan in SKG mice, which includes how NOD2 expression influences inflammatory responses within the joint; 2) Elucidate the deleterious effects of NOD2-deficiency on arthritogenic T cell effector and regulatory responses that are involved in arthritis; 3) Determine whether the CARD9 pathway is essential for induction of arthritis in SKG mice and delineate the proximal CLRs central to arthritis regulated by NOD2 expression. That we have identified an innate immune receptor involved in a T cell- dependent disease may be an important clue into a powerful mechanism that has evolved to protect the joint from inflammation. Understanding the signaling mechanisms utilized by innate immune receptors such as CLRs and the effects of collaboration with NOD2, is an important question that needs to be addressed if the role of this receptor in arthritis is to be fuly understood. Results of the proposed studies delving into the mechanisms through which these innate immune pathways operate could open up new avenues for development of therapies for Blau syndrome and potentially also for other autoinflammatory, arthritic conditions.

描述（由申请人提供）： 炎症性关节炎是一种高度衰弱和慢性免疫性疾病，导致疼痛和关节的进行性破坏。大多数关节炎综合征被认为是病因不明的多基因疾病。一个流行的理论是，在遗传易感性的背景下，环境微生物触发先天免疫，以诱导炎症性疾病。迄今为止，研究的优势集中在关节炎的适应性和T细胞反应上，很少有人了解在疾病诱导中引起关节炎的T细胞激活之前的先天信号。最近发现的基因NOD揭示了关节炎遗传学的重要见解。NOD 2中的单个碱基对变化导致称为Blau综合征的疾病的100%复发，其中患者发展为关节炎，并伴有眼睛和皮肤的炎症。NOD 2属于模式识别受体（PRR）的NOD样受体（NLR）家族，并且是宿主防御微生物病原体的重要方面，从而表明微生物传感和慢性炎症性疾病之间的有趣联系。为了探索NOD 2在关节炎中的作用，我们选择使用遗传易感的SKG小鼠品系中的疾病模型，因为它们发展出一种慢性T细胞介导的关节炎，该关节炎是由暴露于微生物触发物诱导的。在SKG小鼠中，干扰T细胞受体信号传导的自发点突变导致阳性和阴性选择受损以及自身反应性T细胞的产生增强。虽然SKG小鼠中的关节炎与异常T细胞应答有关，但其起始取决于激活C型凝集素受体（C-type lectin receptor，C-type lectin receptor）的先天免疫机制，C-type lectin receptor是一类已知参与宿主防御真菌和分枝杆菌感染的PRR。我们将NOD 2 KO小鼠与SKG小鼠杂交，发现NOD 2表达缺陷的SKG小鼠出现了由可德兰（curdlan）触发的关节炎恶化形式，可德兰激活了Dec tin-1。提出的三个目的涉及本申请的假设中心：NOD 2是关节炎易感性的一个重要决定因素，通过调节由微生物激活CLR引发的免疫应答。我们将：1）确定NOD 2表达如何影响SKG小鼠中由可德兰引发的关节炎的发作和发展，包括NOD 2表达如何影响关节内的炎症反应; 2）阐明NOD 2缺乏对关节炎中涉及的致关节炎性T细胞效应和调节反应的有害影响; 3）确定CARD 9通路是否是SKG小鼠中诱导关节炎所必需的，并描绘出由NOD 2表达调节的关节炎中枢的近端CLR。我们已经确定了一种与T细胞依赖性疾病有关的先天免疫受体，这可能是一条重要的线索，可以揭示一种强大的机制，这种机制已经进化到保护关节免受炎症的影响。了解先天免疫受体（如CLR）利用的信号传导机制以及与NOD 2合作的作用是一个重要的问题，如果要充分了解这种受体在关节炎中的作用，就需要解决这个问题。研究这些先天免疫途径运作机制的结果可能为Blau综合征的治疗开发开辟新的途径，也可能为其他自身炎症，关节炎疾病开辟新的途径。