Immunopathogenesis in fungal asthma

真菌性哮喘的免疫发病机制

• 批准号: 10356139
• 负责人: Chad Steele
• 金额: $ 49.06万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-08 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356139
• 关键词: Allergens; Allergic; Apoptosis; Aspergillus fumigatus; Asthma; Attention; Binding; Bone Marrow; CHI3L1 gene; Cell Wall; Cells; Chimera organism; Chitin; Chitin Synthase; Chitinase; Chronic; Chronic Obstructive Pulmonary Disease; Clinical; Collaborations; Cystic Fibrosis; Data; Dictyoptera; Epithelial Cells; Exposure to; Fluorescein-5-isothiocyanate; Funding; Generations; Homologous Gene; Human; Immune; Immune response; Immunologics; In Vitro; Inflammation; Innate Immune Response; Label; Lung; Lung Lavage Fluid; Lung diseases; Mammals; Mediating; Mediator of activation protein; Mus; National Heart, Lung, and Blood Institute; Particle Size; Physiological Processes; Polysaccharides; Proteins; Publishing; Pyroglyphidae; Reporter; Reporting; Research; Role; Sampling; Severities; Severity of illness; Smooth Muscle Myocytes; Sputum; Therapeutic; Translating; acidic mammalian chitinase; asthmatic; atopy; base; exoskeleton; fungus; immunoreactivity; improved; in vivo; mutant; negative affect; overexpression; particle; programs; protein function; pulmonary function; respiratory smooth muscle; response

The objective of this competitive renewal R01 is to continue to uncover mechanisms that contribute to the severity of disease in the nearly 40% of severe asthmatics who are sensitized to fungi. Chitin, a polysaccharide found in the fungal cell wall and the exoskeletons of house dust mites and cockroaches, has garnered attention as a potential immunoreactive allergen. Mammals have evolved to express chitin-degrading chitinases (acidic mammalian chitinase and chitotriosidase) and chitin-binding chitinase-like proteins (YKL-40 in humans, BRP-39 in mice) that may modulate immune responses to chitin. Our recently published data demonstrated that chronic fungal exposure in acidic mammalian chitinase (AMCase) deficient mice resulted in lower AHR in the presence of lower type 17 responses (Infect Immun 86:e0094, 2018). These observations prompted the question how can lack of chitin degradation in the absence of AMCase result in better lung function and less inflammation? Put another way, how can putatively higher chitin content in the lung during fungal asthma be beneficial? Based on studies reporting that different chitin particle sizes induced different immune responses, we posited that the generation of some chitin particles in vivo results in responses that regulate rather than promote inflammation. Preliminary data demonstrates that chitin particle sizes (detected by a FITC-labeled chitin binding domain in lung lavage fluid) are different between asthmatic WT and AMCase deficient mice, with some sizes increased and some decreased. Studies in Aim 1 will further examine chitin particle sizes in mice with normal, absent and overexpressed AMCase and correlate these with immune responses that positively or negatively regulate type 17 responses. In other data, mice deficient in the murine homologue of YKL-40 (BRP-39, Chi3l1-/-) demonstrated worse AHR during fungal asthma, despite lower type 2 responses. Bone marrow chimera studies confirmed these findings and demonstrated that BRP-39 expression in either the immune or non-immune compartment resulted in better AHR compared to the dual absence of BRP-39 expression in both compartments. Studies in Aim 2 will further determine immune and non-immune responses modulated by BRP-39 chitin binding. We further show that chronic exposure to pure A. fumigatus chitin results in the induction of type 1 and type 17, but not type 2, responses. Overall, our hypothesis is that during chronic lung exposure to live fungi, AMCase degrades chitin into various sizes, some of which may drive responses that enhance AHR. In contrast, BRP-39 functions to bind chitin, resulting in a response(s) that regulate/reduce AHR. The specific aims of the proposal are: (1) to define mechanisms of AMCase-mediated immunopathogenesis during fungal asthma, (2) to define mechanisms of BRP-39-mediated modulation of fungal asthma severity and (3) to examine chitinase and chitinase-like protein levels in lung samples from human asthmatics sensitized to fungi.

本次竞争性更新R 01的目的是继续发现导致严重性的机制 近40%的严重哮喘患者对真菌过敏。甲壳素是一种多糖， 真菌的细胞壁和屋尘螨和蟑螂的外骨骼，已经引起了人们的注意， 潜在的免疫反应性过敏原哺乳动物已经进化到表达几丁质降解几丁质酶（酸性的 哺乳动物几丁质酶和壳三糖苷酶）和几丁质结合几丁质酶样蛋白（人YKL-40，BRP-39 在小鼠中），其可以调节对几丁质的免疫应答。我们最近发表的数据表明， 酸性哺乳动物几丁质酶（AMCase）缺陷小鼠的真菌暴露导致AHR降低， 较低的17型反应（感染免疫86：e0094，2018）。这些观察结果引发了一个问题， 在没有AMCase的情况下，缺乏几丁质降解会导致更好的肺功能和更少的炎症？放 另一方面，真菌性哮喘期间肺中较高的几丁质含量是如何有益的？基于 研究报道不同的甲壳质颗粒大小诱导不同的免疫反应，我们假设， 在体内产生一些几丁质颗粒导致调节而不是促进炎症的反应。 初步数据表明，几丁质颗粒大小（由肺中FITC标记的几丁质结合结构域检测）， 灌洗液）在哮喘WT和AMCase缺陷小鼠之间是不同的，其中一些尺寸增加， 有些下降了。目的1中的研究将进一步检查正常、缺失和缺失的小鼠中几丁质颗粒的大小。 过表达的AMCase，并将这些与免疫反应相关， 17个答案在其他数据中，缺乏YKL-40的鼠同源物（BRP-39，Chi 3l 1-/-）的小鼠表现出 真菌性哮喘时AHR更差，尽管2型反应较低。骨髓嵌合体研究证实 这些发现表明，BRP-39在免疫或非免疫区室中的表达 与两个区室中BRP-39表达的双重缺失相比，研究 目的2将进一步确定由BRP-39几丁质结合调节的免疫和非免疫应答。我们进一步 表明长期暴露于纯A。烟曲霉几丁质诱导1型和17型，但不诱导1型和17型， 2、答案。总的来说，我们的假设是，在慢性肺暴露于活真菌，AMCase降解， 甲壳素变成各种大小，其中一些可以驱动增强AHR的反应。BRP-39 其功能是结合几丁质，导致调节/降低AHR的反应。该委员会的具体目标 我们的建议是：（1）确定真菌性哮喘中AMCase介导的免疫发病机制，（2） 确定BRP-39介导的真菌性哮喘严重程度调节的机制;（3）检测几丁质酶， 对真菌致敏的哮喘患者肺样本中几丁质酶样蛋白水平