Investigation of microbial hetergeneity to sarcoidosis and AAT clinical outcome

结节病微生物异质性和 AAT 临床结果的调查

• 批准号: 8661274
• 负责人: Wonder P. Drake
• 金额: $ 15万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661274
• 关键词: Alleles; Antigens; Antimycobacterial Agents; Bronchiectasis; Clinic; Clinical; Communities; Disease; Elastases; Etiology; Eye; Fibrosis; Genetic Transcription; Granulomatous; High-Throughput Nucleotide Sequencing; Immunity; Immunologics; Infectious Agent; Interleukin-2; Investigation; Leukocyte Elastase; Leukotriene B4; Lung; Lung diseases; Medical; Molecular; Mycobacterium Infections; Mycobacterium ulcerans; Neutrophil Infiltration; Outcome; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Population; Prevalence; Protease Inhibitor; Pulmonary Sarcoidosis; Regimen; Sarcoidosis; Secondary to; Serum Proteins; Severities; Severity of illness; Skin; Specimen; T cell anergy; T-Cell Receptor; T-Lymphocyte; Virulence Factors; Yersinia pestis; airway inflammation; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; anergy; base; cohort; cytokine; improved; lymph nodes; microbial; microbial community; microbiome; microorganism; mycobacterial; neutrophil; pathogen; pathogenic bacteria

DESCRIPTION (provided by applicant): Sarcoidosis is a heterogeneous, granulomatous disease of world-wide prevalence, most commonly involving the lung, skin, lymph node and eyes. Although the etiology is unknown, molecular and immunologic investigations of sarcoidosis specimens suggest that host interactions with infectious antigens, particularly mycobacterial antigens, contribute to pathogenesis among some subjects. In addition, it has been recently demonstrated that broad-spectrum antimycobactehal therapy (CLEAR regimen) provides clinical improvement among pulmonary sarcoidosis subjects without fibrosis, but not among those with advanced fibrotic disease. It is unknown if distinctions in the microbial community exist among heterogeneous sarcoidosis populations. In a similar fashion, an association has been observed between disease severity among patients with Alpha-1-antitrypsin (AAT) deficiency and pathogenic bacteria. Alpha-1 antitrypsin (AAT) is a potent antiprotease with activity against neutrophil elastase (NE). AAT deficiency is associated with a greater neutrophil load, higher elastase activity, leukotriene-B(4) concentration, and serum protein leak than matched patients without deficiency; the resultant airways inflammation with neutrophil recruitment and elastase release is positively correlated with colonizing bacterial load. Microbiome analysis of both sarcoidosis and AAT specimens will enhance understanding of the contribution infectious agents provide to disease severity. Sarcoidosis is also characterized by cellular anergy; we observed improvement in sarcoidosis T cell biologic function among some sarcoidosis subject who completed this antimycobacterial regimen, suggesting the microbial virulence factors may contribute to sarcoidosis T cell anergy. We hypothesize the distinctions in microbiota correlate with disease severity among sarcoidosis and AAT populations, and that the microorganisms present possess the capacity to induce T cell anergy. We propose to define the microbiota within heterogeneous sarcoidosis and AAT populations, and to determine the effects of the microbiome on T cell biologic function. RELEVANCE: Sarcoidosis and AAT are important medical problems. The strength of this proposal is microbial characterization according to disease severity among heterogeneous sarcoidosis and AAT cohorts. This proposal will also enhance understanding of microbial induction of T cell anergy, for which there is a lack of appreciation in idiopathic lung diseases.

描述（由申请人提供）： 结节病是一种异质性肉芽肿性疾病，在世界范围内流行，最常见的是累及肺、皮肤、淋巴结和眼睛。虽然病因不明，但结节病标本的分子和免疫学研究表明，宿主与感染性抗原，特别是分枝杆菌抗原的相互作用，有助于某些受试者的发病机制。此外，最近已经证明，广谱抗分枝杆菌治疗（CLEAR方案）在无纤维化的肺结节病受试者中提供了临床改善，但在晚期纤维化疾病受试者中没有。目前尚不清楚异质性结节病人群之间是否存在微生物群落的差异。以类似的方式，在患有α-1-抗胰蛋白酶（AAT）缺乏症的患者中观察到疾病严重程度与病原菌之间的关联。α-1抗胰蛋白酶（AAT）是一种有效的抗蛋白酶，具有抗中性粒细胞弹性蛋白酶（NE）的活性。AAT缺乏与匹配的无AAT缺乏的患者相比，与更大的中性粒细胞负荷、更高的弹性蛋白酶活性、白三烯-B（4）浓度和血清蛋白渗漏相关;由此产生的伴随中性粒细胞募集和弹性蛋白酶释放的气道炎症与定植细菌负荷呈正相关。结节病和AAT标本的微生物组分析将增强对传染性病原体对疾病严重程度的贡献的理解。结节病的特征还在于细胞无能;我们观察到在完成这种抗分枝杆菌方案的一些结节病受试者中结节病T细胞生物学功能的改善，这表明微生物毒力因子可能有助于结节病T细胞无能。我们假设微生物群的差异与结节病和AAT人群的疾病严重程度相关，并且存在的微生物具有诱导T细胞无能的能力。我们建议定义异质性结节病和AAT人群中的微生物群，并确定微生物群对T细胞生物学功能的影响。 相关性：结节病和AAT是重要的医学问题。该建议的优势在于根据异质性结节病和AAT队列中疾病严重程度进行微生物表征。这一建议也将提高对微生物诱导T细胞无反应性的理解，这在特发性肺病中缺乏认识。

项目成果

Template Creation for High-Resolution Computed Tomography Scans of the Lung in R Software.

在 R 软件中创建肺部高分辨率计算机断层扫描的模板。

• DOI: 10.1016/j.acra.2019.10.030
• 发表时间: 2020
• 期刊: Academic radiology
• 影响因子: 4.8
• 作者: Ryan,SarahM;Vestal,Brian;Maier,LisaA;Carlson,NicholeE;Muschelli,John
• 通讯作者: Muschelli,John