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: 8264828
• 负责人: Wonder P. Drake
• 金额: $ 16.72万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264828
• 关键词: Alleles; Antigens; Antimycobacterial Agents; Bronchiectasis; Clinic; Clinical; Communities; Disease; Elastases; Etiology; Eye; Fibrosis; Genetic Transcription; Granulomatous; 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)： 结节病是一种全球流行的异质性肉芽肿性疾病，最常见的累及肺、皮肤、淋巴结和眼睛。虽然病因尚不清楚，但对结节病标本的分子和免疫学研究表明，宿主与感染抗原，特别是分枝杆菌抗原的相互作用，在某些对象中起到了致病作用。此外，最近已经证明，广谱抗分支杆菌疗法(CLEAR方案)在无纤维化的肺结节病患者中提供了临床改善，但在患有晚期纤维化疾病的患者中则没有。目前尚不清楚在不同的结节病人群中是否存在微生物群落的差异。以类似的方式，已经观察到阿尔法-1抗胰蛋白酶(AAT)缺乏患者的疾病严重程度与病原菌之间的关联。α-1抗胰蛋白酶(AAT)是一种具有抗中性粒细胞弹性蛋白酶(NE)活性的强效抗蛋白酶。AAT缺陷与中性粒细胞负荷、弹性酶活性、白三烯-B(4)浓度和血清蛋白泄漏相关；由此产生的中性粒细胞聚集和弹性蛋白酶释放的呼吸道炎症与定植细菌负荷呈正相关。对结节病和AAT标本的微生物组分析将加强对感染因素对疾病严重程度的贡献的了解。结节病也以细胞无能为特征；我们观察到一些完成抗分枝杆菌方案的结节病患者T细胞生物学功能的改善，提示微生物毒力因素可能参与了结节病T细胞无能。我们假设微生物区系的差异与结节病和AAT人群中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人群中的微生物组，并确定微生物组对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。这项建议的优点是根据不同类型结节病和AAT队列中的疾病严重程度进行微生物特征描述。这项建议还将加强对微生物诱导T细胞无能的理解，这在特发性肺部疾病中缺乏对此的认识。