Adaptive immunity against Pneumocystis

针对肺孢子菌的适应性免疫

• 批准号: 8875748
• 负责人: Chad Steele
• 金额: $ 36.2万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875748
• 关键词: Address; Antibody Formation; Attenuated; Automobile Driving; B-Lymphocytes; C57BL/6 Mouse; CCL17 gene; CD19 gene; CD4 Positive T Lymphocytes; Cells; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical; Cyst; Data; Development; Epidemic; Functional disorder; Generations; HIV; Health; Helper-Inducer T-Lymphocyte; Host Defense; IgG1; Immune response; Immunity; Immunosuppression; Inbred BALB C Mice; Individual; Infection; Interferons; Interleukin-10; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Life Cycle Stages; Lung; Macrophage Activation; Mediating; Mediator of activation protein; Mus; Patients; Phenotype; Pilot Projects; Plasma; Play; Pneumocystis; Pneumocystis Infections; Pneumocystis carinii Pneumonia; Population; Predisposing Factor; Production; Proteins; Reporter; Resistance; Role; SCID Mice; STAT4 gene; Serum; Source; Structure of parenchyma of lung; T cell response; TNFSF5 gene; Th2 Cells; Time; Transgenic Mice; adaptive immunity; cytokine; diphtheria toxin receptor; lymph nodes; mRNA Expression; macrophage; novel; pathogen; response; rituximab; tool; transcription factor

DESCRIPTION (provided by applicant): Pneumocystis has risen to the forefront of lethal, opportunistic lung infections as a result of its close association with the HIV epidemic, yet this atypical fungal pathogen is becoming increasingly associated with pharmacologic-driven immunosuppression as well as patients with chronic lung diseases such as COPD. We have recently investigated the role of transcription factor STAT4 in lung immunity to P. murina. We have discovered that Stat4-/- mice on the C57BL/6 background are resistant to P. murina infection while Stat4-/- mice on the BALB/c background are susceptible (Myers et al. submitted, PLoS Pathogens). To our surprise, although having lower Th1 (IFN-y) responses, both BL/6 Stat4-/- and Balb/c Stat4-/- mice unexpectedly demonstrated significantly impaired CD4+ Th2 (IL-4, IL-5 and IL-13) responses in the lung. In spite of this, BL/6 Stat4-/-, but not Balb/c Stat4/-, mice maintained an enhanced M2 macrophage signature (higher Retnla/FIZZ-1 mRNA expression and CCL17/TARC protein levels). In contrast to lung CD4+ T cells, BL/6 Stat4-/- mice demonstrated enhanced CD4+ Th2 responses in the draining lymph nodes and enhanced P. murina-specific IgG1, IgG2b and IgG2c levels in sera, neither of which were observed in BALB/c Stat4-/- mice. Together, these results suggest that protective immunity to P. murina when lung CD4+ T cell responses are impaired involves systemic CD4+ Th2 responses driving optimal B cell responses (Ab production) and a local type 2 response (IL-4/IL-13) in the lungs, which may not be CD4+ T cell in origin, driving M2 macrophage development. This is further supported by new preliminary data showing that compared to non-colonized HIV- infected individuals, Pneumocystis-colonized HIV-infected individuals have significantly lower plasma levels of the Th2 cytokines IL-4, IL-5 and IL-13, but no difference in the levels of IFN-y, IL-17A or IL-10. In preliminary studies, we show that CD4(-)/CD49b(-)/SiglecF(-)/ICOS(+) innate helper type 2 cells were significantly increased in lung tissue of C57BL/6 mice at 2 weeks post-P. murina challenge, suggesting a potential role for this cell population in generating type 2 responses in the lung during P. murina infection. In other studies, employing CD19-DTR mice, which are CD19-Cre mice crossed with Cre-inducible diphtheria toxin receptor (DTR) transgenic mice, we found that CD4+ Th1 and Th2 responses were attenuated in the lymph nodes of mice when B cells were depleted prior to P. murina infection, yet B cell depletion resulted in enhanced CD4+ Th2 and Th17 responses in the lung. Collectively, our data leads us to hypothesize that the generation of type 2 and Th2 responses mediate protective lung immunity against Pneumocystis. To address this hypothesis, we have proposed the following two independent, interrelated Aims: (1) to define the development of local and systemic type 2/Th2 responses during P. murina lung infection and (2) define the role of B cells in the development of local and systemic CD4+ T cell responses during P. murina lung infection.

描述（由申请人提供）：由于其与HIV流行的关系密切相关，肺炎藻已上升到致命的，机会性肺部感染的最前沿，但是这种非典型真菌病原体正越来越多地与药理学驱动的免疫抑制作用以及患有COPD慢性肺部疾病的患者相关。我们最近研究了转录因子STAT4在对穆琳娜肺部的肺免疫中的作用。我们已经发现，C57BL/6背景上的STAT4 - / - 小鼠对Murina感染具有抵抗力，而BALB/C背景上的STAT4 - / - 小鼠很容易受到敏感（Myers等人。提交的PLOS病原体）。令我们惊讶的是，尽管具有较低的Th1（IFN-Y）响应，但BL/6 STAT4 - / - 和BALB/C Stat4 - / - 小鼠出乎意料地证明了在肺中的CD4+ TH2（IL-4，IL-5和IL-13）反应显着受损。尽管如此，BL/6 STAT4 - / - ，但不能BALB/C Stat4/ - ，小鼠仍保持增强的M2巨噬细胞特征（较高的RETNLA/FIZZ-1 mRNA表达和CCL17/TARC蛋白水平）。与肺CD4+ T细胞相反，BL/6 STAT4 - / - 小鼠在排水淋巴结中表现出增强的CD4+ TH2反应，并增强了Sera中Sera的Murina特异性IgG1，IgG2B和IgG2C水平，在BALB/C Stat4-/c Stat4-/c Stat4 - / - / - 小鼠中都没有观察到。总之，这些结果表明，当肺CD4+ T细胞反应受到损害时，对Murina的保护性免疫涉及全身性CD4+ TH2响应驱动最佳B细胞反应（AB产生）和肺部局部2型反应（IL-4/IL-13），这可能不是源自源的CD4+ T细胞，驱动M2 Moctrophage Moctrophage Moctrophage开发。新的初步数据进一步支持了这一点，该数据表明，与非殖民化的HIV感染个体相比，肺炎囊体殖民化的HIV感染个体的Th2细胞因子IL-4，IL-5和IL-13的血浆水平明显降低，但在IFN，IFN-Y，IL-Y-17A，IL-17A或IL-17A或IL-17A或IL-10或IL-17A或IL-13的水平上没有差异。在初步研究中，我们表明CD4（ - ）/CD49B（ - ）/siglecf（ - ）/ICOS（+）先天助手2型细胞在P时C57BL/6小鼠的肺组织中显着增加了P-P。穆里纳（Murina）的挑战，表明该细胞种群在穆琳娜（P. murina）感染期间在肺中产生2型反应中的潜在作用。在其他研究中，采用CD19-DTR小鼠，这些小鼠是CD19-CRE小鼠，与CRE诱导的双皮毒素受体（DTR）转基因小鼠交叉，我们发现在B细胞中depen+ P. murina Intection deplet deplet deplet时，CD4+ Th1和Th2反应减弱了CD4+ TH1和Th2的反应，但在CD上耗竭。肺部反应。总体而言，我们的数据使我们假设2型和TH2反应的产生介导了针对肺炎胸膜的保护性肺免疫。为了解决这一假设，我们提出了以下两个独立的，相互关联的目的：（1）定义P. murina肺癌期间局部和系统的2/TH2反应的发展，以及（2）定义B细胞在P. murina肺肺肺肺肺癌期间的局部和全身CD4+ T细胞反应中的作用。