Combined immunodeficiencies - understanding the limiting factors in T cell mediated control of viral infections and immune homeostasis.

联合免疫缺陷 - 了解 T 细胞介导的病毒感染控制和免疫稳态的限制因素。

• 批准号: 260998172
• 负责人: Professor Dr. Stephan Ehl
• 金额: --
• 依托单位: Centrum für Chronische Immundefizienz (CCI)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/260998172?language=en
• 关键词: Combined; immunodeficiencies; understanding; limiting; factors

T cell immunity is important for the control of most infections. The overall aim of this project is to further define the molecular basis of human T cell immunity and its relevance for the control of infectious diseases as well as for diseases of immune dysregulation. We will use both a pragmatic and a targeted approach to achieve this goal. In the pragmatic approach, we will study individual patients identified through the phenotypic screen of the P-CID study to better understand the molecular and immunological basis of their disease. In these studies, the biological area of investigation - although connected to T cell immunology - cannot be fully defined a priori. Two approaches will be used: (i) Characterization of the phenotypic and functional basis of combined immunodeficiency (ii) Identification of novel genetic disorders causing combined immunodeficiency In the targeted approach, we will focus on one particular mutation in the common gamma chain that we have observed in a cohort of patients with "leaky" X-SCID with an unusually severe phenotype. Further characterization of the consequences of this mutation will be performed in two lines of experimentation: (iii) Analysis of the cellular and molecular consequences of the p.Arg222Cys mutation for cytokine signaling in human cells (iv) Impact of the p.Arg222Cys and other hypomorphic mutations on T and NK cell development and function, B cell function and antiviral defense in retrogenic mice We expect that the results from this project will identify novel molecular causes for impaired T cell immunity associated with human CID and characterize the immunological consequences of such mutations. Moreover, they will illustrate in a particular model situation, how defects affecting other immune cell population influence the phenotype in situations of partially impaired T cell immunity.

T细胞免疫对于控制大多数感染很重要。该项目的总体目标是进一步确定人类T细胞免疫的分子基础及其与控制传染病和免疫失调疾病的相关性。我们将采取务实和有针对性的方法来实现这一目标。在务实的方法中，我们将研究通过P-CID研究的表型筛选确定的个体患者，以更好地了解其疾病的分子和免疫学基础。在这些研究中，研究的生物学领域-尽管与T细胞免疫学有关-不能完全先验地定义。将采用两种方法：（i）联合免疫缺陷的表型和功能基础的表征（ii）引起联合免疫缺陷的新型遗传疾病的鉴定在靶向方法中，我们将关注我们在具有异常严重表型的“渗漏”X-SCID患者队列中观察到的常见γ链中的一种特定突变。该突变的结果的进一步表征将在两个实验线中进行：（iv）p.Arg222Cys和其它亚型突变对T和NK细胞发育和功能的影响，在逆转录小鼠中的B细胞功能和抗病毒防御我们期望来自该项目的结果将鉴定与人类CID相关的受损T细胞免疫的新分子原因，并表征此类突变的免疫学后果。此外，他们将在特定的模型情况下说明，在部分受损的T细胞免疫的情况下，影响其他免疫细胞群体的缺陷如何影响表型。