The role of SERPINB1 in T cell function and its contribution to human diseases

SERPINB1在T细胞功能中的作用及其对人类疾病的贡献

基本信息

项目摘要

PROJECT SUMMARY Primary immunodeficiencies (PIDs) are a group of monogenic diseases caused by inborn errors of immunity (IEI) that confer risk of severe infection, autoimmunity, and cancer. The genetic and immunological study of IEI is instrumental to understand mechanisms of human immunity and to manage and treat patients with PIDs. Their study is also important to understand more common diseases associated with genetic variants in the same genes. However, despite the relevance and importance of studying PIDs from the basic science and clinical points of view, half of the PID patients lack a genetic diagnosis. By studying a patient with a PID of unknown genetic etiology that confers susceptibility to severe mycobacterial disease, we identified a nonsense mutation in SERPINB1. Using a combination of population genetics, biochemistry, and molecular biology, we showed that this is the first case of SERPINB1 complete deficiency ever described. SERPINB1 is an intracellular serine protease suicide inhibitor. Its absence in mice causes uncontrolled intracellular protease activity, leading to neutrophil death and subsequent neutropenia. Interestingly, our patient does not display any neutrophil abnormality, but instead, our in-depth immunological characterization showed a reduction in the frequency of activated T cells and CD4+ memory T cells. Our findings suggest that SERPINB1 has a previously unknown function in T cells and antimycobacterial immunity. Our data also indicates that SERPINB1 orchestrates an intracellular protease-mediated pathway essential for T cell activation and survival. Given our findings, this application will test the hypothesis that SERPINB1 is critical for human T cell activation and, by controlling intracellular protease activity, to human diseases. Capitalizing on the unique opportunity that this patient offers to understand the function of human SERPINB1, we propose three complementary approaches. In Aim 1, we will characterize the immunological consequences of SERPINB1 deficiency on T cell activation and CD4+ T cell differentiation. We will also study the transcriptional consequences of SERPINB1 deficiency in T cells. With this, we will uncover a previously unknown function of SERPINB1 in human T cells. In Aim 2, we will identify and characterize the pathways orchestrated by SERPINB1 in T cells. The absence of SERPINB1 unleashes the action of intracellular proteases. This rare mechanism of PID will allow for chemical inhibition of these proteases for therapeutic purposes. Furthermore, characterizing the SERPINB1-dependent antimycobacterial mechanisms will lead to the identification of additional IEI in its pathway in patients lacking a genetic diagnosis. In Aim 3, we will perform phenome-wide association studies (pheWAS) to identify associations between genetic variants in the SERPINB1 pathway and additional human diseases. This reverse genetic approach will expand what we will learn from the study of a rare disease to benefit a broader group of patients. Our proposed research has far- reaching clinical and biological implications for understanding SERPINB1 mediated immunity, PIDs, anti- mycobacterial immunity, and the contribution of the SERPINB1 pathway to human disease.
项目总结

项目成果

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Ruben Martinez Barricarte其他文献

Ruben Martinez Barricarte的其他文献

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{{ truncateString('Ruben Martinez Barricarte', 18)}}的其他基金

Gain-of-function complement activators as a new class of immunotherapeutic molecules
功能获得性补体激活剂作为一类新型免疫治疗分子
  • 批准号:
    10629623
  • 财政年份:
    2023
  • 资助金额:
    $ 66.5万
  • 项目类别:
Genetic and immunological dissection of isolated Nocardiosis
分离诺卡氏菌病的遗传和免疫学解剖
  • 批准号:
    10649575
  • 财政年份:
    2022
  • 资助金额:
    $ 66.5万
  • 项目类别:
Genetic and immunological dissection of isolated Nocardiosis
分离诺卡氏菌病的遗传和免疫学解剖
  • 批准号:
    10510731
  • 财政年份:
    2022
  • 资助金额:
    $ 66.5万
  • 项目类别:

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