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| Author(s): |
Tábata Takahashi França
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) |
| Defense date: | 2021-10-08 |
| Examining board members: |
Antonio Condino Neto;
Niels Olsen Saraiva Câmara;
Carolina Sanchez Aranda Lago;
Thiago Andrade Patente
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| Advisor: | Antonio Condino Neto; Otávio Cabral Marques |
| Abstract | |
Patients with CD40L deficiency present severe and heterogeneous clinical manifestations and increased susceptibility to recurrent infections caused by different classes of microorganisms, which begin in the first years of life and significantly contribute to the mortality of these patients. One of the main clinical features of CD40L-deficient patients is neutropenia, a hematologic manifestation that affects approximately 70% of individuals with the disease. Neutrophils are the first line of defense against pathogens, mediating inflammatory reactions and participating in infection control. These cells are produced in the bone marrow in a process called granulopoiesis, in which the progenitor cells sequentially differentiate until they reach the final stage of mature neutrophils. Our group has previously shown that, in addition to presenting changes in neutrophils\' number, patients with CD40L deficiency have circulating neutrophils with impaired effector responses, suggesting failures in cell development. Thus, the present work had two main lines of study: the clinical, laboratory, and genetic characterization of Latin-American patients with CD40L deficiency and the investigation of the molecular mechanisms involved in the development and trafficking of neutrophils in the CD40L deficiency. We retrospectively analyzed data from 50 Latin-American patients affected by the syndrome and investigated the effect of CD40L deficiency on the development and trafficking of neutrophils through functional experiments and transcriptome analysis of neutrophils from patients with CD40L deficiency and knockout mice for Cd40lg (CD40L-/- mice). Clinically, we characterized the largest cohort of Latin American patients with CD40L deficiency, described six new variants in CD40LG, and presented the largest number of pathogens reported so far in a single cohort of CD40L-deficient patients. Experimentally, we revealed that neutrophils from patients with CD40L deficiency showed in vitro migration defects, an immunopathological mechanism not previously described in the syndrome. Furthermore, CD40L-/- mice showed dysregulation in the generation of neutrophils in the bone marrow and reduced cell number in peripheral organs. Corroborating these results, the transcriptome analysis of CD40L-/- mice and patients with CD40L deficiency suggests dysregulation in granulopoiesis and neutrophil trafficking. Together, these results point to defects in the generation and distribution of neutrophils in the absence of CD40L. The clinical characterization and elucidation of the mechanisms involved in the CD40L deficiency contribute to a better understanding of the immunopathological mechanisms associated with the disease and advance the understanding of the role of CD40L in cell development and immune response. (AU) | |
| FAPESP's process: | 17/04187-9 - Functional evaluation of neutrophils in CD40L-DEFICIENCY patients |
| Grantee: | Tábata Takahashi França |
| Support Opportunities: | Scholarships in Brazil - Doctorate |