Dissertation/ Thesis
Genetic deficiencies as natural models to study the immune-checkpoints regulation and to better characterize the autoimmune response ; Des déficiences génétiques comme modèles naturels pour l'étude de la régulation des checkpoints immunitaires et la caractérisation des réponses auto-immunes
| العنوان: | Genetic deficiencies as natural models to study the immune-checkpoints regulation and to better characterize the autoimmune response ; Des déficiences génétiques comme modèles naturels pour l'étude de la régulation des checkpoints immunitaires et la caractérisation des réponses auto-immunes |
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| المؤلفون: | Delage, Laure |
| المساهمون: | Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Cité, Frédéric Rieux-Laucat |
| المصدر: | https://theses.hal.science/tel-04619430 ; Immunologie. Université Paris Cité, 2021. Français. ⟨NNT : 2021UNIP5190⟩. |
| بيانات النشر: | HAL CCSD |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Gray platelet syndrome, GPS, CTLA-4, NBEAL2, LRBA, BEACH domain, BEACH-domain containing protein, Vesicular traffic, Recycling, Lysosomal degradation, Lytic granule, Interactome, Immune checkpoint, Autoimmunity, Syndrome des plaquettes grises, SPG, Domaine BEACH, Protéine contenant un domaine BEACH, Trafic vésiculaire, Recyclage, Dégradation lysosomale, Granule lytique, Checkpoint immunitaire, Auto-immunité, [SDV.IMM]Life Sciences [q-bio]/Immunology |
| الوصف: | Recessive NBEAL2 mutations have been reported in patients with Gray Platelet Syndrome (GPS). This syndrome is characterized by a macro-thrombocytopenia, with platelets lacking alpha-granules, leading to bleeding disorders, often associated with splenomegaly. Thus, NBEAL2 plays a crucial role in the trafficking of alpha-granules in platelets. Moreover, our lab has also described NBEAL2 deficiencies in patients presenting clinical features of the autoimmune lymphoproliferative syndrome, suggesting a role of NBEAL2 in immune homeostasis and tolerance. A broader international cohort of GPS patients has been described, revealing immune system abnormalities (autoimmune diseases, autoantibodies, lymphopenia). If the role of NBEAL2 in the traffic of granules is often investigated, the exact mechanism leading to the development of autoimmune manifestations in GPS patients remains unknown. NBEAL2 belongs to a protein family involved in vesicular trafficking, all of which possess a conserved BEACH domain. Within this BEACH-domain containing proteins family, one of the closest members to NBEAL2 is LRBA. LRBA is involved in the recycling of CTLA-4, an inhibitory immune checkpoint. CTLA-4 plays a crucial role in the regulation of immune responses and tolerance. Recessive mutations of LRBA lead to similar clinical features as partial CTLA-4 deficiency: autoimmunity, lymphocytic infiltrations, and progressive B lymphopenia. Physiologically, LRBA prevents the lysosomal degradation of CTLA-4 and allows its recycling to the membrane. By analogy with LRBA, we investigated the importance of NBEAL2 in immune checkpoints intracellular trafficking and we brought new insights on its role in lymphocytes. Thus, NBEAL2 is a scaffold protein, binding LRBA, and involved in CTLA-4 trafficking as well as in vesicular trafficking in general. This work brings new knowledge to the regulation of CTLA-4 in activated T lymphocytes, a list of new partners for NBEAL2 protein and a new model of vesicular trafficking in which NBEAL2 is involved. ... |
| نوع الوثيقة: | doctoral or postdoctoral thesis |
| اللغة: | French |
| Relation: | NNT: 2021UNIP5190; tel-04619430; https://theses.hal.science/tel-04619430; https://theses.hal.science/tel-04619430/document; https://theses.hal.science/tel-04619430/file/va_Delage_Laure.pdf |
| الاتاحة: | https://theses.hal.science/tel-04619430 https://theses.hal.science/tel-04619430/document https://theses.hal.science/tel-04619430/file/va_Delage_Laure.pdf |
| Rights: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.8D6E689D |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |