DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity

生物 自身免疫 免疫学 细胞生物学 肌动蛋白细胞骨架 免疫系统 FOXP3型 免疫失调 细胞骨架 细胞 遗传学
作者
Charlotte Boussard,Laure Delage,Tania Gajardo,Alexandre Kauskot,Maxime Batignes,Nicolas Goudin,Marie‐Claude Stolzenberg,Camille Brunaud,Patricia Panikulam,Quentin Riller,Maryse Moya‐Nilges,Jean Solarz,Christelle Repérant,Béatrice Durel,Jean‐Claude Bordet,Olivier Pellé,Corinne Lebreton,Aude Magérus‐Chatinet,Vithura Pirabakaran,Pablo Vargas
出处
期刊:Blood [Elsevier BV]
被引量:12
标识
DOI:10.1182/blood.2022018486
摘要

Dedicator of cytokinesis (DOCK) proteins play a central role in actin cytoskeleton regulation. This is highlighted by the DOCK2 and DOCK8 deficiencies leading to actinopathies and immune deficiencies. DOCK8 and DOCK11 activate CDC42, a Rho-guanosine triphosphate hydrolases involved in actin cytoskeleton dynamics, among many cellular functions. The role of DOCK11 in human immune disease has been long suspected but, to the best of our knowledge, has never been described to date. We studied 8 male patients, from 7 unrelated families, with hemizygous DOCK11 missense variants leading to reduced DOCK11 expression. The patients were presenting with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. Patients' platelets exhibited abnormal ultrastructural morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B-lymphoblastoid cell lines from patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. Knock down of DOCK11 recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells and primary activated T cells from healthy controls. Lastly, in line with the patients' autoimmune manifestations, we also observed abnormal regulatory T-cell (Treg) phenotype with profoundly reduced FOXP3 and IKZF2 expression. Moreover, we found reduced T-cell proliferation and impaired STAT5B phosphorylation upon interleukin-2 stimulation of the patients' lymphocytes. In conclusion, DOCK11 deficiency is a new X-linked immune-related actinopathy leading to impaired CDC42 activity and STAT5 activation, and is associated with abnormal actin cytoskeleton remodeling as well as Treg phenotype, culminating in immune dysregulation and severe early-onset autoimmunity.
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