DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity.
Charlotte BoussardLaure DelageTania GajardoAlexandre KauskotMaxime BatignesNicolas GoudinMarie-Claude StolzenbergCamille BrunaudPatricia PanikulamQuentin RillerMaryse Moya-NilgesJean SolarzChristelle ReperantBéatrice DurelJean-Claude BordetOlivier PelléCorinne LebretonAude MagerusVithura PirabakaranPablo VargasSébastien DupichaudMarie JeanpierreAngélique VinitMohammed ZarhrateCecile MassonNathalie AladjidiPeter D ArkwrightBrigitte Bader-MeunierSandrine Baron JolyJoy BenadibaElise BernardDominique BerrebiChristine BodemerMartin CastelleFabienne Charbit-HenrionMarwa ChbihiAgathe DebrayPhilippe DrabentSylvie FraitagMiguel HiéJudith Landman-ParkerLudovic LhermitteDespina MoshousPierre RohrlichFrank M RuemmeleAnne Welfringer-MorinMaud TusseauAlexandre BelotNadine Cerf-BensussanMarie RoelensCapucine PicardBénédicte NevenAlain FischerIsabelle CallebautMickaël Mathieu MénagerFernando E SepulvedaFrédéric AdamFrédéric Rieux-LaucatPublished in: Blood (2023)
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-GTPase involved in actin cytoskeleton dynamics, among many cellular functions. The role of DOCK11 in human immune disease has been long suspected but has never been described so far. We studied eight male patients, from seven 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 (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls. Lastly, in line with the patients' autoimmune manifestations, we also observed abnormal regulatory T cells (Tregs) phenotype with profoundly reduced FOXP3 and IKZF2 expression. Moreover, we found a reduced T cell proliferation and an impaired STAT5B phosphorylation upon IL2 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 associated with abnormal actin cytoskeleton remodeling as well as Tregs phenotype culminating in immune dysregulation and severe early-onset autoimmunity.
Keyphrases
- end stage renal disease
- early onset
- chronic kidney disease
- regulatory t cells
- cell proliferation
- ejection fraction
- systemic lupus erythematosus
- newly diagnosed
- dendritic cells
- peritoneal dialysis
- prognostic factors
- dna methylation
- patient reported outcomes
- cell cycle
- acute lymphoblastic leukemia
- immune response
- poor prognosis
- endothelial cells
- rheumatoid arthritis
- patient reported
- gene expression
- cell migration
- peripheral blood