更新于：2024-11-01

DOCK8 x KRT8

更新于：2024-11-01

基本信息

关联

项与 DOCK8 x KRT8 相关的药物

MR-022

靶点

DOCK8 x KRT8

作用机制

DOCK8 inhibitors [+1]

在研机构-

原研机构

Centre Léon Bérard Lyon et Rhône-Alpes

在研适应症-

非在研适应症

结直肠癌

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 DOCK8 x KRT8 相关的临床结果

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100 项与 DOCK8 x KRT8 相关的转化医学

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0 项与 DOCK8 x KRT8 相关的专利（医药）

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项与 DOCK8 x KRT8 相关的文献（医药）

2024-10-01·Journal of Allergy and Clinical Immunology

Role of DOCK8 in Cytokine Storm Syndromes

Article

作者: Canna, Scott W ; Walter, Mark R ; Gordon, Scott M. ; Atkinson, T. Prescott ; Behrens, Edward M. ; Cron, Randy Q ; Cron, Randy Q. ; Gordon, Scott M ; Behrens, Edward M ; Kreiger, Portia A. ; Eloseily, Esraa M. ; Chu, Niansheng ; Weiser, Peter ; Kreiger, Portia A ; Canna, Scott W. ; Walter, Mark R. ; Atkinson, T Prescott ; Cron, Remy R. ; Cron, Remy R ; Nguyen, Junior ; Zhang, Mingce ; Eloseily, Esraa M

BACKGROUNDCytokine storm syndromes (CSS), including hemophagocytic lymphohistiocytosis (HLH), are increasingly recognized as hyperinflammatory states leading to multi-organ failure and death. Familial HLH (FHL) in infancy results from homozygous genetic defects in perforin-mediated cytolysis by CD8 T-lymphocytes and natural killer (NK) cells. Later onset CSS are frequently associated with heterozygous defects in FHL genes, but genetic etiologies for most are unknown. We identified rare DOCK8 variants in CSS patients.OBJECTIVEWe explore the role of CSS patient-derived DOCK8 mutations on cytolytic activity in NK cells. We further study effects of DOCK8 deficiency in murine models of CSS.METHODSDOCK8 cDNA from 2 unrelated CSS patients with different missense mutations were introduced into human NK-92 NK cells by foamy virus transduction. NK cell degranulation (CD107a), cytolytic activity against K562 target cells, and interferon-gamma (IFNγ) production were explored by flow cytometry. A third CSS patient DOCK8 mRNA splice acceptor site variant was explored by exon trapping. Dock8^-/- mice were assessed for features of CSS (weight loss, splenomegaly, hepatic inflammation, cytopenias, and IFNγ levels) upon challenge with lymphocytic choriomeningitis virus (LCMV) and excess IL-18.RESULTSBoth patient DOCK8 missense mutations decreased cytolytic function in NK cells in a partial dominant-negative fashion in vitro. The patient DOCK8 splice variant disrupted mRNA splicing in vitro. LCMV infection promoted CSS in Dock8^-/- mice and interacted with excess IL-18 limiting T-cell numbers while promoting CD8 T-cell hyperactivation.CONCLUSIONMutations in DOCK8 may contribute to CSS-like hyperinflammatory states by altering cytolytic function in a threshold model of disease.

2020-04-01·Allergy1区 · 医学

ILC3 deficiency and generalized ILC abnormalities in DOCK8‐deficient patients

1区 · 医学

Article

作者: Kaya, Aysenur ; Artac, Hasibe ; Unal, Ekrem ; Kiykim, Ayca ; Metin, Ayse ; Devecioglu, Omer ; Ozcan, Alper ; Guner, Sukru N. ; Okus, Fatma Zehra ; Cipe, Funda ; Arikan Ayyildiz, Zeynep ; Haliloglu, Yesim ; Karakukcu, Musa ; Karakoc Aydiner, Elif ; Reisli, Ismail ; Canatan, Halit ; Keles, Sevgi ; Patiroglu, Turkan ; Aksu, Guzide ; Azizoglu, Zehra Busra ; Eken, Ahmet ; Dönmez Altuntas, Hamiyet ; Cansever, Murat ; Karasu, Gulsun ; Baris, Safa ; Ozen, Ahmet ; Erdem, Serife ; Chatila, Talal A. ; Oukka, Mohamed ; Topal, Erdem ; Uygun, Vedat ; Nain, Ercan

AbstractBackgroundDedicator of cytokinesis 8 (DOCK8) deficiency is the main cause of the autosomal recessive hyper‐IgE syndrome (HIES). We previously reported the selective loss of group 3 innate lymphoid cell (ILC) number and function in a Dock8‐deficient mouse model. In this study, we sought to test whether DOCK8 is required for the function and maintenance of ILC subsets in humans.MethodsPeripheral blood ILC1‐3 subsets of 16 DOCK8‐deficient patients recruited at the pretransplant stage, and seven patients with autosomal dominant (AD) HIES due to STAT3 mutations, were compared with those of healthy controls or post‐transplant DOCK8‐deficient patients (n = 12) by flow cytometry and real‐time qPCR. Sorted total ILCs from DOCK8‐ or STAT3‐mutant patients and healthy controls were assayed for survival, apoptosis, proliferation, and activation by IL‐7, IL‐23, and IL‐12 by cell culture, flow cytometry, and phospho‐flow assays.ResultsDOCK8‐deficient but not STAT3‐mutant patients exhibited a profound depletion of ILC3s, and to a lesser extent ILC2s, in their peripheral blood. DOCK8‐deficient ILC1‐3 subsets had defective proliferation, expressed lower levels of IL‐7R, responded less to IL‐7, IL‐12, or IL‐23 cytokines, and were more prone to apoptosis compared with those of healthy controls.ConclusionDOCK8 regulates human ILC3 expansion and survival, and more globally ILC cytokine signaling and proliferation. DOCK8 deficiency leads to loss of ILC3 from peripheral blood. ILC3 deficiency may contribute to the susceptibility of DOCK8‐deficient patients to infections.