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Öğe Clinical Presentation, Long-Term Outcome and Therapeutic Management of DOCK8 Deficiency-an International Survey of 125 Patients(Springer/Plenum Publishers, 2012) Albert, Michael H.; Aydin, Susanne; Alsum, Zobaida; Chatila, Talal; Su, Helen; Heinz, Valerie; Al-Herz, Waleed[Abstract Not Availabe]Öğe Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes TH17 cell differentiation(Mosby-Elsevier, 2016) Keles, Sevgi; Charbonnier, Louis Marie; Kabaleeswaran, Venkataraman; Reisli, Ismail; Genel, Ferah; Gulez, Nesrin; Al-Herz, WaleedBackground: The autosomal recessive hyper-IgE syndrome (HIES) caused by dedicator of cytokinesis 8 (DOCK8) deficiency shares clinical features with autosomal dominant HIES because of signal transducer and activator of transcription 3 (STAT3) mutations, including recurrent infections and mucocutaneous candidiasis, which are suggestive of T(H)17 cell dysfunction. The mechanisms underlying this phenotypic overlap are unclear. Objective: We sought to elucidate common mechanisms operating in the different forms of HIES. Methods: We analyzed the differentiation of CD4(+) T-H cell subsets in control and DOCK8-deficient subjects. We also examined the role of DOCK8 in regulating STAT3 activation in T cells. T-H cell differentiation was analyzed by ELISA, flow cytometry, and real-time PCR measurements of cytokines and T-H cell transcription factors. The interaction of DOCK8 and STAT3 signaling pathways was examined by using flow cytometry, immunofluorescence, coimmunoprecipitation, and gene expression analysis. Results: There was a profound block in the differentiation of DOCK8-deficient naive CD4(+) T cells into T(H)17 cells. A missense mutation that disrupts DOCK8 guanine nucleotide exchange factor (GEF) activity while sparing protein expression also impaired T(H)17 cell differentiation. DOCK8 constitutively associated with STAT3 independent of GEF activity, whereas it regulated STAT3 phosphorylation in a GEF activity-dependent manner. DOCK8 also promoted STAT3 translocation to the nucleus and induction of STAT3-dependent gene expression. Conclusion: DOCK8 interacts with STAT3 and regulates its activation and the outcome of STAT3-dependent TH17 differentiation. These findings might explain the phenotypic overlap between DOCK8 deficiency and autosomal dominant HIES.Öğe Differences in Granule Morphology yet Equally Impaired Exocytosis among Cytotoxic T Cells and NK Cells from Chediak-Higashi Syndrome Patients(Frontiers Media Sa, 2017) Chiang, Samuel C. C.; Wood, Stephanie M.; Tesi, Bianca; Akar, Himmet Haluk; Al-Herz, Waleed; Ammann, Sandra; Belen, Fatma BurcuChediak-Higashi syndrome (CHS) is caused by autosomal recessive mutations in LYST, resulting in enlarged lysosomal compartments in multiple cell types. CHS patients display oculocutaneous albinism and may develop life-threatening hemophagocytic lymphohistiocytosis (HLH). While NK cell-mediated cytotoxicity has been reported to be uniformly defective, variable defects in T cell-mediated cytotoxicity has been observed. The latter has been linked to the degree of HLH susceptibility. Since the discrepancies in NK celland T cell-mediated cellular cytotoxicity might result from differences in regulation of cytotoxic granule release, we here evaluated perforin-containing secretory lysosome size and number in freshly isolated lymphocytes from CHS patients and furthermore compared their exocytic capacities. Whereas NK cells from CHS patients generally contained a single, gigantic perforin-containing granule, cytotoxic T cells predominantly contained several smaller granules. Nonetheless, in a cohort of 21 CHS patients, cytotoxic T cell and NK cell granule exocytosis were similarly impaired upon activating receptor stimulation. Mechanistically, polarization of cytotoxic granules was defective in cytotoxic lymphocytes from CHS patients, with EEA1, a marker of early endosomes, mislocalizing to lysosomal structures. The results leads to the conclusion that lysosome enlargement corresponds to loss of distinct organelle identity in the endocytic pathway, which on a subcellular level more adversely affects NK cells than T cells. Hence, vesicular size or numbers do not per se dictate the impairment of lysosomal exocytosis in the two cell types studied.Öğe DOCK8 and STAT3 dependent inhibition of IgE isotype switching by TLR9 ligation in human B cells(Academic Press Inc Elsevier Science, 2017) Massaad, Michel J.; Cangemi, Brittney; Al-Herz, Waleed; LeFranc, Gerard; Freeman, Alexandra; Baxi, Sachin; Keles, Sevgi[Abstract Not Availabe]
