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    DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation
    (NATURE PUBLISHING GROUP, 2012) Jabara, Haifa H.; McDonald, Douglas R.; Janssen, Erin; Massaad, Michel J.; Ramesh, Narayanaswamy; Borzutzky, Arturo; Rauter, Ingrid
    The adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27(+) memory B cells. B cell proliferation and immunoglobulin production driven by Toll-like receptor 9 (TLR9) were considerably lower in DOCK8-deficient B cells, but those driven by the costimulatory molecule CD40 were not. In contrast, TLR9-driven expression of AICDA (which encodes the cytidine deaminase AID), the immunoglobulin receptor CD23 and the costimulatory molecule CD86 and activation of the transcription factor NF-kappa B, the kinase p38 and the GTPase Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src-kinase Syk-transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.
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    Successful Engraftment of Donor Marrow After Allogeneic Hematopoietic Cell Transplantation in Autosomal-Recessive Hyper-Ige Syndrome Caused by Dedicator of Cytokinesis 8 Deficiency
    (MOSBY-ELSEVIER, 2010) McDonald, Douglas R.; Massaad, Michel J.; Johnston, Alicia; Keleş, Sevgi; Chatila, Talal; Geha, Raif S.; Pai, Sung-Yun
    The hyper-IgE syndromes are rare combined immune deficiencies associated with marked elevations in plasma IgE levels and eosinophilia. An autosomal-dominant form of hyperIgE syndrome caused by mutations in signal transducer and activator of transcription 3 is characterized by elevated IgE, eosinophilia, eczema, recurrent skin and pulmonary infections, and skeletal abnormalities.1 Recently, an autosomal recessive form of hyper-IgE syndrome caused by mutations in the dedicator of cytokinesis 8 (DOCK8) gene has been identified and is characterized by elevated IgE levels, eosinophilia, atopic dermatitis, asthma, food allergies, recurrent upper and lower respiratory tract infections, and unusual susceptibility to infections with herpesvirus family members (herpes simplex virus, human papilloma virus) and molluscum contagiosum.2,3 Cutaneous infections with human papilloma virus have progressed to squamous cell carcinomas in some cases. Immunologic evaluation of DOCK8- deficient patients has revealed T-cell lymphopenia with impaired proliferative responses of both CD41 and CD81 T cells as well as impaired differentiation of TH17 T cells.