Combined Immunodeficiency Associated with DOCK8 Mutations

Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
New England Journal of Medicine (Impact Factor: 55.87). 09/2009; 361(21):2046-55. DOI: 10.1056/NEJMoa0905506
Source: PubMed


Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of combined immunodeficiency. The genetic causes of these variants are unknown.
We collected longitudinal clinical data on 11 patients from eight families who had recurrent sinopulmonary and cutaneous viral infections. We performed comparative genomic hybridization arrays and targeted gene sequencing. Variants with predicted loss-of-expression mutations were confirmed by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay and immunoblotting. We evaluated the number and function of lymphocytes with the use of in vitro assays and flow cytometry.
Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections. Most patients had severe atopy with anaphylaxis; several had squamous-cell carcinomas, and one had T-cell lymphoma-leukemia. Elevated serum IgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM levels, and variable IgG antibody responses were common. Expansion in vitro of activated CD8 T cells was impaired. Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes.
Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency.

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Available from: Amanda Favreau, Aug 25, 2014
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    • "By definition, CVID does not have hypergammaglobulinemia, but other immunodeficiencies that have been described with elevated immunoglobulins can have autoimmune cytopenias. One example is DOCK8 deficiency (Zhang et al. 2009). "
    09/2014; 2(2):150113084544003. DOI:10.14785/lpsn-2014-0019
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    • "In line with this point of view, it has recently been described [8] the case of a Japanese girl of non-consanguineous family suffering from AEP and presenting loss-of-function mutations in a gene (DOCK8) located on chromosome 9. Other cases with eosinophilic lung diseases have also been observed in the absence of DOCK8 protein in lymphocytes [9]. Since patients with DOCK8 deficiency present defective T cell function, impaired production of antigen-specific antibodies and a severe defect in interstitial dendritic cell migration during immune responses with recurrent pulmonary infections, these reports suggest that AEP represents several pathophysiological processes that can fully and rightly be estimated only by understanding both the genetic and environmental contributions to its etiology and pathogenesis. "
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    ABSTRACT: Acute eosinophilic pneumonia (AEP) is a rare febrile illness which is characterized by respiratory failure and often requires mechanical ventilation. The causes and sequence of events of this disease at a biochemical and histological level remain largely unknown. In this article we report the exceptional case, possibly unique, of a patient who developed AEP and three pneumothoraces within less than one month during her hospitalization . A 39-year-old German woman was admitted to our hospital for a laparoscopy-assisted vaginal hysterectomy under general anaesthesia. The surgical intervention was followed by peritonitis in the early postoperative course. Following anaesthesia induction with propofol/midazolam and during the prolonged therapy with several broad-spectrum antibiotics, she developed AEP and three spontaneous (one left-sided and two right-sided) pneumothoraces, the latter ones observed in quick succession. Symptoms, laboratory markers, and chest radiology significantly improved after a one-day treatment with methylprednisolone. On the whole, these pathological occurrences, together with similar cases reported in literature, can support the conclusion of possible predisposing genetic factors at the lung tissue level of AEP patients, a view that might shed new light on the pathogenesis of this disease. To provide a coherent pattern that explains the reported evidence for AEP and pneumothoraces, independently from the causative stimulus, the supposed molecular mutations could be localized in the connective tissue rather than in the epithelial cells. In order to interpret clinical and laboratory evidence, as well as to support the main conclusions, the important part of scientific research here presented can also assist physicians in making more informed decisions for the treatment of patients with pulmonary infiltrates.
    Multidisciplinary respiratory medicine 01/2014; 9(1):7. DOI:10.1186/2049-6958-9-7 · 0.15 Impact Factor
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    • "For example, DOCK8 is critical to IgE production and to the survival and function of peripheral CD8+ T cells in humans and mice [32]. DOCK8 deficiency results in autosomal recessive hyper-IgE syndrome with severe allergic manifestations, characterized by severe eczema, recurrent skin infection, mucocutaneous candidiasis, elevated serum IgE levels, and eosinophilia [33]. These characteristics align with previous reports from our group of increased serum IgE levels, decreased CD8+ T cell number, and severe eczema in STAT5B-deficient patients [11], [34], and suggest these characteristics of STAT5B deficiency may be related to downregulation of DOCK8 in the absence of STAT5B. "
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    ABSTRACT: Signal transducer and activator of transcription (STAT) comprises a family of universal transcription factors that help cells sense and respond to environmental signals. STAT5 refers to two highly related proteins, STAT5A and STAT5B, with critical function: their complete deficiency is lethal in mice; in humans, STAT5B deficiency alone leads to endocrine and immunological problems, while STAT5A deficiency has not been reported. STAT5A and STAT5B show peptide sequence similarities greater than 90%, but subtle structural differences suggest possible non-redundant roles in gene regulation. However, these roles remain unclear in humans. We applied chromatin immunoprecipitation followed by DNA sequencing using human CD4(+) T cells to detect candidate genes regulated by STAT5A and/or STAT5B, and quantitative-PCR in STAT5A or STAT5B knock-down (KD) human CD4(+) T cells to validate the findings. Our data show STAT5A and STAT5B play redundant roles in cell proliferation and apoptosis via SGK1 interaction. Interestingly, we found a novel, unique role for STAT5A in binding to genes involved in neural development and function (NDRG1, DNAJC6, and SSH2), while STAT5B appears to play a distinct role in T cell development and function via DOCK8, SNX9, FOXP3 and IL2RA binding. Our results also suggest that one or more co-activators for STAT5A and/or STAT5B may play important roles in establishing different binding abilities and gene regulation behaviors. The new identification of these genes regulated by STAT5A and/or STAT5B has major implications for understanding the pathophysiology of cancer progression, neural disorders, and immune abnormalities.
    PLoS ONE 01/2014; 9(1):e86790. DOI:10.1371/journal.pone.0086790 · 3.23 Impact Factor
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