ABSTRACT The discovery that loss-of-function mutations in the gene DOCK8 are responsible for most forms of autosomal recessive hyper-IgE syndrome and some forms of combined immunodeficiency without elevated serum IgE has led to studies into the immunopathogenesis of this disease. In this review, we relate the clinical features of this disease to studies using patients' cells and a mouse model of Dock8 deficiency, which have revealed how DOCK8 regulates T and B cell numbers and functions. The results of these studies help to explain how the absence of DOCK8 contributes to patients' susceptibility to viral, fungal, and bacterial infections. However, unanswered questions remain regarding how the absence of DOCK8 also leads to high IgE and allergic disease, predisposition for malignancy, and unusual clinical features, such as CNS abnormalities and autoimmunity, observed in some patients.
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ABSTRACT: Autosomal recessive loss-of-function mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency characterized by atopy, recurrent infections, and cancer susceptibility. A genotype-phenotype explanation for the variable disease expression is lacking. We investigated whether reversions contributed to the variable disease expression. Patients followed at the National Institutes of Health's Clinical Center were studied. We performed detailed genetic analyses and intracellular flow cytometry to detect DOCK8 protein expression within lymphocyte subsets. We identified 17 of 34 DOCK8-deficient patients who had germline mutations with variable degrees of reversion caused by somatic repair. Somatic repair of the DOCK8 mutations resulted from second-site mutation, original-site mutation, gene conversion, and intragenic crossover. Higher degrees of reversion were associated with recombination-mediated repair. DOCK8 expression was restored primarily within antigen-experienced T cells or natural killer cells but less so in naive T or B cells. Several patients exhibited multiple different repair events. Patients who had reversions were older and had less severe allergic disease, although infection susceptibility persisted. No patients were cured without hematopoietic cell transplantation. In patients with DOCK8 deficiency, only certain combinations of germline mutations supported secondary somatic repair. Those patients had an ameliorated disease course with longer survival but still had fatal complications or required hematopoietic cell transplantation. These observations support the concept that some DOCK8-immunodeficient patients have mutable mosaic genomes that can modulate disease phenotype over time.The Journal of allergy and clinical immunology 05/2014; · 12.05 Impact Factor
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ABSTRACT: Spatiotemporal control of leukocyte dynamics within tissues is critical for successful innate and adaptive immune responses. Homeostatic trafficking and coordinated infiltration into and within sites of inflammation and infection rely on signaling in response to extracellular cues that in turn controls a variety of intracellular protein networks regulating leukocyte motility, migration, chemotaxis, positioning, and cell-cell interaction. In contrast to mesenchymal cells, leukocytes migrate in an amoeboid fashion by rapid cycles of actin polymerization and actomyosin contraction, and their migration in tissues is generally referred to as low adhesive and nonproteolytic. The interplay of actin network expansion, contraction, and adhesion shapes the exact mode of amoeboid migration, and in this review, we explore how leukocyte subsets potentially harness the same basic biomechanical mechanisms in a cell-type-specific manner. Most of our detailed understanding of these processes derives from in vitro migration studies in three-dimensional gels and confined spaces that mimic geometrical aspects of physiological tissues. We summarize these in vitro results and then critically compare them to data from intravital imaging of leukocyte interstitial migration in mouse tissues. We outline the technical challenges of obtaining conclusive mechanistic results from intravital studies, discuss leukocyte migration strategies in vivo, and present examples of mode switching during physiological interstitial migration. These findings are also placed in the context of leukocyte migration defects in primary immunodeficiencies. This overview of both in vitro and in vivo studies highlights recent progress in understanding the molecular and biophysical mechanisms that shape robust leukocyte migration responses in physiologically complex and heterogeneous environments.Seminars in Immunopathology 02/2014; · 5.38 Impact Factor
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ABSTRACT: Increased serum IgE levels are characteristic but not specific for allergic diseases. Particularly, severe atopic dermatitis (AD) overlaps with hyper-IgE syndromes (HIES) regarding eczema, eosinophilia, and increased serum IgE levels. HIES are primary immunodeficiencies due to monogenetic defects such as in the genes DOCK8 and STAT3. As it is not known to date why allergic manifestations are not present in all HIES entities, we assessed the specificity of serum IgE of AD and HIES patients in the context of clinical and immunological findings.Allergy 05/2014; · 5.88 Impact Factor