Whole-exome sequencing reveals activating STAT1 mutations in some patients with autosomal dominant chronic mucocutaneous candidiasis disease.

Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.

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Introduction DOCK8 mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, elevated IgE, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein (WASp) for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse (IS). DOCK8 activates Cdc42, which, together with WASp, coordinates F-actin reorganization. While abnormalities in T and B cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear. Objectives Understand the role of DOCK8 in NK cell function in order to determine if NK cell abnormalities explain the pathogenesis of the clinical syndrome of DOCK8 deficiency. Methods A cohort of DOCK8-deficient patients was assembled and patient NK cells as well as NK cell lines with stably reduced DOCK8 expression were studied. NK cell cytotoxicity, F-actin content, and lytic immunological synapse formation were measured. Results DOCK8-deficient patient NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation. Importantly, DOCK8 deficiency impaired F-actin accumulation at the lytic immunological synapse without affecting overall NK cell F-actin content. Conclusions DOCK8 deficiency results in severely impaired NK cell function owing to an inability to form a mature lytic IS via targeted synaptic F-actin accumulation. This defect may underlie and explain important attributes of the DOCK8 deficiency clinical syndrome including the unusual susceptibility to viral infection and malignancy.

Hyper-IgE syndromes and atopic dermatitis patients showed different sensitization pattern of serum IgE corresponding to the allergic disease manifestations and Th-cell subset data, suggesting a key role of DOCK8 in the development of food allergy.