Dock8

Abstract: Hyper-immunoglobulin E syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with disproportionately milder inflammatory responses, referred to as cold abscesses, and skeletal abnormalities. Although some cases of familial HIES with autosomal dominant or recessive inheritance have been reported, most cases of HIES are sporadic, and their pathogenesis has remained mysterious for a long time. Here we show that dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem HIES. We found that eight out of fifteen unrelated non-familial HIES patients had heterozygous STAT3 mutations, but their parents and siblings did not have the mutant STAT3 alleles, suggesting that these were de novo mutations. Five different mutations were found, all of which were located in the STAT3 DNA-binding domain. The patients' peripheral blood cells showed defective responses to cytokines, including interleukin (IL)-6 and IL-10, and the DNA-binding ability of STAT3 in these cells was greatly diminished. All five mutants were non-functional by themselves and showed dominant-negative effects when co-expressed with wild-type STAT3. These results highlight the multiple roles played by STAT3 in humans, and underline the critical involvement of multiple cytokine pathways in the pathogenesis of HIES.

Abstract: Background 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. Methods 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. Results 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 infectio...

Abstract: Natural killer (NK) cells are part of the innate immune defense against infection and cancer and are especially useful in combating certain viral pathogens. The utility of NK cells in human health has been underscored by a growing number of persons who are deficient in NK cells and/or their functions. This can be in the context of a broader genetically defined congenital immunodeficiency, of which there are more than 40 presently known to impair NK cells. However, the abnormality of NK cells in certain cases represents the majority immunologic defect. In aggregate, these conditions are termed NK cell deficiency. Recent advances have added clarity to this diagnosis and identified defects in 3 genes that can cause NK cell deficiency, as well as some of the underlying biology. Appropriate consideration of these diagnoses and patients raises the potential for rational therapeutic options and further innovation.

Abstract: Background The genetic etiologies of the hyper-IgE syndromes are diverse. Approximately 60% to 70% of patients with hyper-IgE syndrome have dominant mutations in STAT3, and a single patient was reported to have a homozygous TYK2 mutation. In the remaining patients with hyper-IgE syndrome, the genetic etiology has not yet been identified. Objectives We aimed to identify a gene that is mutated or deleted in autosomal recessive hyper-IgE syndrome. Methods We performed genome-wide single nucleotide polymorphism analysis for 9 patients with autosomal-recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes. Homozygosity mapping was performed with 12 patients from 7 additional families. The candidate gene was analyzed by genomic and cDNA sequencing to identify causative alleles in a total of 27 patients with autosomal-recessive hyper-IgE syndrome. Results Subtelomeric biallelic microdeletions were identified in 5 patients at the terminus of chromosome 9p. In all 5 patients, the deleted interval involved dedicator of cytokinesis 8 (DOCK8) , encoding a protein implicated in the regulation of the actin cytoskeleton. Sequencing of patients without large deletions revealed 16 patients from 9 unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, and single exon deletions and microdeletions. DOCK8 deficiency was associated with impaired activation of CD4 + and CD8 + T cells. Conclusion Autosomal-recessive mutations in DOCK8 are responsible for many, although not all, cases of autosomal-recessive hyper-IgE syndrome. DOCK8 disruption is associated with a phenotype of severe cellular immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective T-cell activation and T h 17 cell differentiation, and impaired eosinophil homeostasis and dysregulation of IgE.