Form Of hyper-IgE Syndrome Research Articles

DOCK 8 IMMUNODEFICIENCY

Autosomal recessive (AR) DOCK8 deciency is a well-known actinopathy, a combined primary immune deciency with impaired actin polymerization that results in altered cell mobility and immune synapse. DOCK8-decient patients present early in life with eczema, viral cutaneous infections, chronic mucocutaneous candidiasis, bacterial pneumonia and abscesses, together with eosinophilia, thrombocytosis, lymphopenia, and variable dysgammaglobulinemia that usually includes Hyper-IgE. In fact, before its genetic aetiology was known, patients were described as having a form of Hyper-IgE syndrome, a name now deprecated in favour of genetic defects. We describe a school-age female patient with a clinical picture suggestive of DOCK8 deciency, except for high serum IgE or a family history: early onset, failure to thrive, oral fungating lesion, generalized maculopapular rashes, bronchiolitis, pneumonia, recurrent otitis media, bronchiectasis, candidiasis, leucocytosis, eosinophilia, high IgA, low IgG and low CD4+ T cells. We were able to conrm the diagnosis through protein expression and whole-exome sequencing. We review the clinical, laboratory, and genetic features of 200 DOCK8-decient patients. Despite this, the constellation of signs, symptoms, and ndings allow the suspicion of DOCK8 deciency and other actinopathies.

A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance

Heterozygous in-frame mutations in coding regions of human STAT3 underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in recipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous patients. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the STAT3 complementary DNA, which, when overexpressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phosphorylation, DNA binding, and transcriptional activity. In immortalized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients' primary B and T lymphocytes responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical STAT3 coding mutations, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequencing STAT3 introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.

Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes TH17 cell differentiation

The autosomal recessive hyper-IgE syndrome (HIES) caused by dedicator of cytokinesis 8 (DOCK8) deficiency shares clinical features with autosomal dominant HIES because of signal transducer and activator of transcription 3 (STAT3) mutations, including recurrent infections and mucocutaneous candidiasis, which are suggestive of TH17cell dysfunction. The mechanisms underlying this phenotypic overlap are unclear. We sought to elucidate common mechanisms operating in the different forms of HIES. We analyzed the differentiation of CD4+ TH cell subsets in control and DOCK8-deficient subjects. We also examined the role of DOCK8 in regulating STAT3 activation in Tcells. TH cell differentiation was analyzed by ELISA, flow cytometry, and real-time PCR measurements of cytokines and TH cell transcription factors. The interaction of DOCK8 and STAT3 signaling pathways was examined by using flow cytometry, immunofluorescence, coimmunoprecipitation, and gene expression analysis. There was a profound block in the differentiation of DOCK8-deficient naive CD4+ Tcells into TH17cells. Amissense mutation that disrupts DOCK8 guanine nucleotide exchange factor (GEF) activity while sparing protein expression also impaired TH17cell differentiation. DOCK8 constitutively associated with STAT3 independent of GEF activity, whereas it regulated STAT3 phosphorylation in a GEF activity-dependent manner. DOCK8 also promoted STAT3 translocation to the nucleus and induction of STAT3-dependent gene expression. DOCK8 interacts with STAT3 and regulates its activation and the outcome of STAT3-dependent TH17 differentiation. These findings might explain the phenotypic overlap between DOCK8 deficiency and autosomal dominant HIES.

The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency

Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management. We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/μL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4(+) and CD8(+) T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). Acombination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.

Hyper-IgE syndrome and autoimmunity in Mexican children

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by recurrent skin abscesses, recurrent pneumonia with pneumatocele formation, eczema, eosinophilia, and elevated levels of serum IgE. Patients with the autosomal recessive (AR) form of HIES appear to be prone to developing autoimmune diseases. We present two cases of HIES with autoimmune complications; one case was a product of a consanguineous marriage, the other one was a sporadic case. The first patient presented with recurrent episodes of erythema nodosum, warts, bronchiolitis obliterans and thrombocytopenia. The second patient developed glomerulonephritis resulting in endstage renal failure. She later developed malar rash, oral ulcers, cerebral infarcts with vasculitis and positive ANA, anti-dsDNA, and antiphospholipid antibodies. We discuss the dilemma in treating patients who present with both primary immunodeficiency and autoimmunity.

Assignment of the Acute Phase Response Factor (APRF) Gene to 17q21 by Microdissection Clone Sequencing and Fluorescencein SituHybridization of a P1 Clone

Hyper-IgE syndrome is a primary immunodeficiency marked by abnormalities in the coordination of cell-cell signaling with the potential to affect TH17 cell, B cell, and neutrophil responses. Clinical manifestations include recurrent skin and lung infections, serum IgE elevation, connective tissue repair and development alterations, and the propensity for vascular abnormalities and tumor development. Signal transducer and activator of transcription 3 (STAT3) signaling, dedicator of cytokinesis 8 (DOCK8) signaling, and tyrosine kinase 2 (TYK2) signaling alterations have been implicated in 3 forms of hyper-IgE syndrome.