Pathogenesis of Hyper IgE Syndrome

Abstract

Hyper IgE syndrome (HIES) is a rare primary immunodeficiency characterized by the triad of elevated IgE and eosinophilia, eczema, and recurrent skin and pulmonary infections. The autosomal dominant (AD) form of HIES results from mutations in STAT3 and is characterized by disordered inflammation, connective tissue, and skeletal abnormalities. Tissue-specific STAT3 deficiency in animals, cytokine and transcriptional array data, and careful clinical phenotyping have explained some of the pathophysiology of the immunologic and non-immunologic abnormalities of AD-HIES. In depth study of the role of STAT3 mutations in specific aspects of HIES may lead to better understanding and new approaches to treatment of conditions intrinsic to HIES that are common in the general population, such as staphylococcal infections, scoliosis, osteoporosis, bronchiectasis, and arterial aneurysms. As the genotypes of STAT3 deficiency are further characterized, genotype-phenotype correlations may emerge that will be informative regarding specific molecular interactions. Autosomal recessive forms of hyper IgE (AR-HIES) have also been reported. A single case of homozygous deficiency of the signal protein Tyk2 has been reported as well as a recessive syndrome with some features overlapping AD-HIES, but for which the genetic etiology is unknown. Better understanding of the pathophysiology and mechanisms of dominant and recessive hyper IgE syndromes will shed light on somatic and immune biology and may improve quality of life and survival for HIES patients.

Ten-Year Follow-Up of a DOCK8-Deficient Child With Features of Systemic Lupus Erythematosus

“…3,4,7 Viral skin infections most commonly seen are severe and sometimes mutilating infections with Herpes simplex, Varicella zoster, Molluscum contagiosum, and human papilloma virus, which are often diffuse and resistant to usual therapies. 5,8,9,10 Some authors have reported efficiency of topical cidofovir for recalcitrant molluscum contagiosum in immunocompromised children. The facies described in AD-HIES are found in recessive forms but are less marked.…”

Right-sided endocarditis in an adult patient with hyperimmunoglobulin-E syndrome successfully treated with high-dose daptomycin

“…The most characteristic facial feature is a broad nasal base and broad nasal bridge, protrusion of the forehead, wide outer canthal distances, and deep set eyes [6,7] .…”

Cardiovascular abnormalities in primary immunodeficiency diseases

“…Description: Hyper-IgE Syndrome (HIES) represents a group of disorders characterized by recurrent skin and lung infections, eczema, and elevated IgE levels (Heimall et al 2010). An autosomal dominant form (OMIM# 147060), also known as Job's Syndrome, is associated with distinctive coarse facial features, delayed shedding of primary teeth, frequent bone fractures, spinal deformities, vascular anomalies, and development of lymphoma (Heimall et al 2010).…”

“…An autosomal dominant form (OMIM# 147060), also known as Job's Syndrome, is associated with distinctive coarse facial features, delayed shedding of primary teeth, frequent bone fractures, spinal deformities, vascular anomalies, and development of lymphoma (Heimall et al 2010). Pulmonary infections often result in pneumatoceles and (or) bronchiectasis.…”