Hyperimmunoglobulin E-Recurrent Infection Syndrome

 Hyperimmunoglobulin E-Recurrent Infection Syndrome

The hyperimmunoglobulin E - recurrent infection syndrome, or Job's syndrome, is a rare multisystem disease in which the immune and somatic systems are affected, including neutrophils, monocytes, T cells, B cells, and osteoclasts. Autosomal dominant inhibitory mutations in signal transducer and activator of transcription 3 (STAT 3) lead to inhibition of normal STAT signaling with broad and profound effects. Patients have characteristic facies with broad nose, kyphoscoliosis, and eczema. The primary teeth erupt normally but do not deciduate, often requiring extraction. Patients develop recurrent sinopulmonary and cutaneous infections that tend to be much less inflamed than appropriate for the degree of infection and have been referred to as "cold abscesses". Characteristically, pneumonias cavitate, leading to pneumatoceles. Coronary artery aneurysms are common, as are cerebral demyelinated plaques that accumulate with age. Importantly, IL-17-producing T cells, which are thought responsible for protection against extracellular and mucosal infections, are profoundly reduced in Job's syndrome. Despite very high IgE levels, these patients have only mildly elevated with the dominant negative STAT 3 deficiency is due to autosomal recessive defects in dedicator of cytokinesis 8 (DOCK8). In DOCK8 deficiency, IgE elevation is joined to severe allergy, viral susceptibility, and increased rates of cancer. Autosomal dominant gain-of-function mutations in STAT3 lead to a disease characterized by onset in childhood of lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity, infections, and interstitial lung disease.