An update on the hyper-IgE syndromes

Abstract

The hyper-IgE syndromes (HIES; originally named Job's syndrome) are a collection of primary immunodeficiency syndromes resulting in elevated serum IgE levels and typified by recurrent staphylococcal skin abscesses, eczema and pulmonary infections. The disorder has autosomal dominant and recessive forms. Autosomal dominant HIES has been shown to be mainly due to STAT3 mutations and additionally results in connective tissue, skeletal, vascular and dental abnormalities. Autosomal recessive HIES has been shown to be mainly due to mutations in DOCK8; these patients are more prone to viral skin infections instead. This review article discusses the common clinical features of the syndrome, the genetic mutations responsible and the pathogenesis of the disease, as well as treatments currently used.

Figure 1

Clinical features in AD-HIES (with approximate frequencies) [4]. MRI, magnetic resonance imaging; SD, standard deviation.

Figure 2

Role of STAT3 and consequences of its dysfunction in the differentiation of Th17 cells and defence against infection. Secretion of IL-1 and IL-6 by dendritic cells (DCs) under appropriate conditions results in Th17 differentiation. IL-6 is a STAT3-dependent cytokine that activates the transcription factor retinoic acid-related RORγt. Th17 cells secrete IL-17A, IL17-F and IL-22. IL-17A and IL-17F stimulate epithelial cells to produce chemokines that recruit polymorphonuclear leukocytes (PMNs) for killing of pathogens by phagocytosis. IL-22 secretion triggers the production of defensins by epithelial cells for further defence against extracellular pathogens. Mutations in STAT3 result in failure of Th17 differentiation, which, in turn, leads to susceptibility to fungi and extracellular bacteria.