The genetics of hyper IgE syndromes

Abstract

Hyper IgE syndromes (HIES) form a rare group of primary immunodeficiency disorders (PIDs) distinguished by persistent skin abscesses, dermatitis, allergies, and infections, in addition to their characteristic high serum IgE levels. Autosomal dominant (AD) and autosomal recessive (AR) genetic defects have been reported in HIES. From a clinical perspective, AD-HIES cases generally exhibit several non-immunologic features, including connective tissue, dental and skeletal abnormalities, whilst AR-HIES conditions have a higher incidence of neurologic complications and cutaneous viral infections. Genetic defects associated with HIES lead to impaired immune signaling, affecting pathways crucial for immune cell development, function, and immune response to pathogens/allergens. As a result, HIES patients are predisposed to recurrent bacterial and/or fungal infections, as well as atopic allergic responses. In many cases, the exact biological mechanisms responsible for the variations observed in the clinical phenotypes between the two inherited forms of HIES are still unclear. In this review, we describe the genetic basis of HIES with a distinction between the AR-HIES and AD-HIES forms, to better comprehend the different underlying molecular mechanisms, a distinction which is imperative for the accurate diagnosis, management, and development of targeted therapies for HIES patients.

Keywords: HIES; Mendelian disorders; atopic dermatitis; elevated serum IgE; genetic etiology; immune signaling; primary immunodeficiency disorders; recurrent infections.

Figure 1

Signaling pathways and associated genes with mutations linked to hyper-IgE syndrome. (A) Components of cytokine signaling such as STAT3, ZNF341, STAT6, IL6R, and IL6ST; (B) TGF-β signaling pathway genes, including TGFBR1, TGFBR2, and ERBIN; (C) the antigen receptor signaling molecule CARD11; and (D) the actin cytoskeleton signaling molecule DOCK8. These pathways highlight the major molecular mechanisms currently identified which contribute to the clinical phenotypes of hyper-IgE syndrome. HIES genes are highlighted in red boxes or in red font and phosphorylation is indicated by yellow circles. JAK, Janus Kinase; STAT, Signal Transducer and Activator of Transcription; ZNF, zinc-finger; IL, Interleukin; ST, Signal Transducer; TGFBR, Transforming Growh Factor Beta Receptor; NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; SMAD, Suppressor of Mothers Against Decapentaplegic; ERBIN, Erbb2 Interacting Protein; A20, Tumor Necrosis Factor; Alpha-Induced Protein 3; TCR, T Cell Receptor; PKC, Protien Kinase C; CARD11, Caspase recruitment domain-containing protein 11; Bcl10, B-cell lymphoma/leukemia 11; MALT1, Mucosa-associated lymphoid tissue lymphoma translocation protein 1; TRAF6, TNF receptor associated factor 6; TAB2/3, TGFb activated kinase 1 binding protein 2; TAK1, TGFb-activated kinase 1; CYLD, Cylindromatosis deubiquitinase; IKK, Inhibitor of nuclear factor kappa-B kinase; DOCK8, Dedicator of cytokinesis protein 8; WIP, WAS/WASL-interacting protein; WASP, Wiskott–Aldrich syndrome protein; ARP, actin-related protein.