Human hyper-IgE syndrome: singular or plural?

Abstract

Spectacular progress has been made in the characterization of human hyper-IgE syndrome (HIES) over the last 50 years. HIES is a primary immunodeficiency defined as an association of atopy in a context of very high serum IgE levels, characteristic bacterial and fungal diseases, low-level clinical and biological inflammation, and various non-hematopoietic developmental manifestations. Somewhat arbitrarily, three disorders were successively put forward as the underlying cause of HIES: autosomal dominant (AD) STAT3 deficiency, the only disorder corresponding to the original definition of HIES, and autosomal recessive (AR) DOCK8 and PGM3 deficiencies, in which atopy and high serum IgE levels occur in a context of manifestations not seen in patients with typical HIES. Indeed, these three disorders disrupt different molecular pathways, affect different cell types, and underlie different clinical phenotypes. Surprisingly, several other inherited inborn errors of immunity in which serum IgE levels are high, sometimes almost as high as those in HIES patients, are not considered to belong to the HIES group of diseases. Studies of HIES have been further complicated by the lack of a high serum IgE phenotype in all mouse models of the disease other than two Stat3 mutant strains. The study of infections in mutant mice has helped elucidate only some forms of HIES and infection. Mouse models of these conditions have also been used to study non-hematopoietic phenotypes for STAT3 deficiency, tissue-specific immunity for DOCK8 deficiency, and cell lineage maturation for PGM3 deficiency. We review here the history of the field of HIES since the first clinical description of this condition in 1966, together with the three disorders commonly referred to as HIES, focusing, in particular, on their mouse models. We propose the restriction of the term "HIES" to patients with an AD STAT3-deficiency phenotype, including the most recently described AR ZNF341 deficiency, thus excluding AR DOCK8 and PGM3 deficiencies from the definition of this disease.

Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution

“…Clear insight into the contributions of STAT3 in humans is provided by reviewing the features of patients with autosomal-dominant hyper-IgE syndrome (AD-HIES) or Job's syndrome (Yong et al, 2012;Zhang et al, 2018). AD-HIES is a rare multisystem disorder classified as a primary immunodeficiency disease, usually of children, in which patient's cells have diminished STAT3 activity due to an autosomaldominant, loss-of-function STAT3 mutation that leads to STAT3 protein instability and reduced half-life (Bocchini et al, 2016).…”

“…AD-HIES is a rare multisystem disorder classified as a primary immunodeficiency disease, usually of children, in which patient's cells have diminished STAT3 activity due to an autosomaldominant, loss-of-function STAT3 mutation that leads to STAT3 protein instability and reduced half-life (Bocchini et al, 2016). Their primary immune defects are as follows: 1) impaired barrier functions, especially of the skin and respiratory tract, due to delayed wound healing (Table 1); 2) decreased generation of Th17 cells and production of IL-17 and IL-22, which reduces epithelial production of chemokines and defensins (Yong et al, 2012;Zhang et al, 2018); and 3) intrinsic impairments in neutrophil chemotaxis Panopoulos et al, 2006;Mintz et al, 2010;Nguyen-Jackson et al, 2010;Mogensen, 2013 Increased presbycardia and MI susceptibility Jacoby et al, 2003;Hilfiker-Kleiner et al, 2004 Hepatocytes Insulin resistance; impaired liver regeneration Inoue et al, 2004;Moh et al, 2007 Adipocyte Increased body weight and adiposity Cernkovich et al, 2008 Neural cells Obesity, diabetes, infertility, and thermal dysregulation Gao et al, 2004 Hematopoietic progenitors Unaltered basal hematopoiesis; impaired stem cell regeneration after 5-FU Lee et al, 2002;Chung et al, 2006 Hematopoietic-derived cells Impaired DC function: defective transition of CMP/CLP to common DC precursors Laouar et al, 2003 Bone marrow cells Impaired myeloid cells resulting in Crohn's disease-like pathology Welte et al, 2003 T cells Increased apoptosis and impaired Th17 development Takeda et al, 1998b;Yang et al, 2007b B cells Reduced B cell compartments and plasma cells Chou et al, 2006;Fornek et al, 2006 Macrophages and neutrophils High susceptibility to endotoxin shock, ↑ TNF-a, IL-1, and IFN-g Takeda et al, 1999 CLP, common lymphoid progenitor; 5-FU, fluorouracil.…”

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity

“…Their phenotype was more closely resembled that of patients with STAT3 DN mutations than that of patients with other PIDs involving high serum IgE levels often referred to as AR forms of HIES, such as DOCK8 deficiency (25–29) and PGM3 deficiency (30, 31). Indeed, patients with DOCK8 deficiency present none of the extrahematopoietic features of AD-HIES but are highly vulnerable to skin-tropic viral infections.…”

CDG and immune response: From bedside to bench and back

“…From the 12 reported patients, six presented glycosylation anomalies and three of these experienced recurrent infections . Notably, the Ala391Thr SLC39A8 missense variant was correlated with Crohn's disease and microbiome composition, immune related traits and growth . Stimulation of various mouse tissues with proinflammatory molecules led to a general increase in the levels of Slc39a8 .…”