Milder clinical hyperimmunoglobulin E syndrome phenotype is associated with partial interleukin-17 deficiency

Abstract

Mutations in the signal transducer and activator of transcription 3 (STAT3) were reported to cause hyperimmunoglobulin E syndrome (HIES). The present study investigates T helper type 17 (Th17) responses triggered by the relevant stimuli Staphylococcus aureus and Candidia albicans in five 'classical' HIES patients, and a family with three patients who all had a milder HIES phenotype. We demonstrate that patients with various forms of HIES have different defects in their Th17 response to S. aureus and C. albicans, and this is in line with the clinical features of the disease. Interestingly, a partial deficiency of interleukin (IL)-17 production, even when associated with STAT3 mutations, leads to a milder clinical phenotype. We also observed defective Th17 responses in patients with the 'classical' presentation of the disease but without STAT3 mutations. These data demonstrate that defective IL-17 production in response to specific pathogens can differ between patients with HIES and that the extent of the defective Th17 response determines their clinical phenotype.

Fig. 1

The pedigree of a family with hyperimmunoglobulin E syndrome (HIES) of Dutch ancestry. Clinical symptoms characteristic for HIES were recorded in a large kindred, with patients affected [closed black symbols are family members affected signal transducer and activator of transcription 3 (STAT 3) mutation] from several generations. Closed grey symbols represent suspicion for the STAT3 mutation, but not proven. Line through symbol represents deceased family member.

Fig. 2

Defective interleukin (IL)-17 and interferon (IFN)-γ production in hyperimmunoglobulin E syndrome (HIES) patients in response to Staphylococcus aureus and Candida albicans. Human peripheral blood mononuclear cells (PBMCs) from healthy controls (n = 8), ‘classical’ HIES (n = 5) and three members of the HIES family bearing the STAT3 linker domain mutation were stimulated for 5 days with C. albicans (a) or S. aureus (b). Cytokines were measured by enzyme-linked immunosorbent assay. (c) IL-17 production by PBMC stimulated as in (a) and (b) from ‘classical’ HIES patients and familial HIES patients.

Fig. 3

T helper type 17 (Th17) cell generation in hyperimmunoglobulin E syndrome (HIES) patients. Human peripheral blood mononuclear cells (PBMCs) from healthy controls (n = 4), ‘classical’ HIES (n = 3) and three members of the HIES family bearing the signal transducer and activator of transcription 3 (STAT 3) linker domain mutation were stimulated for 5 days with Candida albicans or Staphylococcus aureus. The interleukin (IL)-17- or interferon (IFN)-γ-producing Th17 cells were assessed by intracellular staining (see description in the Methods).

Fig. 4

Defective interleukin (IL)-6, but not IL-10, pathway in hyperimmunoglobulin E syndrome (HIES) patients. Human peripheral blood mononuclear cells (PBMCs) from healthy controls (n = 8), ‘classical’ HIES (n = 5) and three members of the HIES family bearing the signal transducer and activator of transcription 3 (STAT 3) linker domain mutation were stimulated for 5 days with Candida albicans or Staphylococcus aureus. The effect of either IL-6 or IL-10 on the induction of IL-17 was assessed by enzyme-linked immunosorbent assay. *P < 0·05.