Staphylococcus aureus and Hyper-IgE Syndrome.

Bonggoo Park,George Y. Liu

doi:10.3390/ijms21239152

Abstract

Hyper-immunoglobulin E syndrome (HIES) is a primary immunodeficiency disease characterized by recurrent Staphylococcus aureus (S. aureus) infections, eczema, skeletal abnormalities and high titers of serum immunoglobulin E. Although the genetic basis of HIES was not known for almost a half century, HIES most frequently exhibits autosomal dominant trait that is transmitted with variable expressivity. Careful genetic studies in recent years identified dominant-negative mutations in human signal transducer and activator of transcription 3 (STAT3) gene as the cause of sporadic and dominant forms of HIES. The STAT3 mutations were localized to DNA-binding, SRC homology 2 (SH2) and transactivating domains and disrupted T helper 17 (TH17) cell differentiation and downstream expression of TH17 cytokines IL-17 and IL-22. Deficiency of IL-17 and IL-22 in turn is responsible for suboptimal expression of anti-staphylococcal host factors, such as neutrophil-recruiting chemokines and antimicrobial peptides, by human keratinocytes and bronchial epithelial cells. TH17 cytokines deficiency thereby explains the recurrent staphylococcal lung and skin infections of HIES patients.

Highlights

S. aureus causes a wide range of pathological conditions ranging from minor skin and soft tissue infections to life-threatening invasive diseases [1]
These findings indicate that T helper 17 (TH17) cells play a key role in immune responses to extracellular bacteria and fungi in mice
hyper-IgE syndrome (HIES) started as a constellation of discrete clinical and laboratory findings, which were linked by specific genetic defects

Summary

Introduction

S. aureus causes a wide range of pathological conditions ranging from minor skin and soft tissue infections to life-threatening invasive diseases [1]. Staphylococci use many strategies to evade host innate and adaptive immune defenses and survive hostile environments [1,3,4,5,6]. These strategies include resistance to specific antimicrobial peptides, neutralization of reactive oxygen species (ROS), inactivation of complement, inhibition of neutrophil migration, and evasion of phagocytosis [1,7]. Useful insight on alternative staphylococcal vaccine strategies and host adaptive immune responses to S. aureus have come from studies of a particular immunodeficiency condition, hyper-IgE syndrome (HIES), which confers susceptibility to recurrent S. aureus infections. Hyper-IgE syndrome (HIES), called Job’s syndrome or Buckley’s syndrome, was first described as a rare primary immunodeficiency disease characterized by recurrent staphylococcal “cold” skin and pulmonary abscesses, eczematoid dermatitis, markedly elevated levels of serum IgE and eosinophilia, reduced neutrophil chemotaxis, and variably impaired T cell function [14,15]

Genetics

TH17 Cells

STAT3 Mutations

Findings

Conclusions