Hyperimmunoglobulin E syndrome and tyrosine kinase 2 deficiency.

PURPOSE OF REVIEW: The purpose of the review is to provide recent insight into the pathogenesis and pathophysiology of hyperimmunoglobulin E syndrome.

RECENT FINDINGS: We recently identified a homozygous four base-pair deletion in the coding region of the tyrosine kinase 2 gene in a hyperimmunoglobulin E syndrome patient who exhibited susceptibility to intracellular bacteria.

SUMMARY: Hyperimmunoglobulin E syndrome is a primary immunodeficiency characterized by recurrent staphylococcal skin abscesses and pneumonia, and elevated serum immunoglobulin E. This syndrome is subdivided into types 1 and 2. Type 1 displays abnormalities in multiple systems, including the skeletal/dental and immune systems, whereas type 2 abnormalities are confined to the immune system. We recently identified a homozygous mutation in the tyrosine kinase 2 gene in a type 2 patient. Analyses of cytokine responses in the patient's cells revealed that the tyrosine kinase 2 deficiency had resulted in severe impairment of the signal transduction for multiple cytokines, including interleukin-6, -10, -12 and -23, and interferon-alpha/beta. The cytokine signals were successfully restored by transducing the intact tyrosine kinase 2 gene. Thus, tyrosine kinase 2 plays obligatory roles in human immunity. Based on this finding, we propose that hyperimmunoglobulin E syndrome is a primary immunodeficiency caused by genetic alterations leading to the defect in multiple cytokine signals.