Pathogenesis of hyper IgE syndrome

II. Pathogenesis of hyper-IgE syndrome

 The hyper-IgE syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent bacterial infections such as skin abscesses (so-called ‘cold abscesses') and cyst-forming pneumonia, severe chronic eczema indistinguishable from atopic dermatitis, and skeletal abnormalities. Most cases of HIES are sporadic, although some cases of familial HIES with autosomal dominant or recessive inheritance have been reported. In many cases (also called Job's syndrome), their clinical manifestations extend over multiple systems in the body, including the immune system, skeletal/dental system and soft tissue. In contrast, the abnormalities in familial autosomal recessive (AR)-HIES patients appear to be confined to the immune system. The gene(s) responsible for HIES and the molecular basis of the complex clinical manifestations have remained mysterious though the syndrome was described for the first time 40 years ago.

(1) Identification of Tyk2 as a gene causative of AR-HIES

 We first investigated, from an immunological point of view, a patient who showed AR-HIES and susceptibility to infection with viruses and intracellular bacteria such as mycobacteria and salmonella. Peripheral blood cells from the patient displayed severe defects in the signaling pathways of multiple cytokines including type I IFN, IL-6, IL-10, IL-12 and IL-23. We identified a homozygous mutation of the Tyk2 gene in the patient, and his parents were both heterozygous for the same mutation (Immunity, 2006; Curr. Opin. Allergy Clin Immunol. 2007). Transduction of the intact gene rescued the patient's cells from the cytokine signaling defects, providing definitive evidence that the Tyk2 mutation was responsible for the HIES in the patient. The defects in multiple cytokine signals involved in innate and acquired immunity appeared to account for the complex clinical manifestations of the patient, including impaired Th1- and accelerated Th2-differentiation. The clinical phenotype of the human Tyk2 deficiency is much severer than that observed in the Tyk2 knock-out mice, indicating a species difference. Thus, Tyk2 plays indispensable roles in the human immune system.

(2) Identification of STAT3 as a gene causative of classical HIES (Job's syndrome)

 The identification of a Tyk2 deficiency in AR-HIES prompted us to examine possible mutations in the Jak-STAT signaling axis in sporadic and classical HIES patients. We found that eight out of fifteen HIES patients had heterozygous STAT3 mutations, but their parents and siblings did not have the mutant STAT3 alleles, indicating these were de novo mutations (Nature, 2007). Five different mutations were found, all of which were located in the DNA-binding domain of STAT3. All five mutations were non-functional by themselves and showed dominant-negative effects when co-expressed with wild-type STAT3. Accordingly, the patients' peripheral blood cells showed defective responses to cytokines, including IL-6 and IL-10, the DNA-binding ability of STAT3 in these cells was greatly diminished. These results highlight the multiple roles played by STAT3 in humans, and underline the critical involvement of multiple cytokine pathways in the pathogenesis of HIES.

 The diagnosis of HIES early in life is often hampered by a paucity of specific clinical features. Our discovery of STAT3 as a major causative gene of this disease will facilitate earlier and definitive diagnosis, leading to the prevention of serious complications by prompting the start of prophylactic antibiotic treatment early in life.



  • Minegishi, Y., Saito, M., Morio, T., Watanabe, K., Agematsu, K., Tsuchiya, S., Takada, H., Hara, T., Kawamura, N., Ariga, T., Kaneko, H., Kondo, N., Tsuge, T., Yachie, A., Sakiyama, Y., Iwata, T., Bessho, F., Ohishi, T., Joh, K., Imai, K., Kogawa, K., Shinohara, M., Fujieda, M., Wakiguchi, H., Pasic, S., Abinun, M., Ochs, H., D., Renner, E., D., Jansson, A., Belohradsky, B., H., Metin, A., Shimizu, N., Mizutani, S., Miyawaki, T., Nonoyama, S., and Karasuyama, H.: Human Tyk2 deficiency reveals requisite roles of Tyk2 in multiple cytokine signals involved in innate and acquired immunity.Immunity 25: 745-755, 2006 (PubMed)
  • Minegishi, Y., Saito, M., Tsuchiya, S., Tsuge, I., Takada, H., Hara T., Kawamura, N., Ariga, T., Pasic, S., Stojkovic, O., Metin, A., and Karasuyama, H .: Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448: 1058-1062, 2007 (PubMed).
  • Minegishi, Y. and Karasuyama, H.: Hyperimmunoglobulin E syndrome and tyrosine kinasae 2 deficiency. Curr. Opin. Allergy Clin Immunol . 7: 506?509, 2007 (PubMed).