Hyper-immunoglobulin E syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with disproportionately milder inflammatory responses, referred to as cold abscesses, and skeletal abnormalities1. Although some cases of familial HIES with autosomal dominant or recessive inheritance have been reported, most cases of HIES are sporadic, and their pathogenesis has remained mysterious for a long time. Here we show that dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem HIES. We found that eight out of fifteen unrelated non-familial HIES patients had heterozygous STAT3 mutations, but their parents and siblings did not have the mutant STAT3 alleles, suggesting that these were de novo mutations. Five different mutations were found, all of which were located in the STAT3 DNA-binding domain. The patients’ peripheral blood cells showed defective responses to cytokines, including interleukin (IL)-6 and IL-10, and the DNA-binding ability of STAT3 in these cells was greatly diminished. All five mutants were non-functional by themselves and showed dominant-negative effects when co-expressed with wild-type STAT3. 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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Grimbacher, B., Holland, S. M. & Puck, J. M. Hyper-IgE syndromes. Immunol. Rev. 203, 244–250 (2005)
Gould, H. J. et al. The biology of IGE and the basis of allergic disease. Annu. Rev. Immunol. 21, 579–628 (2003)
Grimbacher, B., Belohradsky, B. H. & Holland, S. M. Immunoglobulin E in primary immunodeficiency diseases. Allergy 57, 995–1007 (2002)
Davis, S. D., Schaller, J. & Wedgwood, R. J. Job's Syndrome. Recurrent, “cold”, staphylococcal abscesses. Lancet 1, 1013–1015 (1966)
Buckley, R. H., Wray, B. B. & Belmaker, E. Z. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics 49, 59–70 (1972)
Grimbacher, B. et al. Hyper-IgE syndrome with recurrent infections—an autosomal dominant multisystem disorder. N. Engl. J. Med. 340, 692–702 (1999)
Renner, E. D. et al. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J. Pediatr. 144, 93–99 (2004)
Minegishi, Y. et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25, 745–755 (2006)
Schindler, C. & Darnell, J. E. Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu. Rev. Biochem. 64, 621–651 (1995)
Ihle, J. N. Cytokine receptor signalling. Nature 377, 591–594 (1995)
Levy, D. E. & Darnell, J. E. STATs: transcriptional control and biological impact. Nature Rev. Mol. Cell Biol. 3, 651–662 (2002)
Kisseleva, T., Bhattacharya, S., Braunstein, J. & Schindler, C. W. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285, 1–24 (2002)
Grimbacher, B. et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am. J. Hum. Genet. 65, 735–744 (1999)
Horvath, C. M., Wen, Z. & Darnell, J. E. A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. Genes Dev. 9, 984–994 (1995)
Chapgier, A. et al. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease. PLoS Genet. 2, e131 (2006)
Takeda, K. et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl Acad. Sci. USA 94, 3801–3804 (1997)
Darnell, J. E. STATs and gene regulation. Science 277, 1630–1635 (1997)
Levy, D. E. & Lee, C. K. What does Stat3 do? J. Clin. Invest. 109, 1143–1148 (2002)
O'Brien, C. A., Gubrij, I., Lin, S. C., Saylors, R. L. & Manolagas, S. C. STAT3 activation in stromal/osteoblastic cells is required for induction of the receptor activator of NF-κB ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin-1 but not 1,25-dihydroxyvitamin D3 or parathyroid hormone. J. Biol. Chem. 274, 19301–19308 (1999)
Itoh, S. et al. A critical role for interleukin-6 family-mediated Stat3 activation in osteoblast differentiation and bone formation. Bone 39, 505–512 (2006)
Akira, S. et al. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77, 63–71 (1994)
Zhong, Z., Wen, Z. & Darnell, J. E. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264, 95–98 (1994)
Li, W., Liang, X., Kellendonk, C., Poli, V. & Taub, R. STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration. J. Biol. Chem. 277, 28411–28417 (2002)
Robinson, D. S., Larche, M. & Durham, S. R. Tregs and allergic disease. J. Clin. Invest. 114, 1389–1397 (2004)
Yang, X. O. et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J. Biol. Chem. 282, 9358–9363 (2007)
Happel, K. I. et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J. Exp. Med. 202, 761–769 (2005)
Wolk, K. et al. IL-22 increases the innate immunity of tissues. Immunity 21, 241–254 (2004)
Minegishi, Y. & Conley, M. E. Negative selection at the pre-BCR checkpoint elicited by human μ heavy chains with unusual CDR3 regions. Immunity 14, 631–641 (2001)
Minegishi, Y. et al. Mutations in Igα (CD79a) result in a complete block in B-cell development. J. Clin. Invest. 104, 1115–1121 (1999)
Minegishi, Y. et al. An essential role for BLNK in human B cell development. Science 286, 1954–1957 (1999)
We appreciate the willingness of the patients and the families to participate in this research study. This work is supported by the Japanese Ministry of Education, Culture, Sports, Science and Technology, and the Japanese Ministry of Health, Labor and Welfare.
Author Contributions Y.M. designed and conducted most of the experiments; M.S. conducted the genetic analysis and the generation of osteoclasts; S.T., I.T., H.T., T.H., N.K., T.A., S.P. and A.M. diagnosed and collected samples; O.S. collected samples; H.K. oversaw the entire project; Y.M. and H.K. wrote the manuscript with comments from all co-authors.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
About this article
Cite this article
Minegishi, Y., Saito, M., Tsuchiya, S. et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448, 1058–1062 (2007). https://doi.org/10.1038/nature06096
Molecular & Cellular Toxicology (2021)
Clinical and Immunological Heterogeneity in Japanese Patients with Gain-of-Function Variants in STAT3
Journal of Clinical Immunology (2021)
Molecular and Cellular Endocrinology (2021)
Periodontology 2000 (2021)
Molecular Cancer Therapeutics (2021)