Blood Journal
Leading the way in experimental and clinical research in hematology

A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3

  1. Scott M. Steward-Tharp1,2,
  2. Arian Laurence1,
  3. Yuka Kanno1,
  4. Alex Kotlyar1,
  5. Alejandro V. Villarino1,
  6. Giuseppe Sciume1,
  7. Stefan Kuchen3,
  8. Wolfgang Resch3,
  9. Elizabeth A. Wohlfert4,
  10. Kan Jiang1,
  11. Kiyoshi Hirahara1,
  12. Golnaz Vahedi1,
  13. Hong-wei Sun5,
  14. Lionel Feigenbaum6,
  15. Joshua D. Milner7,
  16. Steven M. Holland8,
  17. Rafael Casellas3,
  18. Fiona Powrie2, and
  19. John J. O'Shea1
  1. 1Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD;
  2. 2Sir William Dunn School of Pathology, University of Oxford, United Kingdom;
  3. 3Genomics & Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD;
  4. 4Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY;
  5. 5Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD;
  6. 6Laboratory Animal Science Program, National Cancer Institute, National Institutes of Health, Frederick, MD; and
  7. 7Laboratory of Allergic Diseases, and
  8. 8Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

Key Points

  • Mice that express a mutation in STAT3 phenocopy patients with HIES.

  • Bone marrow transplantation does not fully correct the susceptibility of these animals to bacterial infection.

Abstract

Mutations of STAT3 underlie the autosomal dominant form of hyperimmunoglobulin E syndrome (HIES). STAT3 has critical roles in immune cells and thus, hematopoietic stem cell transplantation (HSCT), might be a reasonable therapeutic strategy in this disease. However, STAT3 also has critical functions in nonhematopoietic cells and dissecting the protean roles of STAT3 is limited by the lethality associated with germline deletion of Stat3. Thus, predicting the efficacy of HSCT for HIES is difficult. To begin to dissect the importance of STAT3 in hematopoietic and nonhematopoietic cells as it relates to HIES, we generated a mouse model of this disease. We found that these transgenic mice recapitulate multiple aspects of HIES, including elevated serum IgE and failure to generate Th17 cells. We found that these mice were susceptible to bacterial infection that was partially corrected by HSCT using wild-type bone marrow, emphasizing the role played by the epithelium in the pathophysiology of HIES.

  • Submitted September 17, 2013.
  • Accepted February 26, 2014.
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