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Update on Job ’ s (Hyper IgE) Syndrome: the many paths of STAT3

Update on Job ’ s (Hyper IgE) Syndrome: the many paths of STAT3. Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov. Autosomal dominant Hyper IgE Syndrome (Job ’ s syndrome).

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Update on Job ’ s (Hyper IgE) Syndrome: the many paths of STAT3

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  1. Update on Job’s (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov

  2. Autosomal dominant Hyper IgE Syndrome (Job’s syndrome) “So Satan went forth from the presence of the Lord, and smote Job with sore boils from the sole of his foot unto his crown.”

  3. Staph aureus driven skin and lung infections

  4. Characteristic facial appearance Domingo et al, Oral Diseases, 2008

  5. Skeletal, joint and Dental abnormalities

  6. Brain MRI Abnormalities Chiari I malformation: 18% of 50 patients 70% with focal hyperintensities Freeman et al, Pediatrics, 2007

  7. 2007

  8. Cytokine (IL-6, IL-10, IL-17 IL-21, IL-22, IL-23) Cytokine receptor Key mediator for many pathways including those of the immune system, cancer, wound healing, vascular remodeling. Expressed widely in most tissue types. Jak Tyk STAT3 STAT3 P SH2 STAT3 P Transcription STAT3 STAT3 Nucleus

  9. Leung et al, Cellular and Molecular Immunology 2010

  10. Mucocutaneous candidiasis STAT3 involved in the generation of Th17 cells

  11. Overnight SEB Stimulation Gated on CD4+ Absence of Th17 Cell differentiation Milner et al, Nature, 2008

  12. Candida Immunity Th17 lymphocyte Yeast Dectin-1 STAT3 Syk Card9 IL-6, IL-23 IL-17, IL-22 Antimicrobial peptides Epithelial cell

  13. Candida Immunity Th17 lymphocyte Yeast X X Dectin-1 STAT3 Syk X Card9 IL-6, IL-23 IL-17, IL-22 X Antimicrobial peptides Epithelial cell

  14. HIES with decreased salivary antimicrobial peptides Conti et al, Mucocal Immunology, 2011

  15. Decreased histatins in HIES Assessed by acid –urea PAGE

  16. GI susceptibility to Endemic Fungi?

  17. Lots and Lots of Histo

  18. S. Aureus Susceptibility? • Infections epithelial • Antimicrobial peptides with S. aureus activity and Th17/IL-17 pathway involvement implicated in mouse studies • But, other human diseases disrupting Th17/IL-17 pathway are not characterized by Staphylococcus susceptibility

  19. STAT3 also involved in the differentiation to and maintenance of central memory CD4 and CD8 T and memory B cells

  20. Increased Zoster Reactivation Decreased Memory T cells Patient Age Minimum lifetime prevalence 19/60=31.7% Siegel et al, Immunity 2011

  21. Decreased Memory B cells Variable specific antibody production Consider immune globulin replacement Speckmann et al, Clinical Immunology 2008

  22. But what about everything else in HIES? \

  23. A 43 year old with an MI

  24. Coronary Artery MRI Left anterior descending artery dilation and aneurysm, and RCA Tortuosity

  25. Other Aneurysms in HIES • Two patients with subarachnoid hemorrhages secondary to cerebral aneurysms • One patient with a mycotic MCA aneurysm • Aneurysm at the carotid bifurcation • Tortuous vessels common

  26. Job’s syndrome as a disease of impaired tissue remodeling

  27. Complications of pneumonia

  28. Impaired healing after lung surgeries 15 year old with infected pneumatocoele resected at his local hospital. Persistent air leak requiring chest tube for 9 months

  29. Surgical Experience Prolonged Bronchopleural fistulae in about half of lung surgeries often leading to repeat surgeries Freeman et al, J of Clin Immunology 2013

  30. Other Surgeries? • Impaired healing after certain GI surgeries (biliary leak, duodenum) • Apparently normal healing after bone/joint surgeries.

  31. Other evidence of abnormal tissue remodeling?

  32. Matrix Metalloproteinases (MMPs) • Involved in tissue remodeling • Found to be dysregulated in coronary artery aneurysms of Kawasaki disease and abdomimal aortic aneurysms • Involved in lung remodeling after injury

  33. Dysregulated MMPs *P< 0.0001 • Plasma levels: MMP-8 and MMP-9 were higher than controls; MMP-3 lower than controls • STAT3 binding sites in multiple MMP promoters • Can lead to abnormal wound healing/tissue remodeling *P: 0.0038 *P< 0.0001 Sekhsaria et al, JACI 2011

  34. Job’s syndrome (AD-HIES) • More than just a primary immunodeficiency • Understanding how defects in STAT3 lead to the diverse features of HIES will help us understand common medical conditions such as atherosclerosis, scoliosis, osteoporosis, and degenerative joint disease • Understanding the diverse roles of STAT3 is essential as its pathway is targeted in malignancies and autoimmunity

  35. Thanks Steven Holland Gulbu Uzel Ken Olivier Amy Hsu Joie Davis Pam Welch, Chris Spalding Vickey Anderson, Lisa Boris OP11 nurse case managers Josh Milner Ahmed Gharib Manfred Boehm AvramWalts Heidi Kong Theo Heller NikiMoutsopoulos Referring medical teams All of the patients with HIES and their families

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