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

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Presentation on theme: "Update on Job’s (Hyper IgE) Syndrome: the many paths of STAT3"— Presentation transcript:

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

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.” AD-HIES was initially described as Job’s syndrome in the 1960s in 2 girls with eczema, boils, pneumonias……few years later Becky Bucky discorbered IgE, put together HIES.

3 Staph aureus driven skin and lung infections
The clinical phenotype of the disease was well described over the next few decades but the etiology and pathogenesis were very poorly understood. Presentation newborn….boils..

4 Characteristic facial appearance
In addition It was recognized that this was a multisystem disorder….. Domingo et al, Oral Diseases, 2008

5 Skeletal, joint and Dental abnormalities
Fractures, hyperextensibility.

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

7 In 2007, the genetic etiology was discovered and finally the focus changed to being able to start understanding pathogenesis. Dominant negative mutations…protein positive. 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 STAT3 is a major signal transduction protein Transcription STAT3 STAT3 Nucleus

9 But the non-immunologic features still needed to be understood.

10 Leung et al, Cellular and Molecular Immunology 2010
Recognized that mice made deficient in the IL-17 pathway had trouble with candida as well as extracellular bacterial infections….although unfortunately not staph Leung et al, Cellular and Molecular Immunology 2010

11 Mucocutaneous candidiasis
STAT3 involved in the generation of Th17 cells

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

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

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

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

16 Decreased histatins in HIES
Assessed by acid –urea PAGE

17 GI susceptibility to Endemic Fungi?
Not only does the lack of Th17 cells explain the epithelial candida mmunity but also could explain the funny GI susceptbility to endemic fungi

18 Lots and Lots of Histo Yet more Histoplasma

19 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

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

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

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

23 But what about everything else in HIES?
But the non-immunologic features still needed to be understood. But what about everything else in HIES? \

24 A 43 year old with an MI

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

26 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

27 Job’s syndrome as a disease of impaired tissue remodeling

28 Complications of pneumonia

29 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

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

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

32 Other evidence of abnormal tissue remodeling?


34 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

35 Dysregulated MMPs *P< 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: *P< Sekhsaria et al, JACI 2011

36 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

37 All of the patients with HIES and their families
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 Avram Walts Heidi Kong Theo Heller Niki Moutsopoulos Referring medical teams All of the patients with HIES and their families

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