update on jobs (hyper ige) syndrome: the many paths of stat3 alexandra freeman md laboratory of...
TRANSCRIPT
![Page 1: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/1.jpg)
Update on Job’s (Hyper IgE) Syndrome: the many paths of STAT3
Alexandra Freeman MDLaboratory of Clinical Infectious Diseases
NIAID/[email protected]
![Page 2: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/2.jpg)
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.”
![Page 3: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/3.jpg)
Staph aureus driven skin and lung infections
![Page 4: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/4.jpg)
Characteristic facial appearance
Domingo et al, Oral Diseases, 2008
![Page 5: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/5.jpg)
Skeletal, joint and Dental abnormalities
![Page 6: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/6.jpg)
Brain MRI Abnormalities
70% with focal hyperintensities
Freeman et al, Pediatrics, 2007
Chiari I malformation: 18% of 50 patients
![Page 7: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/7.jpg)
2007
![Page 8: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/8.jpg)
Jak Tyk
STAT3STAT3
STAT3STAT3
Nucleus
STAT3
STAT3
STAT3STAT3
P
P
Transcription
SH2
Cytokine receptor
Cytokine (IL-6, IL-10, IL-17 IL-21, IL-22, IL-23)
Key mediator for many pathways including those of the immune system, cancer, wound healing, vascular remodeling. Expressed widely in most tissue types.
![Page 9: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/9.jpg)
![Page 10: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/10.jpg)
Leung et al, Cellular and Molecular Immunology 2010
![Page 11: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/11.jpg)
Mucocutaneous candidiasisSTAT3 involved in the generation of Th17 cells
![Page 12: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/12.jpg)
Overnight SEBStimulationGated on CD4+
Milner et al, Nature, 2008
Absence of Th17 Cell differentiation
![Page 13: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/13.jpg)
Candida Immunity
YeastYeast
Epithelial cell
Dectin-1
SykSyk
Card9Card9
IL-6, IL-23IL-6, IL-23
STAT3
Th17 lymphocyteTh17 lymphocyte
IL-17, IL-22
Antimicrobial peptidesAntimicrobial peptides
![Page 14: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/14.jpg)
Candida Immunity
YeastYeast
Epithelial cell
Dectin-1
SykSyk
Card9Card9
IL-6, IL-23IL-6, IL-23
STAT3
Th17 lymphocyteTh17 lymphocyte
IL-17, IL-22
Antimicrobial peptidesAntimicrobial peptides
![Page 15: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/15.jpg)
HIES with decreased salivary antimicrobial peptides
Conti et al, Mucocal Immunology, 2011
![Page 16: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/16.jpg)
Decreased histatins in HIES
Assessed by acid –urea PAGE
![Page 17: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/17.jpg)
GI susceptibility to Endemic Fungi?
![Page 18: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/18.jpg)
Lots and Lots of Histo
![Page 19: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/19.jpg)
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
![Page 20: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/20.jpg)
STAT3 also involved in the differentiation to and maintenance of central memory CD4 and CD8 T and
memory B cells
![Page 21: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/21.jpg)
Increased Zoster Reactivation Decreased Memory T cells
Patient AgeMinimum lifetime prevalence 19/60=31.7%
Siegel et al, Immunity 2011
![Page 22: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/22.jpg)
Speckmann et al, Clinical Immunology 2008
Variable specific antibody productionConsider immune globulin replacement
Decreased Memory B cells
![Page 23: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/23.jpg)
\
But what about everything else in HIES?
![Page 24: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/24.jpg)
A 43 year old with an MI
![Page 25: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/25.jpg)
Coronary Artery MRI
Left anterior descending artery dilation and aneurysm, and RCA Tortuosity
![Page 26: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/26.jpg)
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
![Page 27: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/27.jpg)
Job’s syndrome as a disease of impaired tissue remodeling
![Page 28: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/28.jpg)
Complications of pneumonia
![Page 29: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/29.jpg)
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
![Page 30: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/30.jpg)
Surgical Experience
Prolonged Bronchopleural fistulae in about half of lung surgeries often leading to repeat surgeries
Freeman et al, J of Clin Immunology 2013
![Page 31: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/31.jpg)
Other Surgeries? • Impaired healing after certain GI surgeries (biliary leak,
duodenum)• Apparently normal healing after bone/joint surgeries.
![Page 32: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/32.jpg)
Other evidence of abnormal tissue remodeling?
![Page 33: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/33.jpg)
![Page 34: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/34.jpg)
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
![Page 35: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/35.jpg)
Dysregulated MMPs• 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< 0.0001
*P: 0.0038
*P< 0.0001
Sekhsaria et al, JACI 2011
![Page 36: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/36.jpg)
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
![Page 37: Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH freemaal@mail.nih.gov](https://reader035.vdocuments.site/reader035/viewer/2022062511/5515c3e2550346a3758b4786/html5/thumbnails/37.jpg)
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