update on jobs (hyper ige) syndrome: the many paths of stat3 alexandra freeman md laboratory of...
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Update on Job’s (Hyper IgE) Syndrome: the many paths of STAT3
Alexandra Freeman MDLaboratory of Clinical Infectious Diseases
NIAID/[email protected]
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.”
Staph aureus driven skin and lung infections
Characteristic facial appearance
Domingo et al, Oral Diseases, 2008
Skeletal, joint and Dental abnormalities
Brain MRI Abnormalities
70% with focal hyperintensities
Freeman et al, Pediatrics, 2007
Chiari I malformation: 18% of 50 patients
2007
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.
Leung et al, Cellular and Molecular Immunology 2010
Mucocutaneous candidiasisSTAT3 involved in the generation of Th17 cells
Overnight SEBStimulationGated on CD4+
Milner et al, Nature, 2008
Absence of Th17 Cell differentiation
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
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
HIES with decreased salivary antimicrobial peptides
Conti et al, Mucocal Immunology, 2011
Decreased histatins in HIES
Assessed by acid –urea PAGE
GI susceptibility to Endemic Fungi?
Lots and Lots of Histo
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
STAT3 also involved in the differentiation to and maintenance of central memory CD4 and CD8 T and
memory B cells
Increased Zoster Reactivation Decreased Memory T cells
Patient AgeMinimum lifetime prevalence 19/60=31.7%
Siegel et al, Immunity 2011
Speckmann et al, Clinical Immunology 2008
Variable specific antibody productionConsider immune globulin replacement
Decreased Memory B cells
\
But what about everything else in HIES?
A 43 year old with an MI
Coronary Artery MRI
Left anterior descending artery dilation and aneurysm, and RCA Tortuosity
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
Job’s syndrome as a disease of impaired tissue remodeling
Complications of pneumonia
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
Surgical Experience
Prolonged Bronchopleural fistulae in about half of lung surgeries often leading to repeat surgeries
Freeman et al, J of Clin Immunology 2013
Other Surgeries? • Impaired healing after certain GI surgeries (biliary leak,
duodenum)• Apparently normal healing after bone/joint surgeries.
Other evidence of abnormal tissue remodeling?
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
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
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
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