Transcript 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
[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
Chiari I malformation: 18% of 50 patients
70% with focal hyperintensities
Freeman et al, Pediatrics, 2007
2007
Cytokine (IL-6, IL-10, IL17 IL-21, IL-22, IL-23)
Cytokine receptor
Jak
Key mediator for many pathways including
those of the immune system, cancer, wound
healing, vascular remodeling. Expressed
widely in most tissue types.
Tyk
STAT3
SH2
STAT3
P
P
Transcription
Nucleus
Leung et al, Cellular and Molecular Immunology 2010
Mucocutaneous candidiasis
STAT3 involved in the generation of Th17 cells
Overnight SEB
Stimulation
Gated on CD4+
Absence of Th17 Cell differentiation
Milner et al, Nature, 2008
Candida Immunity
Yeast
Th17
lymphocyte
Dectin-1
Syk
Card9
STAT
3
IL-6,
IL-23
Epithelial cell
Antimicrobial
peptides
IL-17,
IL-22
Candida Immunity
Yeast
Th17
lymphocyte
Dectin-1
Syk
Card9
STAT
3
IL-6,
IL-23
Epithelial cell
Antimicrobial
peptides
IL-17,
IL-22
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/IL17 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
35
30
25
20
No Shingles
15
Shingles
10
5
0
0-20
20-40
40-55
Patient Age
Minimum lifetime prevalence 19/60=31.7%
Siegel et al, Immunity 2011
Decreased Memory B cells
Variable specific antibody production
Consider immune globulin
replacement
Speckmann et al, Clinical Immunology 2008
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
Atherosclerosis in Controls
Atherosclerosis in HIES
Moderate-Severe
12%
Minimal
21%
None
49%
Minimal
39%
Moderate-Severe
0%
None
79%
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
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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