Presentation on theme: "Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH"— Presentation transcript:
Update on Jobs (Hyper IgE) Syndrome: the many paths of STAT3 Alexandra Freeman MD Laboratory of Clinical Infectious Diseases NIAID/NIH
Autosomal dominant Hyper IgE Syndrome (Jobs 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
JakTyk STAT3 Nucleus STAT3 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 candidiasis STAT3 involved in the generation of Th17 cells
Overnight SEB Stimulation Gated on CD4+ Milner et al, Nature, 2008 Absence of Th17 Cell differentiation
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 Age Minimum lifetime prevalence 19/60=31.7% Siegel et al, Immunity 2011
Speckmann et al, Clinical Immunology 2008 Variable specific antibody production Consider 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
Jobs 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< *P: *P< Sekhsaria et al, JACI 2011
Jobs 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