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 MDLaboratory of Clinical Infectious DiseasesNIAID/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 patients70% with focal hyperintensitiesFreeman 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 receptorKey mediator for many pathways including those of the immune system, cancer, wound healing, vascular remodeling. Expressed widely in most tissue types.JakTykSTAT3STAT3PSH2STAT3PSTAT3 is a major signal transduction proteinTranscriptionSTAT3STAT3Nucleus
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 staphLeung 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 SEBStimulationGated on CD4+Absence of Th17 Cell differentiationMilner et al, Nature, 2008
19 S. Aureus Susceptibility? Infections epithelialAntimicrobial peptides with S. aureus activity and Th17/IL-17 pathway involvement implicated in mouse studiesBut, 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 AgeMinimum lifetime prevalence 19/60=31.7%Siegel et al, Immunity 2011
22 Decreased Memory B cells Variable specific antibody productionConsider immune globulin replacementSpeckmann 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?\
34 Matrix Metalloproteinases (MMPs) Involved in tissue remodelingFound to be dysregulated in coronary artery aneurysms of Kawasaki disease and abdomimal aortic aneurysmsInvolved in lung remodeling after injury
35 Dysregulated MMPs*P<Plasma levels: MMP-8 and MMP-9 were higher than controls; MMP-3 lower than controlsSTAT3 binding sites in multiple MMP promotersCan 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 immunodeficiencyUnderstanding 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 diseaseUnderstanding 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 ThanksSteven HollandGulbu UzelKen OlivierAmy HsuJoie DavisPam Welch, Chris SpaldingVickey Anderson, Lisa BorisOP11 nurse case managersJosh MilnerAhmed GharibManfred BoehmAvram WaltsHeidi KongTheo HellerNiki MoutsopoulosReferring medical teamsAll of the patients with HIES and their families