Update on Job’s (Hyper IgE) Syndrome: the many paths of STAT3

Alexandra Freeman MDLaboratory of Clinical Infectious Diseases

NIAID/NIHfreemaal@mail.nih.gov

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

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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