Autosomal dominant hyper-IgE syndrome

Reduced Ab responsesB-cell lymphoma 5-10%

Grimbacher et al. 2005. Immunol Rev. 203: 244

Autosomal dominant hyper-IgE syndrome

(images provided by Bodo Grimbacher, Gulbu Uzel)

Lung cysts

Autosomal dominant hyper-IgE syndrome

Grimbacher et al. 2005. Immunol Rev. 203: 244

Autosomal dominant hyper-IgE syndrome

(images provided by Bodo Grimbacher, Gulbu Uzel)

Hyper-IgE Syndrome• autosomal recessive

Freeman & Holland. 2008. Immunol Allergy Clin N Am. 28: 277

Severe allergy

Hyper-IgE Syndrome• autosomal recessive

Hyper-IgE Syndrome

Grimbacher et al. 2005. Immunol Rev. 203: 244Specific Ab defic’y Yes Yes (variable)Severe allergy Not really Yes!!

Genetic causes of HIES - 1

AR-HIES• susceptibility to

- viruses (molluscum, HSV)- fungi (candidiasis)- mycobacteria (BCG infection)- bacteria (salmonella)

• atopic dermatitis

• hyper IgE

Impaired responses of AR-HIES cells to multiple cytokines

T cells

B cells Monocytes

ControlAR-HIES

Consequences of TYK2 deficiency

Watford & O’Shea 2006. Immunity. 25: 695

Impaired Th1 responses g mycobacterial infection(phenocopy IL-12/IL-12R, IFN-γ/R, partial STAT1 mutants)

Impaired response to type I IFN’s g viral (herpes) infection (a la complete STAT1 deficiency)

*Impaired Th17 responses g candida infection

*Impaired Th17 responses g candida infection

*JEM 2015

g

g

Genetic causes of HIES - 2

“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.” Book of Job 2.7

William Blake 1826

Chandesris et al. 2012. Medicine. 91: e1-19

Genetic causes of HIES - 2

Mutations in STAT3

STAT3 activating cytokines• IL-2/γc family of cytokines

- IL-2, IL-4, IL-7, IL-9, IL-15, IL-21

• IL-6/gp130 family- IL-6, IL-11, IL-27, IL-31, LIF, oncostatin M, CNTF

• IL-10 family- IL-10, IL-19, IL-20, IL-22, IL-24, IL-26

• IFN family- IFN-γ, IFN-α/β, IL-28, IL-29

• CSF’s- G-CSF, M-CSF, Flt3L

• other- IL-12, IL-23, leptin, growth hormone

STAT3 LoF mutations

Genetic causes of HIES - 3

Genetic causes of HIES - 3

Engelhardt et al 2009. JACI

AR HIES – DOCK8 deficiency