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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