Hyper-IgE syndrome

Hyper-IgE Syndrome
Jintana Chataroopwijit
28 October 2016

Group of primary immunodeficiencies
Significant elevation of IgE
Recurrent skin infections
Eczema
Pulmonary infection
Cur Opin Hematol 2015, 22:12-22

Autosomal dominant hyperIgE syndrome
STAT3 deficiency
Autosomal recessive hyperIgE syndrome
DOCK8 deficiency
Other : Tyrosine kinase 2 deficiency

Autosomal dominant
hyper-IgE syndrome

First described as "Job's syndrome" in 1966
Bablical Job : smote with sore boil
In 1972, extremely high serum IgE level
In 2008, known about mutation of STAT3
Immunol Allergy Clin N Am 28(2008) 227-291

Dominant-negative heterogenous mutation in
STAT3
STAT3 located at 17q21.31
Mutation mostly in SH2 and DNA binding
domains of STAT3 and mostly missense
mutations --> single amino acid changes or
short in-frame deletion
Immunol Allergy Clin N Am 35 (2015) 767-778
Artritis research and therapy 2012 14:228

Current Opinion in Immunology 2014, 28:49-57

JAK-STAT 2013; 2:e23435
Immunological and somatic phenotypes and associated
pathogenesis

Newborn rash usually first manifestation
First month of life : Pustular and eczematoid
rash esp. at face and scalp
Histology : eosinophilic infiltration
Culture : Staphylococcus aureus
Boils : cold abcess

Recurrent pyogenic pneumonia
Organisms : S aureus, Streptococcus
pneumoniae and Haemophilus influenzae
Complication : pneumatoceles, bronchiectasis
Structural abnormalities --> gram negative
bacterial infection ex. Pseudomonas and fungal
infection

Not much
Do not have Th2 predominance
Most IgE is not allergen-specific
Impaired IL-10 induced generation of tolerogenic
dendritric cells --> reduced generation of induced
regulatory T cell SO patient may manifest
anaphylaxis and have more allergy compared to
healthy

Facial asymmetry
Broad nose
Deep-set eye
Prominent forehead
India Journal of Dermatology2015

Scoliosis : vary in severity
Osteopenia
Minimal trauma fractures
Hyperextensibility : large and small joint
Degenerative joint disease

Craniosynostosis
Chiari 1 malformation
Unspecific white matter lesion
Journal of Clinical Immunology 2013

Failure of the primary dental teeth to exforiate
Immunol Allergy Clin N Am 28(2008) 227-291 Oral disease 2008

Peripheral and brain artery abnormalities
Coronary artery abnormalities : ectasias and
aneurysm
In mouse model, inhibited STAT3 signaling
and IL-17A blockage resulted in increased
aneurysm severity and fatal ruptures

Hodgkin's lymphoma
Non-Hodgkin's lymphoma : B cell
Leukemia
Solid tumors : liver, lung

Artritis research and therapy 2012 14:228

Gold standard : molecular diagnosis with
sequencing of STAT3
Often leucocytosis, rare neutopenia
Normal IgG

DOCK8-deficient autosomal
recessive hyper-IgE
syndrome

Firstly described in 2004 by Renner et al.
Consanguineous families
Feature of HIES but lack of connective tissue
disease and skeletal affect
Increased in viral infections
More neurologic symptoms, autoimmunity,
food allergy and higher rate of malignancies

DOCK8 : guanine nucleotide exchange factor
Interacts with Rho GTPases
Regulatory function in cell migration,
morphology, adhesion and growth

Mutation in DOCK8 : 9p24.3
Premature termination
Frameshift
Splice site disruption
Single exon deletions
Microdeletion

Mutation in DOCK8 : 9p24.3
Premature termination
Frameshift
Splice site disruption
Single exon deletions
Microdeletion
Loss of function

Severe reduction of memory B cells
Some impaired antibody responses to
immunization and long term memory
T cell number below average and some
diminishes proliferation

Impaired NK cell function
Decreased plasmacytoid dendritic cell
numbers
Decreased expression of TNF-alpha, IFN-
gamma and IL-2

Elevated serum IgE level with
CD3+, CD4+, naive CD8+ T cell
Lymphopenia
Normal total B lymphocyte percentage but
low memory B lymphocyte value

• Molluscum contagiosum
• Herpes simplex
• Varicella zoster

Herpetic
dermatitis and
mucositis at
eyelid
Oral ulcer of herpetic
gingivostomatitis
The Journal of Pediatrics 2016

Ranging from facial palsy to hemiplegia
Some had severe vasculits

Food allergy esp. Cow milk
Increased ratio of IL-4 compared to other
cytokine --> Th2 predominance

DOCK 8
Tumor surveillance
Tumor suppressor function
20% of patients develop at least one
cancer
10% of patients dying from cancer

Most common : squamous cell carcinomas
Second common : lymphoma
Others : microcystic adenoma, leiomyoma

Autoimmune hemolytic anemia
CNS vasculitis

Gold standard : molecular sequencing of
DOCK8 gene
Usually low T cell in number, low IgM level
and failure to sustain protective titer against
vaccination

First reported in 2006
Multiple episodes of staphylococcus disease,
severe eczema and elevated IgE level
Additionally, suffered from susceptibility to
BCG and Salmonella : IFN-gamma/IL-12
defect

Compilation of most
commonly reported
immunological
abnormalities

Overall survival
propability(%)
Age-related event-
free survival(%)
10 years of age
20 years of age
30 years of age
J Clin Immunol 2015, 35:189-98

Multidisciplinary approach
Prevention and management of infection
Bone marrow transplantation may be curative
Ann N.Y. Acad. Sci. 1246(2011) 26-33

Coverage organism
Staphylococcus aureus
Haemophilus influenzae
Streptococcus pneumoniae
Pseudomonas aeruginosa
Other gram negative bacteria
Fungi ex. Aspergillus fumigatus
Ann N.Y. Acad. Sci. 1246(2011) 26-33

Coverage organism
Staphylococcus aureus
Haemophilus influenzae
Streptococcus pneumoniae
Pseudomonas aeruginosa
Other gram negative bacteria
Fungi ex. Aspergillus fumigatus
Abnormal structural lung
Pneumatocele
Bronchiectasis
Ann N.Y. Acad. Sci. 1246(2011) 26-33

Hyper-IgE syndrome

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