hyper-ige syndrome
TRANSCRIPT
Hyper-IgE SyndromeJintana Chataroopwijit
28 October 2016
Introduction
Group of primary immunodeficiencies
Significant elevation of IgE
Recurrent skin infections
Eczema
Pulmonary infectionCur Opin Hematol 2015, 22:12-22
ClassificationAutosomal dominant hyperIgE syndrome
STAT3 deficiency
Autosomal recessive hyperIgE syndrome
DOCK8 deficiency
Other : Tyrosine kinase 2 deficiency
Cur Opin Hematol 2015, 22:12-22
Autosomal dominant hyper-IgE syndrome
Introduction
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-
291Current Opinion in Immunology 2014,
28:49-57
Pathogenesis
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
Role of STAT3 and its dysfunction in differentiation of Th17 cells and defence against infection
Current Opinion in Immunology 2014, 28:49-57
STAT3 and humoral immune respond
Current Opinion in Immunology 2014, 28:49-57
JAK-STAT 2013; 2:e23435
Immunological and somatic phenotypes and associated pathogenesis
Clinical characteristic of STAT3 deficiency
Immunol Allergy Clin N Am 28(2008) 227-291
Skin manifestationNewborn 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 Immunol Allergy Clin N Am 28(2008) 227-291
Pulmonary manifestationRecurrent pyogenic pneumonia
Organisms : S aureus, Streptococcus pneumoniae and Haemophilus influenzae
Complication : pneumatoceles, bronchiectasis
Structural abnormalities --> gram negative bacterial infection ex. Pseudomonas and fungal infectionImmunol Allergy Clin N Am 28(2008) 227-
291
Pulmonary manifestation
Allergic disease
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
Cur Opin Hematol 2015, 22:12-22
Clinical characteristic of STAT3 deficiency
Immunol Allergy Clin N Am 28(2008) 227-291
Characteristic face
Facial asymmetry
Broad nose
Deep-set eye
Prominent forehead
Immunol Allergy Clin N Am 28(2008) 227-291
India Journal of Dermatology2015
Musculoskeletal abnormalities
Scoliosis : vary in severity
Osteopenia
Minimal trauma fractures
Hyperextensibility : large and small joint
Degenerative joint diseaseImmunol Allergy Clin N Am 28(2008) 227-
291
Neurologic abnormalities
Craniosynostosis
Chiari 1 malformation
Unspecific white matter lesion
Immunol Allergy Clin N Am 28(2008) 227-291
Journal of Clinical Immunology 2013
Dental abnormalities
Failure of the primary dental teeth to exforiate
Immunol Allergy Clin N Am 28(2008) 227-291 Oral disease 2008
Vascular abnormalities
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
Cur Opin Hematol 2015, 22:12-22
Malignancies
Hodgkin's lymphoma
Non-Hodgkin's lymphoma : B cell
Leukemia
Solid tumors : liver, lung
Immunol Allergy Clin N Am 28(2008) 227-291
Immunological and infection feature
Artritis research and therapy 2012 14:228
Scoring system with clinical and laboratory test
Diagnosis
Gold standard : molecular diagnosis with sequencing of STAT3
Often leucocytosis, rare neutopenia
Normal IgG
Immunol Allergy Clin N Am 35 (2015) 767-778
DOCK8-deficient autosomal recessive hyper-IgE syndrome
IntroductionFirstly 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
Cur Opin Hematol 2015, 22:12-22
Pathogenesis
DOCK8 : guanine nucleotide exchange factor
Interacts with Rho GTPases
Regulatory function in cell migration, morphology, adhesion and growth
Cur Opin Hematol 2015, 22:12-22
Pathogenesis
Mutation in DOCK8 : 9p24.3
Premature termination
Frameshift
Splice site disruption
Single exon deletions
MicrodeletionCur Opin Hematol 2015, 22:12-22
Pathogenesis
Mutation in DOCK8 : 9p24.3
Premature termination
Frameshift
Splice site disruption
Single exon deletions
MicrodeletionCur Opin Hematol 2015, 22:12-22
Loss of function
Immune cell compartment
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
Cur Opin Hematol 2015, 22:12-22
Immune cell compartment
Impaired NK cell function
Decreased plasmacytoid dendritic cell numbers
Decreased expression of TNF-alpha, IFN-gamma and IL-2
Cur Opin Hematol 2015, 22:12-22
Immunology
Elevated serum IgE level with
CD3+, CD4+, naive CD8+ T cell
Lymphopenia
Normal total B lymphocyte percentage but low memory B lymphocyte value
Clinical manifestation
Immunol Allergy Clin N Am 28(2008) 227-291
Clinical manifestation
Immunol Allergy Clin N Am 28(2008) 227-291
Clinical manifestation
Immunol Allergy Clin N Am 28(2008) 227-291
• Molluscum contagiosum• Herpes simplex• Varicella zoster
Herpetic dermatitis and mucositis at
eyelid
Oral ulcer of herpetic gingivostomatitis
The Journal of Pediatrics 2016
Clinical manifestation
Immunol Allergy Clin N Am 28(2008) 227-291
Ranging from facial palsy to hemiplegia
Some had severe vasculits
Allergic disease
Food allergy esp. Cow milk
Increased ratio of IL-4 compared to other cytokine --> Th2 predominance
Cur Opin Hematol 2015, 22:12-22
Malignancy
DOCK 8
Tumor surveillance
Tumor suppressor function
20% of patients develop at least one cancer
10% of patients dying from cancer
Malignancy
Most common : squamous cell carcinomas
Second common : lymphoma
Others : microcystic adenoma, leiomyoma
Autoimmune disease
Autoimmune hemolytic anemia
CNS vasculitis
Diagnosis
Gold standard : molecular sequencing of DOCK8 gene
Usually low T cell in number, low IgM level and failure to sustain protective titer against vaccination
Immunol Allergy Clin N Am 35 (2015) 767-778
Other hyper-IgE syndrome
Tyrosine kinase 2 deficient hyper-IgE syndrome
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
Cur Opin Hematol 2015, 22:12-22
Cur Opin Hematol 2015, 22:12-22
Compilation of most commonly
reported immunological abnormalities
Cur Opin Hematol 2015, 22:12-22
Cur Opin Hematol 2015, 22:12-22
Cur Opin Hematol 2015, 22:12-22
Prognosis
Overall survival propability(%)
Age-related event-free survival(%)
10 years of age 87 44
20 years of age 47 18
30 years of age 33 4
J Clin Immunol 2015, 35:189-98
Treatment
Multidisciplinary approach
Prevention and management of infection
Bone marrow transplantation may be curative
Immunol Allergy Clin N Am 35 (2015) 767-778
Ann N.Y. Acad. Sci. 1246(2011) 26-33
Prevention and management of infection
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
Prevention and management of infection
Coverage organism
Staphylococcus aureus
Haemophilus influenzae
Streptococcus pneumoniae
Pseudomonas aeruginosa
Other gram negative bacteria
Fungi ex. Aspergillus fumigatus
Abnormal structural lung
PneumatoceleBronchiectasis
Ann N.Y. Acad. Sci. 1246(2011) 26-33
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