Hyper-IgE syndrome

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


Clinical characteristic of STAT3 deficiency


Characteristic face

Facial asymmetry

Broad nose

Deep-set eye

Prominent forehead


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


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


Malignancies

Hodgkin's lymphoma

Non-Hodgkin's lymphoma : B cell

Leukemia

Solid tumors : liver, lung


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


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


Pathogenesis

DOCK8 : guanine nucleotide exchange factor

Interacts with Rho GTPases

Regulatory function in cell migration, morphology, adhesion and growth


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


Immune cell compartment

Impaired NK cell function

Decreased plasmacytoid dendritic cell numbers

Decreased expression of TNF-alpha, IFN-gamma and IL-2


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




• 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

Allergic disease

Food allergy esp. Cow milk

Increased ratio of IL-4 compared to other cytokine --> Th2 predominance


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


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


Compilation of most commonly

reported immunological abnormalities


Prognosis

Overall survival propability(%)

Age-related event-free survival(%)

10 years of age 87 44



J Clin Immunol 2015, 35:189-98

Treatment

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

PneumatoceleBronchiectasis

Ann N.Y. Acad. Sci. 1246(2011) 26-33

Thank you

Hyper-IgE syndrome

Health & Medicine

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