HyperIgE syndrome: primary immune deficiency.pdf

HyperIgE syndrome
Suravat Homvises, MD.

• Immediate hypersensitivity diseases are initiated by introduction
of an allergen
• Allergen stimulates IL-4– and IL-13–producing helper T cell
responses and IgE production
• IgE sensitizes mast cells by binding to FcεRI
• Subsequent exposure to allergen activates mast cells to secrete
mediators for pathologic reactions of immediate hypersensitivity
Biology of IgE
Abbas, Cellular and Molecular Immunology (Tenth Edition).

• Antigen-specific B cell binds antigen via surface IgM, internalizes and processes,
and presents to allergen-specific Th2 cell as MHC II–associated peptide fragment
• Engagement of TCR by MHC class II–antigen complex results in initiation of
cytokine transcription and rapid expression of CD40L (CD154)
• CD40L engages CD40, which is constitutively expressed on B cells
Holgate ST. Middleton’s allergy, 9th edition

• T/B cell signals mediated via CD40/CD40L are amplified by interactions between
costimulatory molecules (CD28/CD80-CD86 ligand/receptor pair)
• Engagement of CD40 upregulates CD80-CD86 expression on B cells
• Secretion of IL-4 and/or IL-13
• Engagement of receptors provides cytokine signal for isotype switching and results
in activation of transcription factor, STAT-6 Holgate ST. Middleton’s allergy, 9th edition

• CD40 signaling activates NF-κB transcription factors, which induce expression of
enzyme activation induced cytidine deaminase (AID), and lead to class switching
and IgE secretion
Holgate ST. Middleton’s allergy, 9th edition

• HyperIgE syndrome is characterized by a triad of
• Eczema
• Recurrent skin and pulmonary infections
• Elevated IgE levels
HyperIgE syndrome
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.

Diagnosis
• ESID Diagnostic criteria
• IgE >10 times the norm for age
• AND pathologic susceptibility to infectious diseases
• AND no evidence of T-cell deficiency (low T cell numbers, low naive T cells,
reduced proliferation)
• AND no evidence of B cell deficiency (low B cell numbers,
hypogammaglobulinemia)
Seidel MG, et al. J Allergy Clin Immunol Pract 2019;7:1763-70.

National Institute of Health (NIH) scoring system
Grimbacher B, et al. Am J Hum Genet 1999;65:735-44.

• Score >40: likely
• Score 20-40: intermediate
• Score <20: unlikely
National Institute of Health (NIH) scoring system
Grimbacher B, et al. Am J Hum Genet 1999;65:735-44.

STAT3 deficiency
• Classic AD-HIES (Job syndrome) is caused by heterozygous mutations with
dominant negative effect in STAT3 gene
• STAT3 is transcription factor involved in signal transduction of multiple cytokines,
most notably IL-6, IL-10, IL-11 and IL-21
• IL-6
• Promotes release of prostaglandin E in the brain causing fever
• Crucial for both T-helper-17 cell (Th17) and early stages of T follicular helper
cell (Tfh) differentiation

• Decreased IL-6
• Decreased PGE2 release in brain >> No fever, cold abscess
• Impaired Th17 differentiation >> Chronic mucocutaneous candidiasis
• Impaired Tfh differentiation >> Impaired class switching, affinity maturation in B
cells >> Antibody deficiency
• Decreased IL-10
• Impaired anti-inflammatory and broad immunosuppressive effects
STAT3 deficiency

• Decreased IL-11
• Delayed shedding of primary teeth, susceptibility to bone fractures, development
of aneurysms and the coarse facial features
(Skeletal, Dental, and Connective tissue abnormalities)
• Decreased IL-21
• Impaired B cell differentiation to plasma cells >> Antibody deficiency
STAT3 deficiency

Development of Th17 Cells
• Various bacteria and fungi act on DCs and macrophages and
stimulate production of cytokines, including IL-6, IL-1, and IL-23
• IL-6 and IL-1 stimulate early steps in Th17 differentiation
• IL-23 may be more important for the proliferation and
maintenance of differentiated Th17 cells
• TGF-β promotes the development of proinflammatory Th17 cells
when IL-6 or IL-1, are present
• Th17 differentiation is inhibited by IFN-γ (Th1) and IL-4 (Th2)

Development of Th17 Cells
• TGF-β, IL-6 and IL-1 work cooperatively to induce production of RORγt
• Transcription factor that is member of retinoic acid receptor family
• IL-6 activate the transcription factor STAT3
• Functions with RORγt to drive the Th17 response
• Th17 cells appear to be abundant in mucosal tissues (GI tract)
• High local concentrations of TGF-β and inflammatory cytokines

Function of Th17 cells
• Recruit leukocytes (mainly neutrophils) to sites of infection
• IL-17
• Produced by Th17 cells as well as ILC3s
• Induces neutrophil-rich inflammation
• Stimulates the production of chemokines such as IL-8,
TNF that recruit neutrophils and monocytes
• Enhances neutrophil generation by increasing production
of G-CSF and receptor expression
• Stimulates production of antimicrobial substances (defensins)

Function of Th17 cells
• IL-22
• Produced by activated T cells, particularly Th17 cells, and
some NK cells and ILCs
• Promoting barrier function of epithelia, by stimulating repair
reactions, and inducing production of antimicrobial peptides
• IL-21
• Produced by activated CD4+ T cells, including Th17 cells and
Tfh cells
• Stimulates generation of Tfh cells and activates B cells in
germinal centers (antibody responses)

• Mutations are mostly confined to DNA binding and SH2 domains of STAT3 gene
• Important for STAT3 homodimerization with each other or heterodimerization
with other STAT proteins, required for its transfer across the nuclear membrane
STAT3 deficiency
- Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
- Mogensen TH, et al. Scand J Infect Dis 2013;45:235-8.

Clinical manifestations of STAT3 deficiency
• Neonatal onset eczema (57%)
• Recurrent cutaneous staphylococcal infections with abscess formation (74%)
• Recurrent pneumonias caused by Staphylococcus aureus (72%) and Aspergillus
fumigatus (27%) often resulting in pneumatoceles
• Deep organ abscesses
• Mucocutaneous candidiasis (MCC)
• Skeletal, dental and connective tissue abnormalities

Skeletal, dental and connective tissue abnormalities
• Characteristic facial features: increased interalar distance, prominent forehead and
facial asymmetry)
• Retained primary teeth (41%)
• Hyperextensible joints (4%)
• Scoliosis (34%)
• Recurrent pathological fractures (39%)
• Vascular anomalies

Less frequent than DOCK8 deficiency
• Food (37%) and environmental (18%) allergies

Characteristic Facial Appearance Failure of Dental Exfoliation
Grimbacher B, et al. N Engl J Med 1999;340:692-702.

Gharehzadehshirazi A, et al. Clin Immunol 2022;237:108988.

• Newborn rash
• Infections: skin infections/abscess, pneumonia,
candidiasis
• Skeletal, dental and connective tissue
abnormalities
Schimke LF, et al. J Allergy Clin Immunol 2010;126:611-7 e1.

Schimke LF, et al. J Allergy Clin Immunol 2010;126:611-7 e1.

Complications
• Pneumatoceles and bronchiectasis
• Combination of pulmonary infections and impaired connective tissue remodeling
• Suitable for colonization with wide spectrum of pathogens such as
Pseudomonas aeruginosa, nontuberculous mycobacteria and A. fumigatus
• Major cause of morbidity and mortality

Laboratory findings
• Marked elevation in serum IgE (2000-100,000 IU/mL)
• Inversely correlated with age (start to rise after birth and decrease or normalize
during adulthood)
• Normal or IgE level <2000 is not exclusive of diagnosis
• Eosinophilia more than 90% of patients (usually ≥700 cells/µL)
• IgE concentration and eosinophilia are not correlate with disease activity
• Normal immunoglobulin concentrations

• Impaired vaccine responses
• Decreased CD27+ switched memory B cells (abnormal B-cell maturation)
• Normal T-cell number
• Decreased central memory T cells
• Normal lymphocyte proliferative responses to mitogens
Laboratory findings

Diagnosis
• 96% of STAT3 deficiency had NIH scored ≥40

Treatment
• Proactive skin care
• Prophylactic ATB: anti-staphylococcal and antimycotic agents
• Early antimicrobials for skin and pulmonary infections
• Systemic anti-staphylococcal antibiotics combined with conventional topical
agents for extent and severe atopic dermatitis
• Immunoglobulin replacements in patients with documented antibody deficiency

Controversy
• High dose intravenous immunoglobulin in improving eczema
• HSCT
Treatment

Tsilifis C, et al. J Clin Immunol 2021;41:864-80.

• Improvement in rates of infection, resolution of skin disease, and stabilization or
improvement of pulmonary function both clinically and radiologically
• Fell serum IgE and normal population of IL-17-secreting Th17 lymphocytes
HSCT

ZNF431 deficiency
• Biallelic mutations in gene coding for transcription factor ZNF431
• Low constitutive levels of STAT3 mRNA
• Impaired autoinduction of STAT3 generation and function by the cytokines that
activate STAT3 (functional STAT3-deficient state)

Impaired STAT3-dependent B- and T-cell function
• Decreased Th17
• Excess Th2
• Decreased memory B cells
Clinical manifestations of ZNF431 deficiency

Redundant STAT3-dependent functions in monocytes and other cell types
• Absence of cold abscesses
• Low incidence of skeletal, dental and/or connective tissue abnormalities
• Dysmorphic facial features, raised palate, primary teeth retention, scoliosis, joint
hyperextensibility and pneumatoceles were infrequently
Clinical manifestations of ZNF431 deficiency

Diagnosis and treatment
• Only 25% ZNF431- deficient patients had NIH score of ≥40
• No consensus on treatment
• HSCT may be more effective than in AD-HIES

• ERBIN
• Protein encoded by ERBIN2IP gene, is essential for inhibiting regulation
of transforming growth factor beta (TGF-β)
• Activated by STAT3
• Overactivation of IL4/IL4receptor (IL4R), Th2 cytokine expression and elevated IgE
• Clinical features overlap with STAT3-HIES
• No susceptibility to candidiasis
• Normal class-switching and B-and-T-cell memory cells
ERBIN deficiency

IL6 signal transducer (IL6ST) deficiency
• IL6 signal transducer (IL6ST)
• Encodes glycoprotein 130 (GP130), protein that belongs to subunit of IL6
signaling receptors
• Stimulation of receptors, several JAK/STAT pathways are activated
• Crucial for transferring signals from cell-membrane receptors to nucleus
• Regulating the differentiation of T helper cell

• Autosomal recessive IL6ST mutation
• Selective impairment in signaling pathway of IL6 and IL11
• Decreased PGE2 release in brain >> No fever, cold abscess
• Impaired Tfh differentiation >> Impaired class switching, affinity maturation in
B cells >> Antibody deficiency
• Skeletal, Dental, and Connective tissue abnormalities
• Th17 responses are present >> not prone to MCC

• Autosomal dominant IL6ST mutation (dominant negative)
• Typical clinical manifestations of STAT3 deficiency
• Severe pulmonary infections, eczema, skeletal abnormalities, and elevated IgE
• Pulmonary involvement is usually severe in AD cases
• Severe cystic bronchiectasis and bronchitis
• No craniosynostosis, because of residual IL11 responses

• IL-6 and IL-11 bind to receptors and
form complex with GP130
• Phosphorylation JAK and STAT
• ZNF341 positively regulates STAT3
transcription
• STAT3 dimers bind to DNA

DOCK8 deficiency
• Caused by homozygous or compound heterozygous deletions spanning multiple exons
• Less frequently by point mutations >> premature stop codons or deleterious splice sites
• DOCK8
• Member of DOCK180 superfamily of guanine nucleotide exchange factors
• Works upstream of Wiskott-Aldrich syndrome protein and regulates cytoskeletal
rearrangement required for cellular migration and immune synapse formation
• In DOCK8 knockout mice, DCs failed to migrate to lymph node parenchyma

• DOCK8
• Important for proper T-cell development
• DOCK8- deficient memory CD4+ T cells are biased toward T-helper cell 2 (Th2)
cytokines at expense of Th17 cytokines
• Attenuated T cell receptor (TCR) signaling favoring Th2 differentiation
• Impaired activation and nuclear translocation of STAT3
• Key transcription factor for Th17-cell differentiation
DOCK8 deficiency

• DOCK8
• Treg dysfunction results in dysregulated Th2-cell expansion >> autoimmunity
• DOCK8 is required for optimal T-regulatory (Treg) cell function through IL-2 signaling
• Impaired survival and function of CD8+ T cells (memory CD8+ T cells generation)
• Impaired NK cell effector function
• NK cells from DOCK8- deficient patients have reduced production of IFN-γ and
TNF-α upon NKp30 stimulation
• Defects in CD8+ T and/or NK cells >> viral infections and impaired tumor surveillance
DOCK8 deficiency

• Immune synapse formation (DOCK8-dependent)
• B-cell activation by activated T cells
• Germinal center formation
• Generation of memory B cells
DOCK8 deficiency

• Recurrent sinopulmonary infections
• Staphylococcal skin infections
• Mucocutaneous candidiasis (MCC)
• Cutaneous viral infections (herpes simplex, human papillomavirus and molluscum
contagiosum)
• Vulvar and anal squamous cell carcinomas
• Truly atopic!!! >> Food allergy (85%)
• Absent skeletal, dental and connective tissue abnormalities
Clinical manifestations of DOCK8 deficiency

Ravendran S, et al. Front Genome Ed 2022;4:793010.

• Neurologic manifestations including
• Infectious manifestations (Encephalitis)
• Noninfectious manifestations (CNS vasculitis, vascular aneurysm and brain
infarction)
Complications

• Eosinophilia
• Elevated IgE levels
• Lymphopenia, especially T cell lymphopenia (less frequent B-cell lymphopenia)
• Impaired lymphocyte proliferative response to mitogens
• Variable immunoglobulin levels
• Low IgM levels are frequently observed
• IgG and IgA are usually normal or elevated
• Poor vaccine responses
Laboratory findings

• NIH scores of ≥40
• Less frequent than AD-STAT3 deficiency
• Flow cytometric analysis for DOCK8 protein expression
• Mutational analysis by Sanger sequencing may be difficult because of prevalence of
large deletion in DOCK8
Diagnosis

Treatment
• Proactive skin care
• Prophylactic ATB: anti-staphylococcal and antimycotic agents
• Early antimicrobials agents for infections
• Immunoglobulin replacements
• HSCT more effective than in AD-HIES

Tyk2 deficiency
• Autosomal recessive mutation in Tyk2 gene
• Tyk2
• Nonreceptor tyrosine kinase of Janus kinase family involved in signaling through
multiple cytokines including type 1 interferon, IL-6, IL10, IL-12 and IL-23
• Impaired IL-12 signaling >> susceptibility to intracellular organisms
• Clinical manifestations
• Atypical mycobacterial and viral infections
• Not develop HIES triad

Phosphoglucomutase-3 (PGM3) deficiency
• Homozygous hypomorphic mutations in phosphoglucomutase-3 (PGM3) gene
• PGM3
• Required for synthesis of uridine diphosphate N-acetylglucosamine (UDP-
GlcNAc)
• UDP-GlcNAc modulates cellular signaling including TCR signaling via NF-κB
and NFAT >> Th2 expansion

Clinical manifestations of PGM3 deficiency
• Share features of both STAT3 and DOCK8 deficiency
• Early onset atopic dermatitis
• Recurrent bacterial skin and sinopulmonary infections
• Food allergy
• Viral cutaneous infections and MCC (occasion)
• Facial dysmorphism (wide nostrils and prominent lips) and skeletal abnormalities
(scoliosis, joint hypermobility)
• Primary teeth retention is not a feature
less prevalent than
DOCK8 deficiency

• Neurological manifestations (key features)
• Developmental delay
• Intellectual impairment
• Motor symptoms (ataxia, hypotonia)
• Renal manifestations (membranoproliferative glomerulonephritis)
• Erythema multiforme major
• T-B-NK+ severe combined immunodeficiency-like phenotype (rare)
Clinical manifestations of PGM3 deficiency

• Eosinophilia
• Elevated serum IgE
• B-cell lymphopenia
• Decreased memory B-cell percentage
• Hypergammaglobulinemia
• Normal vaccine responses (carbohydrate and protein)
• T-cell lymphopenia (predominantly CD4+ subset)
• Reversed CD4:CD8 ratio
• Variable lymphocyte proliferative responses to mitogens
Laboratory findings

• 87% of PGM3 deficiency had NIH scored ≥40
• Higher than in DOCK8 deficiency
• PGM3 protein level may be normal
• PGM3 activity is decreased in fibroblasts
Diagnosis

Treatment
• Oral N-acetyl-galactosamine (GlcNAc) supplementation
• Theoretically bypass metabolic defect and ameliorate pathologic phenotype
• Restore in vitro intracellular UDPGlcNAc levels in PGM3-deficient cells
• Immunoglobulin replacements may not be helpful
• HSCT
• 2 patients with SCID phenotype were successfully treated

CARD11 deficiency
• Heterozygous mutations in CARD11 with dominant negative effect
• CARD11
• Caspase recruitment domain family member 11
• Scaffold protein in CARMA1-BCL-9-MALT1 complex which is essential for T-
and B-cell receptor signaling via NF- κB and mTORC activation

Clinical manifestations of CARD11 deficiency
• Severe atopy: predominant clinical manifestations
• Atopic dermatitis, food and environmental allergies and asthma
• Recurrent infections associated with combined immunodeficiency
• Bacterial infections
• Viral infections: molluscum contagiosum
• Autoimmunity
• Colitis, lichen planus and autoimmune ovarian failure
• Absent skeletal, dental and connective tissue abnormalities

• Elevated serum IgE (lower than STAT3 deficiency)
• Eosinophilia
• Mostly normal immunoglobulin levels
• Moderately reduced IgG, elevated IgA levels (infrequent)
• Variable antibody responses to vaccines
• Reduced responses to carbohydrate antigens
• Normal B- and T-cell numbers
• Subnormal lymphocyte proliferative responses to mitogens
Laboratory findings

• Clinical and immunological phenotypes overlap with DOCK8-deficient patients
• Cutaneous viral infections and MCC are less common
• Only one affected patient had neurologic complications
CARD11 deficiency

• None of CARD11 deficiency had NIH scored ≥40
Diagnosis

• Immunoglobulin replacements
Treatment

Summary

• Skeletal abnormalities
• STAT3, ERBIN, IL6ST (AR)
• Skin viral infection
• DOCK8, ZNF341, PGM3, CARD11
• Malignancy
• STAT3, DOCK8
• Autoimmunity
• PGM3, CARD11
• Neurocognitive abnormalities
• PGM3

• Abbas, Abul K., Lichtman, Andrew H., Pillai, Shiv. (2021). Cellular and Molecular Immunology (Tenth Edition). Philadelphia: Elsevier.
• Kathleen E. Sullivan, E. Richard Stiehm. (2014). Stiehm's Immune Deficiencies
• Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for
the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract 2019;7:1763-70.
• Grimbacher B, Schaffer AA, Holland SM, Davis J, Gallin JI, Malech HL, et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet 1999;65:735-
44.
• Al-Shaikhly T, Ochs HD. Hyper IgE syndromes: clinical and molecular characteristics. Immunol Cell Biol 2019;97:368-79.
• Mogensen TH, Jakobsen MA, Larsen CS. Identification of a novel STAT3 mutation in a patient with hyper-IgE syndrome. Scand J Infect Dis 2013;45:235-8.
• Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, et al. Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem
disorder. N Engl J Med 1999;340:692-702.
• Schimke LF, Sawalle-Belohradsky J, Roesler J, Wollenberg A, Rack A, Borte M, et al. Diagnostic approach to the hyper-IgE syndromes: immunologic and clinical key
findings to differentiate hyper-IgE syndromes from atopic dermatitis. J Allergy Clin Immunol 2010;126:611-7 e1.
• Tsilifis C, Freeman AF, Gennery AR. STAT3 Hyper-IgE Syndro
• Gharehzadehshirazi A, Amini A, Rezaei N. Hyper IgE syndromes: A clinical approach. Clin Immunol 2022;237:108988.
• me-an Update and Unanswered Questions. J Clin Immunol 2021;41:864-80.
• Ravendran S, Hernandez SS, Konig S, Bak RO. CRISPR/Cas-Based Gene Editing Strategies for DOCK8 Immunodeficiency Syndrome. Front Genome Ed
2022;4:793010.
References

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