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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.
HyperIgE syndrome
HyperIgE syndrome
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.
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• 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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• 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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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)
Abbas, Cellular and Molecular Immunology (Tenth Edition).
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
Abbas, Cellular and Molecular Immunology (Tenth Edition).
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)
Abbas, Cellular and Molecular Immunology (Tenth Edition).
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Clinical manifestations of STAT3 deficiency
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Less frequent than DOCK8 deficiency
• Food (37%) and environmental (18%) allergies
Clinical manifestations of STAT3 deficiency
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• 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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Diagnosis
• 96% of STAT3 deficiency had NIH scored ≥40
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Controversy
• High dose intravenous immunoglobulin in improving eczema
• HSCT
Treatment
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Tsilifis C, et al. J Clin Immunol 2021;41:864-80.
Tsilifis C, et al. J Clin Immunol 2021;41:864-80.
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)
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Impaired STAT3-dependent B- and T-cell function
• Decreased Th17
• Excess Th2
• Decreased memory B cells
Clinical manifestations of ZNF431 deficiency
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• 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
Gharehzadehshirazi A, et al. Clin Immunol 2022;237:108988.
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
Gharehzadehshirazi A, et al. Clin Immunol 2022;237:108988.
• 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
IL6 signal transducer (IL6ST) deficiency
Gharehzadehshirazi A, et al. Clin Immunol 2022;237:108988.
• 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
IL6 signal transducer (IL6ST) deficiency
Gharehzadehshirazi A, et al. Clin Immunol 2022;237:108988.
• 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
Tsilifis C, et al. J Clin Immunol 2021;41:864-80.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• 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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• 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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• Immune synapse formation (DOCK8-dependent)
• B-cell activation by activated T cells
• Germinal center formation
• Generation of memory B cells
DOCK8 deficiency
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• 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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Ravendran S, et al. Front Genome Ed 2022;4:793010.
Gharehzadehshirazi A, et al. Clin Immunol 2022;237:108988.
• Neurologic manifestations including
• Infectious manifestations (Encephalitis)
• Noninfectious manifestations (CNS vasculitis, vascular aneurysm and brain
infarction)
Complications
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• 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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• 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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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)
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• 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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• 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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• 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
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• None of CARD11 deficiency had NIH scored ≥40
Diagnosis
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
• Immunoglobulin replacements
Treatment
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
Summary
• Skeletal abnormalities
• STAT3, ERBIN, IL6ST (AR)
• Skin viral infection
• DOCK8, ZNF341, PGM3, CARD11
• Malignancy
• STAT3, DOCK8
• Autoimmunity
• PGM3, CARD11
• Neurocognitive abnormalities
• PGM3
Gharehzadehshirazi A, et al. Clin Immunol 2022;237:108988.
• 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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  • 2. • 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).
  • 3. • 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
  • 4. • 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
  • 5. • 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
  • 6. • 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.
  • 9. 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.
  • 10. National Institute of Health (NIH) scoring system Grimbacher B, et al. Am J Hum Genet 1999;65:735-44.
  • 11. • 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.
  • 12. Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 13. Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 14.
  • 15. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 16. • 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 17. • 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 18. Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 19. 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) Abbas, Cellular and Molecular Immunology (Tenth Edition).
  • 20. 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 Abbas, Cellular and Molecular Immunology (Tenth Edition).
  • 21. 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) Abbas, Cellular and Molecular Immunology (Tenth Edition).
  • 22. 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)
  • 23. • 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.
  • 24. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 25. 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 Clinical manifestations of STAT3 deficiency Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 26. Less frequent than DOCK8 deficiency • Food (37%) and environmental (18%) allergies Clinical manifestations of STAT3 deficiency Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 27. Characteristic Facial Appearance Failure of Dental Exfoliation Grimbacher B, et al. N Engl J Med 1999;340:692-702.
  • 28. Gharehzadehshirazi A, et al. Clin Immunol 2022;237:108988.
  • 29.
  • 30. • 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.
  • 31. Schimke LF, et al. J Allergy Clin Immunol 2010;126:611-7 e1.
  • 32. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 33. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 34. • 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 35. Diagnosis • 96% of STAT3 deficiency had NIH scored ≥40 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 36. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 37. Controversy • High dose intravenous immunoglobulin in improving eczema • HSCT Treatment Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 38. Tsilifis C, et al. J Clin Immunol 2021;41:864-80.
  • 39. Tsilifis C, et al. J Clin Immunol 2021;41:864-80.
  • 40. 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
  • 41. 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) Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 42. Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 43. Impaired STAT3-dependent B- and T-cell function • Decreased Th17 • Excess Th2 • Decreased memory B cells Clinical manifestations of ZNF431 deficiency Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 44. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 45. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 46. Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 47. • 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 Gharehzadehshirazi A, et al. Clin Immunol 2022;237:108988.
  • 48. 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 Gharehzadehshirazi A, et al. Clin Immunol 2022;237:108988.
  • 49. • 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 IL6 signal transducer (IL6ST) deficiency Gharehzadehshirazi A, et al. Clin Immunol 2022;237:108988.
  • 50. • 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 IL6 signal transducer (IL6ST) deficiency Gharehzadehshirazi A, et al. Clin Immunol 2022;237:108988.
  • 51. • 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 Tsilifis C, et al. J Clin Immunol 2021;41:864-80.
  • 52. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 53. • 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 54. • 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 55. • Immune synapse formation (DOCK8-dependent) • B-cell activation by activated T cells • Germinal center formation • Generation of memory B cells DOCK8 deficiency Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 56.
  • 57.
  • 58. • 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 59. Ravendran S, et al. Front Genome Ed 2022;4:793010.
  • 60. Gharehzadehshirazi A, et al. Clin Immunol 2022;237:108988.
  • 61. • Neurologic manifestations including • Infectious manifestations (Encephalitis) • Noninfectious manifestations (CNS vasculitis, vascular aneurysm and brain infarction) Complications Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 62. • 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 63. • 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 64. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 65. Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 66. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 67. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 68. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79. less prevalent than DOCK8 deficiency
  • 69. • 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) Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79. Clinical manifestations of PGM3 deficiency
  • 70. • 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 71. • 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 72. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 73. Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 74. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 75. 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 76. • 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 77. • 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 Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 78. • None of CARD11 deficiency had NIH scored ≥40 Diagnosis Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 79. • Immunoglobulin replacements Treatment Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 80. Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79.
  • 81. Al-Shaikhly T, Ochs HD. Immunol Cell Biol 2019;97:368-79. Summary
  • 82. • Skeletal abnormalities • STAT3, ERBIN, IL6ST (AR) • Skin viral infection • DOCK8, ZNF341, PGM3, CARD11 • Malignancy • STAT3, DOCK8 • Autoimmunity • PGM3, CARD11 • Neurocognitive abnormalities • PGM3 Gharehzadehshirazi A, et al. Clin Immunol 2022;237:108988.
  • 83. • 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