Hyperimmunoglobulinemia E (Job) Syndrome

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Hyperimmunoglobulin E syndrome (HIES) was first described as Job syndrome in 1966, when 2 patients were reported with eczematous dermatitis, recurrent staphylococcal boils, hyperextensible joints/recurrent bone fractures, and distinctive coarse faces. [1] See the images below.

Buckley et al expanded the clinical picture in 1972 and reported the association with elevated immunoglobulin E (IgE) in patients with hyperimmunoglobulin E syndrome. [2] Hyperimmunoglobulin E syndrome is now recognized as a primary immunodeficiency disease characterized by recurrent skin abscesses, recurrent pneumonica with pneumotocele, eczematous dermatitis, and elevated serum IgE levels. HIES was initially reported to have an autosomal dominant (AD) inheritance pattern, but cases with autosomal recessive (AR) inheritance and sporadic cases have been reported.

Mutations of the signal transducer and activator of transcription 3 (STAT3) gene were shown to cause the AD HIES by 2 groups independently. [3, 4] In addition, tyrosine kinase 2 deficiency (tyk2) deficiency was reported in 2 patients with HIES, but tyk2 deficiency is also characterized by severe viral and bacterial infections. [5, 6] A fair numbers of patients with AD HIES have STAT3 mutations (around 70%); however, some patients have AD HIES-like disease without STAT3 mutations.

In AD HIES and sporadic cases, HIES manifests as a disease that affects multiple organ systems, including the skeleton, connective tissue, and dentition. AD HIES is inherited as a single-locus trait with various expressivity in some families. In contrast, patients with AR HIES lack skeletal or dental involvement and do not develop cystic lung disease. However, patients with AR HIES are susceptible to viral infection characterized by severe Molluscum contagiosum and may develop severe neurological complications for unknown reasons. [7] Some patients with AR HIES have mutations in DOCK8. [8] Subsequent studies in animals and affected humans revealed an important role in DOCK8 in T and B cell development and functions; DOCK8 deficiency is now known to cause a combined immunodeficiency rendering the affected patients susceptible to viral, fungal, and bacterial infections. [9]

Because recurrent skin and lung infections and marked elevation of IgE levels are the hallmarks of HIES, investigations have focused on defining a basic immune defect that leads to both recurrent infection with certain organisms (S aureus and Candida species) and elevated IgE synthesis in HIES. This line of research led to the findings of an imbalance of TH 1 and TH 2 responses, decreased production/expression of interferon (IFN)-γ in contrast to relatively elevated production/expression of interleukin (IL)-4, defects in IFN-γ and IL-12 pathways, underexpression of certain chemokines and adhesion molecules, and reduced expression of transforming growth factor β (TGF-β) and IFN-γ messenger RNA (mRNA) in circulating activated (DR+) T cells. [10, 11] However, serum IgE levels do not positively or negatively correlate with production or expression of these cytokines.

More important, the above-referred immune abnormalities do not explain the facial, skeletal, joint, and dental defects in AD HIES. Patients with receptor defects of IFN-γ or IL-12 have disseminated atypical mycobacterial infections with incomplete granuloma formation and do not exhibit clinical features of HIES. [12] Studies in toll-like receptor (TLR)–mediated signaling in patients with HIES did not reveal anty abnormalities either. [13, 14]

In addition to immune defects that affect IgE synthesis, defects of cell-mediated immunity have also been reported, consistent with decreased TH 1 responses. These include decreased or absent delayed-type hypersensitivity in some patients with HIES and decreased lymphoproliferative responses to S aureus, Candida species, and tetanus antigens. A decrease in T cells that express CD45RO, the marker for memory T cells, was also reported by other investigators. In one patient with HIES, the presence of the IL-4-producing γ/δ T-cell clone was reported. [15]

Puzzling clinical features of AD HIES became better understood following identification of STAT3 mutations as a cause of AD HIES. The initial report of the STAT3 mutation in patients with HIES described dominant-negative mutations in the DNA binding domain of STAT3. [3] A subsequent study reported 2 hot spots of mutations: DNA binding and SH2 domains. [4] Other mutations of STAT3 in AD HIES have also been described. [16]

STAT3 is implicated in the signal transduction of multiple cytokine families including the IL-2/common g chain family (IL-2, IL-7, IL-9, IL-15, IL-21), the IL-6/gp130 family (IL-6, IL-11, IL-27, IL-31, ciliary neurotropic factor, oncostatin M, leukemia inhibitory factor), IFNs, and the IL-10 family (IL-10, IL-19, IL-20, IL-22, IL-24, IL-26). STAT3 is also implicated in signaling pathways of IL-12, IL-23, Flt3 ligand, macrophage-colony stimulating factor (M-CSF), granulocyte-colony stimulating factor (G-CSF), leptin, and growth hormone. [17] STAT3 mutations have a key role in the signaling pathways of multiple cytokines and affect multiple organ systems, as revealed in humans and STAT3 knockout (KO) mice. Impaired STAT3 signaling is implicated with the following abnormalities [18] as described below:

CD4+ T cells: Impaired STAT3 signaling causes deficiency of Th17 cells and impaired IL-10 production. [19] Th17 cells are aTh-cell subset characterized by the production of IL-17A, IL-17F, IL-21, IL-22, IL-26, and CCL20. They play a major immune defense against extracellular pathogens such as mycobacterium and fungi. Patients with AD HIEA are shown to have impaired Th17 cell differentiation. [20, 16] This is attributed to impaired STAT3 mediated signaling of IL-6, a key differentiation factor for Th17 cells. STAT3 deficiency abrogates the ability of IL-6 and IL-27 to induce production of IL-10 by CD4+ T cells, resulting in impaired IL-10 production.

B cells: In STAT3 KO mice, these mice are found to have impaired antibody (Ab) production against T-dependent antigens (TD-Ags). Patients with AD HIEA are also reported to have impaired production of functional Abs. However, reduced numbers of isotype-switched memory B cells in patients with AD HIES are reported to be not associated with their functional Ab production or infection history. [21]

Myeloid cells: Patients with AD HIES have up-regulated proinflammatory cytokine production. One of the counter-regulatory measures for proinflammatory cytokines is autocrine production of IL-10 by myeloid lineage cells such as macrophages and monocytes. Because IL-10 receptor signaling is mediated by STAT3, this IL-10 mediated suppression is lost in STAT3 KO mice as well as in patients with AD HIES who have STAT3 mutations. This defect likely explains hyperinflammatory features of AD HIES. Impaired signaling via Flt3 ligand also affects dendritic cell (DC) development and results in lower numbers of DCs in STAT3 KO mice. [17]

Osteoclasts: Cytokines of IL-6 family have roles in bone homeostasis and their signaling pathways mediates via STAT3. Thus, impaired STAT signaling results in increased bone resorption by osteoclasts. This may explain why AD HIES affect the skeletal system.

The discovery of the dedicator of cytokinesis 8 (DOCK8) mutation as a cause of AR HIES was also helpful to understand clinical features of AR HIES with this mutation. [8, 22] AR-HIE syndrome is distinguished by recurrent sinopulmonary infection, severe cutaneous viral infection often caused by HSV, HPV, HZV, and molluscum contagiosum virus in addition to elevated IgE and lack features involving the skeletal system. These patients are also known to be at high risk of malignancies including squamous cell carcinoma, cutaneous T cell lymphoma/leukemia, and Burkitt lymphoma in late childhoold and early adulthood. [23] Recent studies also revealed that DOCK8 serves as an adaptor that links TLR9-MyD88 signaling to B-cell activation. [24] This may partly explain Ab deficiency observed in DOCK8 deficiency. Recent studies of 25 patients with AR HIES at one center also report a high frequency of hepatic disorders. [25]

These patients are also characterized by CNS symptoms caused by CNS vasculitis and infection including JC virus associated progressive multifocal leukoencephalopathy. DOCK8 belongs to the DOCK180 superfamily of proteins which have a role in guanine nucleotide exchange for Rho family GTPases. DOCK180- related guanine nucleotide exchange factors are shown to have roles in actin cytoskeletal rearrangement, cell migration, integrin mediated cell adhesion, phagocytosis, cell fusion, cell polarization, and synapse formation. Patients with AR HIES were also shown to have impaired Th17 cell development. [26]

It should also be noted that patients with AR HIES have low T-cell excision circles (TRECs), indicating that these patients may be detected by severe combined immunodeficiency (SCID) newborn screening with low, but not absent, TREC copies. [27]

United States

Frequency is undetermined. Published reports are from the United States and Europe. A recent population-based study concluded that the incidence of all primary immunodeficiencies markedly increased between 1976-2006. [28]

International

Frequency is undetermined.

Although the oldest reported patient was aged approximately 60 years, deaths in the second and third decades of life due to severe pulmonary disease and infection of pneumatoceles with Aspergillus species, Pseudomonas aeroginosa, or other organisms have been reported in patients with AD HIES. [29] Infections are the major cause of morbidity; approximately 80% of patients have pneumatoceles secondary to pneumonia, and a similar percentage have chronic mucocutaneous and ungual candidiasis. Morbidity includes bone fractures with minor injury in approximately 60% of patients with AD HIES.

In patients with AR HIES, morbidity and mortality are closely associated with CNS complications [30] , autoimmunity, and malignancy. Patients with AR HIES with DOCK8 mutations are known to have frequent complications with cutaneous viral infections caused by varicella-zoster, herpes simplex viruses, HPV, and molluscum contagiosum virus at a younger age. Patients with AR HIES are also know to develop severe chronic refractory molluscum contagiosum at high frequency. DOCK8 mutation is now considered to cause combined immunodeficiency affecting T and B cell numbers and functions profoundly, resembling an SCID variant.

HIES has been reported in all racial groups in the United States, but exact incidence cannot be determined because of the rarity of the disease. The presence of disease in multiple racial groups is significant because it suggests that multiple different mutations in the same genes are present.

Prevalence is equal in males and females. AD and AR HIES is inherited with variable penetrance.

Patients with AD HIES range in age from 0-60 years. Because not all the patients have the same spectrum of infections, facial features, and skeletal anomalies, some patients with AD HIES are not identified until later in life when more chronic illness develops. Most patients with AR HIES are diagnosed when younger than 20 years because of characteristic clinical features (eg, severe cutaneous viral infection, recurrent sinopulmonary infection, and markedly elevated IgE levels).

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Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter’s University Hospital

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Pediatric Research, Society for Mucosal Immunology

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David J Valacer, MD 

David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, New York Academy of Sciences

Disclosure: Nothing to disclose.

Russell W Steele, MD Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, Southern Medical Association

Disclosure: Nothing to disclose.

James M Oleske, MD, MPH François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, Rutgers New Jersey Medical School; Professor, Department of Quantitative Methods, Rutgers New Jersey Medical School

James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Allergy Asthma and Immunology, American Academy of Hospice and Palliative Medicine, American Association of Public Health Physicians, American College of Preventive Medicine, American Pain Society, Infectious Diseases Society of America, Infectious Diseases Society of New Jersey, Medical Society of New Jersey, Pediatric Infectious Diseases Society, Arab Board of Family Medicine, American Academy of Pain Management, National Association of Pediatric Nurse Practitioners, Association of Clinical Researchers and Educators, American Academy of HIV Medicine, American Thoracic Society, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Hyperimmunoglobulinemia E (Job) Syndrome

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