Signal Transducer And Activator Of Transcription 3 Mutations Research Articles

A 1-Year-Old Girl with a Gain-of-Function STAT1 Mutation Treated with Hematopoietic Stem Cell Transplantation

We report the case of a 1-year-old Peruvian girl who displayed recurrent infections by Candida albicans and pyogenic bacteria from the neonatal period onward. Our patient was born to non-consanguineous Mestizo parents. There was no family history suggestive of Primary Immunodeficiencies (PIDs). The patient suffered from Candida albicans infections since 3 days of age, predominantly affecting body skin, oral cavity and oropharynx, which required systemic antifungal therapy. Without antifungals the patient developed dysphonia and persistent cough, suggestive of laryngeal and respiratory tract involvement, which completely resolved when antifungal therapy was resumed. Computer tomography of the chest at 3 months of age revealed signs of residual inflammatory process in upper and medium lobes of right lung. Several chest X-rays taken later were not compatible with pneumonic processes. Alveolar lavage was not performed. From the age of 1 month onward the patient presented with recurrent diarrhea. Stool culture grew enteropathogenic Escherichia coli and Klebsiella pneumoniae on different occasions. Diarrhea improved after intravenous antibiotic therapy. As the patient grew older, diarrhea episodes were less frequent. At 1 year old, failure to thrive was remarkable; patient’s weight was persistently below third percentile. There were no clinical and immunological signs of endocrine or autoimmune disease. Available hematologic, metabolic and immunologic work up performed when the patient was 4 months old did not reveal significant abnormalities, except for hypergammaglobulinemia. Patient’s blood samples were analyzed and a heterozygous mutation (N397D) located in the DNA binding domain of the transcription factor Signal Transducer and Activator of Transcription 1 (STAT1 ) was found. Further DNA sequencing in patient’s parents, brother and sister revealed wild type STAT1 , implying that the mutation had occurred de novo . This mutation was biochemically shown to be gain-of-function. The patient displayed low proportions of interleukin (IL)-17 producing T cells. Candida resistance to antifungal therapy developed over time. When the patient was 13 months, clinical resistance was noted to Itraconazole, Posaconazole and Amphotericin B. Due to the poor prognosis and quality of life of the patient we performed a reduced-intensity-conditioning Hematopoietic Stem Cell Transplantation (HSCT) from her 9-year-old 6/6 HLA-matched brother. The conditioning regimen and graftversus-host disease (GVHD) prophylaxis that we used is detailed in Table I. Antifungal treatment with Caspofungin was indicated all over the procedure. J. C. Aldave (*) : E. Cachay : L. Nunez :A. Koo Allergy and Immunology Division, Hospital Nacional Edgardo Rebagliati Martins, Calle Manuel Candamo 257, Lince, Lima, Peru e-mail: jucapul_84@hotmail.com

STAT3 mutations indicate the presence of subclinical T-cell clones in a subset of aplastic anemia and myelodysplastic syndrome patients

AbstractLarge granular lymphocyte leukemia (LGL) is often associated with immune cytopenias and can cooccur in the context of aplastic anemia (AA) and myelodysplastic syndromes (MDS). We took advantage of the recent description of signal transducer and activator of transcription 3 (STAT3) mutations in LGL clonal expansions to test, using sensitive methods, for the presence of these mutations in a large cohort of 367 MDS and 140 AA cases. STAT3 clones can be found not only in known LGL concomitant cases, but in a small proportion of unsuspected ones (7% AA and 2.5% MDS). In STAT3-mutated AA patients, an interesting trend toward better responses of immunosuppressive therapy and an association with the presence of human leukocyte antigen-DR15 were found. MDSs harboring a STAT3 mutant clone showed a lower degree of bone marrow cellularity and a higher frequency of developing chromosome 7 abnormalities. STAT3-mutant LGL clones may facilitate a persistently dysregulated autoimmune activation, responsible for the primary induction of bone marrow failure in a subset of AA and MDS patients.

Clinical Features, STAT3 Gene Mutations and Th17 Cell Analysis in Nine Children with Hyper‐IgE Syndrome in Mainland China

Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency disease characterized by eczema, recurrent staphylococcal aureus skin abscesses, pneumonia with pneumatocele formation, remarkably high serum IgE levels, eosinophilia and involvement of skeleton and connective tissues. Heterozygous signal transducer and activator of transcription 3 (STAT3) mutations were shown to be the cause of autosomal dominant HIES (AD-HIES). In this study, we diagnosed nine patients with HIES from 9 unrelated families on the basis of a National Institutes of Health (NIH) score of ≥40 points, sequenced the STAT3 gene of all nine patients, and quantified Th17 cells in peripheral blood of seven patients by flow cytometry in mainland China. All nine patients had characteristic manifestation of HIES with the range of NIH scores 45-77 points. STAT3 hot mutations V637M or R382W/Q were identified in five patients. We identified two novel heterozygous missense mutations (T620S and R609G) located in Src homology 2 (SH2) domain in two patients, respectively. In two other patients, no STAT3 mutations were found. Quantified Th17 cell numbers were markedly decreased or absent (0-0.28% of CD4(+) T cells) in six patients with STAT3 mutations and almost normal (0.53% of CD4(+) T cells) in one wild-type STAT3 patient compared with healthy controls (0.40-2.25% of CD4(+) T cells). These results suggest that not all patients with HIES who had NIH scores over 40 points carry STAT3 mutations, those whose Th17 cell numbers strikingly decreased probably had AD-HIES with STAT3 mutations.

Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8+ T-cell memory formation and function

The capacity of CD8(+) T cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8(+) T-cell effector function and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8(+) T-cell immunity in human subjects is unknown. We sought to determine which signaling pathways mediate the effects of IL-21 on human CD8(+) T cells and whether defects in these pathways contribute to disease pathogenesis in patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade. Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in signal transducer and activator of transcription 1 (STAT1), STAT3, or IL-21 receptor (IL21R) were used to assess the respective roles of these genes in human CD8(+) T-cell differentiation in vivo and in vitro. Mutations in STAT3 and IL21R, but not STAT1, led to a decrease in multiple memory CD8(+) T-cell subsets in vivo, indicating that STAT3 signaling, possibly downstream of IL-21R, regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21-stimulated naive CD8(+) T cells. However, this defect was overcome by T-cell receptor engagement. The IL-21R/STAT3 pathway is required for many aspects of human CD8(+) T-cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3- and IL-21R-deficient subjects.

Intermediate phenotypes in patients with autosomal dominant hyper-IgE syndrome caused by somatic mosaicism

Autosomal dominant hyper-IgE syndrome (AD-HIES) is caused by mutations in signal transducer and activator of transcription 3 (STAT3). We describe 2 subjects in whom somatic mosaicism was associated with intermediate phenotypes. Somatic mosaics might shed light on the pathogenesis of dominant STAT3 mutations and the mechanisms behind the immunologic and nonimmunologic features of the disease. Clinical evaluations were conducted. Mutant STAT3 was amplified from different tissues and sequenced, and the percentage of mosaicism in various cell types was calculated. Flow cytometry was performed to determine percentages of IL-17(+) cells, IL-22(+) cells, or both. Suction blisters were induced in 1 subject, and exudate fluid was analyzed for whether emigrating neutrophils were STAT3 mutant or wild-type; neutrophils from peripheral blood were simultaneously examined. The 2 subjects with STAT3 somatic mosaicism had intermediate phenotypes and were found to have preserved TH17 cell compartments and apparently normal CD8 cells. However, they still had infections, including mucocutaneous candidiasis. The percentage of STAT3 mutant neutrophils migrating into blisters at 16 hours was the same as in peripheral blood, suggesting normal chemotaxis. STAT3 mosaicism accounts for a milder phenotype and allows for further investigation into the pathogenesis of AD-HIES. Despite having a preserved TH17 cell compartment, both subjects with mosaicism had chronic mucocutaneous candidiasis, suggesting that candidiasis in subjects with AD-HIES is not driven solely by low TH17 cell numbers. The percentage of STAT3 mutant neutrophils emigrating into a suction blister at 16 hours was the same as the percentage in peripheral blood, suggesting that early chemotaxis of STAT3 neutrophils is normal invivo.

Blood CD4+CD45RO+CXCR5+ T cells are decreased but partially functional in signal transducer and activator of transcription 3 deficiency

The generation of high-affinity antibodies requires the presence of a population of CD4+ T cells (follicular TH [TFH] cells) in the lymph node follicles. These cells differ from TH1, TH2, and TH17 effector cells in that they strongly express activation markers and the chemokine receptor CXCR5 and secrete large amounts of IL-21 and CXCL13. Small numbers of nonactivated CD4+CD45RO+CXCR5+ T cells are also found in the blood. We sought to obtain in vitro a population close to the TFH cells and to study the presence of this cell population among patients with autosomal dominant hyper-IgE syndrome carrying heterozygous signal transducer and activator of transcription 3 (STAT3) mutations that impair the IL-21 signaling required for B-cell differentiation. CD4+CD45RO+CXCR5+ T cells were isolated from blood and activated by CD3/T-cell receptor. We found that CD4+CD45RO+CXCR5+ activated T cells corresponding to circulating bona fide memory TFH cells and that STAT3-deficient patients have abnormally low numbers of "TFH-like" blood T cells. However, STAT3-deficient TFH cells have much the same phenotypic and functional characteristics as TFH cells from healthy control subjects. The ability of STAT3-deficient TFH cells to produce IL-21 on CD28/T-cell receptor activation and to proliferate did not differ from that observed for control TFH cells in vitro. Although the STAT3-deficient TFH cells were also able to help control B cells to produce IgG and IgA, induction of IgG production by naive B cells was impaired. Heterozygous mutations in STAT3 lead to reduced numbers of circulating TFH-like cells, a finding that might account (at least in part) for the observed defect in antibody production.

Advances in basic and clinical immunology in 2012

Basic and clinical immunology articles published in the Journal in 2012 were mostly related to the expanding area of primary immunodeficiencies (PIDs). Novel forms of PID were identified by using whole-exome sequencing or after careful examination of flow cytometric data, as in the reports of lymphocyte-specific protein tyrosine kinase, CD27, and CD21 deficiencies. Absent IgG and IgA memory B cells were described in patients with hyper-IgE syndrome, which is consistent with defective antibody response and suggests a potential benefit of immunoglobulin replacement. Impaired production of antibodies to polysaccharide antigens by the human B-cell subset analog to murine B-1 cells was reported in a child with selective polysaccharide antibody deficiency. Increased production of inflammatory cytokines by monocyte-derived cells on Toll-like receptor activation was reported in patients with X-linked agammaglobulinemia, underscoring the important role of Bruton tyrosine kinase in modulation of inflammation. The mechanisms explaining susceptibility to yeast infections and development of chronic mucocutaneous candidiasis were extensively studied. Universal newborn screening for T-cell deficiencies is being implemented in several states, resulting in the diagnosis of a higher number of immunodeficient newborns than previously estimated. The use of laboratory testing to distinguish PIDs from HIV infection was clarified. In the management of PIDs, refinement of indication and strategies to hematopoietic stem cell transplantation resulted in improved outcomes. The use of anti-IL-6 mAbs showed promise as an alternative treatment in patients with Schnitzler syndrome.

STAT3 Gene Mutations and the Association with Pure Red Cell Aplasia in Large Granular Lymphocyte Leukemia.

AbstractAbstract 2668Large granular lymphocyte leukemia (LGL-L) is a proliferative disorder of cytotoxic T cells or NK cells frequently complicated with cytopenia and autoimmune phenomena. In the current WHO classification, T-cell large granular lymphocyte leukemia (T LGL-L), and chronic lymphoproliferative disorders of NK cells (CLPD-NK) are included in this category. Aggressive NK cell leukemia (ANKL) and Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease of childhood (EBV-T LPD) are also categorized as entities in the classification based on the clinical characteristics and EBV-positivity, and their morphologies closely resemble LGL. There has been controversy concerning the nature of these diseases, whether they are reactive processes or neoplasms. Recently, recurrent somatic mutations in the src homology (SH) 2 domain of the signal transducer and activator of transcription 3 (STAT3) gene have been found in T LGL-L and CLPD-NK, leading to constitutive activation of STAT3 and dysregulation of genes downstream of STAT3. Since LGL-L consists of various disorders and is suggested to differ based on racial backgrounds, these findings prompted us to investigate mutations in STAT3 in a Japanese cohort of LGL-L.The study included a total of 36 patients (pts) with LGL. Genes of exons 19 to 24 in STAT3 were amplified by PCR and sequenced directly using genomic DNA isolated from peripheral blood mononuclear cells. Since Y604F and D661Y mutations in STAT3 gene were representative and frequently recognized, allele specific PCR (AS-PCR) assays for these mutations were also performed.Pts consisted of 18 with T LGL-L (14 with αβ T cell receptor (TCR) type and 4 with γΔ TCR type), 11 with CLPD-NK, 5 with ANKL, and 2 with EBV-T LPD; one pt with αβ TCR type and 1 with γΔ TCR type, as well as 1 with reactive NK lymphocytosis used as control.By direct sequencing, two mutations, Y640F and D661Y, were identified. Y640F was recognized in 1 pt with αβ T LGL-L and D661Y in 3 pts with CLPD-NK. By AS-PCR, 10 additional pts were found to be positive for mutations of either Y604F or D661Y. A pt with T LGL-L was positive for both mutations by AS-PCR, although no mutations were detected by direct sequencing. A pt with CLPD-NK was positive for Y640F by AS-PCR in addition to D661Y recognized by direct sequencing. All 4 pts positive for the mutations by direct sequencing were confirmed to be positive by AS-PCR. In total, 7 pts with αβ TCR type T LGL-L and three T LGL-L pts with γΔ TCR type were positive for mutations. All these mutations were heterozygous. Mutations in SH2 domains of the STAT3 gene were not found in ANKL or EBV T-LPD pts by either direct sequencing or AS-PCR. Samples from fifty healthy controls were examined by AS-PCR and all were negative for Y604F or D661Y mutations. Reactive NKL lymphocytosis and three cell lines, Jurkat, NKL and NK92, were also negative for the mutations. The frequencies of STAT3 mutations in T LGL-L and CLPD-NK were 55.6% and 27.3%, respectively (P = 0.25). Among the pts with T LGL-L and CLPD-NK, the frequency of pure red cell aplasia (PRCA) was significantly higher in pts with the mutations (8/13) than in those without the mutations (3/16) (P = 0.03). In three T LGL-L pts positive for the mutations examined on subsequent occasions, the mutation became undetectable after cyclosporine A treatment in one pt, and was persistently found at stable amounts in two other pts by quantitative PCR.Our results indicate that mutations in the SH2 domain of the STAT3 gene frequently occur in T LGL-L and CLPD-NK in a Japanese cohort and these mutations are closely associated with PRCA and treatment requirements. STAT3 mutation thus likely contributes to the pathogenesis of T LGL-L and CLPD-NK, while EBV-associated LGL diseases, such as ANKL or EBV T-LPD, might be driven by mechanisms other than STAT3-associated pathways. Disclosures:No relevant conflicts of interest to declare.

Autosomal Dominant STAT3 Deficiency and Hyper-IgE Syndrome

Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.

Signal Transducer and Activator of Transcription 3 Mutation with Invasive Eosinophilic Disease

Hyper-IgE syndrome (HIES), or Jobs disease, is a rare immunologic disorder characterized by the triad of staphylococcal abscesses, pneumonia with pneumatocele formation, and elevated IgE. It has been shown to have multiple modes of inheritance, autosomal dominant being more common than autosomal recessive, with sporadic cases as well. A mutation in signal transducer and activator of transcription 3 (STAT3) gene has been linked to the development of the sporadic and dominant forms of HIES. Peripheral eosinophilia, typically greater than two standard deviations from the normal population, is often seen in association with HIES. Despite these elevated levels of blood eosinophils, there have been no reported cases of invasive eosinophilic disease, such as eosonophilic esophagitic. Here we report the first description, to our knowledge, of a patient with HIES with a STAT3 mutation involving exon 12, Thr389Ile, and invasive eosinophilic disease of the esophagus. STAT3 modulates the expression of several genes that control central cell processes such as growth and death in response to external soluble stimuli. A mutation in the STAT3 molecule may affect the eosinophil's response to IL-5 and thus reduce the chemotaxic ability of those cells to migrate into tissues. This may then explain the paucity of eosinophilic infiltrative disease in patients with STAT3 mutations. The level of eosinophilic involvement may be related to the site or type of mutation within the STAT3 molecule. As more data are collected, we may be able to assess whether certain mutations dictate different clinical outcomes, which could prove helpful in directing therapy.

Heterozygous signal transducer and activator of transcription 3 mutations in hyper-IgE syndrome result in altered B-cell maturation

Heterozygous signal transducer and activator of transcription 3 mutations in hyper-IgE syndrome result in altered B-cell maturation

Plasma metalloproteinase levels are dysregulated in signal transducer and activator of transcription 3 mutated hyper-IgE syndrome

Plasma metalloproteinase levels are dysregulated in signal transducer and activator of transcription 3 mutated hyper-IgE syndrome

Advances in basic and clinical immunology in 2010

Reports in basic and clinical immunology in 2010 reflected the use of state-of-the-art genetic and immunologic tools to characterize the pathogenesis of immunologic diseases and the development of novel therapies directed to these conditions. B-cell biology has been explained in greater detail, significantly with lessons from the genetic defects found in the humoral immunodeficiencies. Therapeutic mAbs are given for an increasing number of indications, such as anti-CD20 antibodies or rituximab, which was initially developed for non-Hodgkin lymphomas and is currently used in diverse autoimmune and inflammatory disorders. The report of an infant with severe combined immunodeficiency (SCID) in Massachusetts detected by means of newborn screening and successfully treated with hematopoietic stem cell transplantation validated recent efforts toward newborn screening for SCID. Improvement of survival outcomes for patients with primary immunodeficiencies treated with hematopoietic stem cell transplantation was demonstrated in a large European cohort, with significant appreciation of the type of donor graft, particularly the use of HLA-matched unrelated donors for patients with non-SCID. Progress in cellular mechanisms of drug hypersensitivity included the characterization of nitroso-modified drug metabolites as potent T-cell activators and the identification of the relocation of plasmacytoid dendritic cells from blood to skin as a potential risk factor for reactivation of viral disease.

Clinical Aspects and Genetic Analysis of Taiwanese Patients with the Phenotype of Hyper-Immunoglobulin E Recurrent Infection Syndromes (HIES)

Hyper-immunoglobulin E recurrent infection syndromes (HIES) has characteristic features and identified mutations. This study investigated clinical features and causal candidate mutations in Taiwanese patients with the HIES phenotype on referral base over 23million inhabitants. Clinical manifestations of the HIES phenotype, severity scoring, immunological functions and candidate genes of signal transducer and activator of transcription 3 (STAT3), tyrosine kinase 2 (TYKZ), and dedicator of cytokineses 8 (DOCK8) were analyzed. Between 1985 and 2009, six sporadic and two siblings met HIES criteria (onset age: 2-54months; severity score: 31-65) out of 187 patients with primary immunodeficiencies. Five patients with the autosomal dominant (AD)-HIES phenotype presented as pneumatocoele, bronchiectasis, retained primary teeth, minor trauma fracture, scoliosis, coronary aneurysm, and lymphoma. Three with the autosomal recessive (AR)-HIES phenotype and impaired lymphocyte proliferation function had herpes simplex virus infection, molluscum contagiosum, and cerebral vasculitis. Notably in one patient with the AR-HIES phenotype, unintentional lead component in traditional application herbs for accelerating wound healing deposited in basal ganglia and aggravated involuntary movement relative to cerebral vacculitis. Those with mildly elevated memory T cells and decreased memory B cells trended to develop arteritis. Of five AD-HIES patients, three were mortalities from acute myocardial infarction, Proteus mirabilis, and Staphylococcus aureus sepsis. Only one had de novo novel STAT3 (Gln 469 Arg) mutation with "relative" lower HIES STAT3 score. Known genetic defects responsible for the HIES phenotype are not so common in Taiwan. This may infer genetic variations in different ethnicities although selection bias and under-diagnosis for HIES with known genetic defects could be contribution factors.

Diagnostic approach to the hyper-IgE syndromes: Immunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis

Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by Staphylococcus aureus abscesses, recurrent pneumonia, increased serum IgE levels, and eczema. The association of heterozygous signal transducer and activator of transcription 3 (STAT3) mutations with autosomal dominant (AD)-HIES allows the differentiation of AD-HIES from disorders associated with eczema and increased serum IgE levels, such as other primary immunodeficiencies and atopic dermatitis. To facilitate early diagnosis of AD-HIES to initiate appropriate therapy. The clinical phenotype (suggested by a National Institutes of Health [NIH] score of >or=40 points), STAT3 genotype, and T(H)17 cell counts were compared in a cohort of 78 patients suspected of having HIES. Heterozygous STAT3 missense mutations and in-frame deletions were identified in 48 patients, all but 2 with an NIH score >or=40 points. Patients with STAT3 mutations with HIES showed significantly lower T(H)17 cell counts compared with patients with wild-type STAT3 and control subjects. Only 1 patient with wild-type STAT3 had both an NIH score >or=40 points and abnormal T(H)17 cell counts (<or=0.2% of CD4(+) cells), with this exception being identified with a homozygous dedicator of cytogenesis 8 protein (DOCK8) mutation. Pathologic shedding of primary teeth was present in 3 patients with wild-type STAT3 and 33 patients with STAT3 mutations. Internal abscesses and severe infections were exclusively seen in patients with STAT3 mutations, who also had increased pneumatocele formation and skeletal or connective tissue manifestations compared with patients with wild-type STAT3. We expanded the number of STAT3 mutations and validated that the NIH score sensitively identifies patients with HIES. Based on our patient cohort, we propose key findings that, when combined with T(H)17 cell numbers, predict patients with AD-HIES with STAT3 mutations, supporting early diagnosis of AD-HIES.

Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome

The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues. Recently, HIES has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of T(H)17 cells. To determine whether there is a correlation between the genotype and the phenotype of patients with HIES and to establish diagnostic criteria to distinguish between STAT3 mutated and STAT3 wild-type patients. We collected clinical data, determined T(H)17 cell numbers, and sequenced STAT3 in 100 patients with a strong clinical suspicion of HIES and serum IgE >1000 IU/mL. We explored diagnostic criteria by using a machine-learning approach to identify which features best predict a STAT3 mutation. In 64 patients, we identified 31 different STAT3 mutations, 18 of which were novel. These included mutations at splice sites and outside the previously implicated DNA-binding and Src homology 2 domains. A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy. T(H)17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (<1%) T(H)17 cells but were distinct by markedly reduced IFN-gamma-producing CD4(+)T cells. We propose the following diagnostic guidelines for STAT3-deficient HIES. Possible: IgE >1000IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate. Probable: These characteristics plus lack of T(H)17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.

Hyper‐IgE Syndrome with STAT3 Mutation: A Case Report in Mainland China

Hyper-immunoglobulin E syndromes (HIES) including compound primary immunodeficiency and nonimmunological abnormalities are characterized by extremely high serum IgE levels, eosinophilia, eczema, susceptibility to infections, distinctive facial appearance, retention of deciduous teeth, cyst-forming pneumonias, and skeletal abnormalities. Itis reported that some cases of familial HIES are relative to autosomal dominant or recessive inheritance, but most cases are sporadic, and result from mutations in the human signal transducer and activator of transcription 3 (STAT3) gene. In this paper, we firstly report a young man diagnosed of Hyper-IgE syndrome with STAT3 mutation in Mainland China, and investigate the autosomal dominant trait of his family members.

Milder clinical hyperimmunoglobulin E syndrome phenotype is associated with partial interleukin-17 deficiency

Mutations in the signal transducer and activator of transcription 3 (STAT3) were reported to cause hyperimmunoglobulin E syndrome (HIES). The present study investigates T helper type 17 (Th17) responses triggered by the relevant stimuli Staphylococcus aureus and Candidia albicans in five 'classical' HIES patients, and a family with three patients who all had a milder HIES phenotype. We demonstrate that patients with various forms of HIES have different defects in their Th17 response to S. aureus and C. albicans, and this is in line with the clinical features of the disease. Interestingly, a partial deficiency of interleukin (IL)-17 production, even when associated with STAT3 mutations, leads to a milder clinical phenotype. We also observed defective Th17 responses in patients with the 'classical' presentation of the disease but without STAT3 mutations. These data demonstrate that defective IL-17 production in response to specific pathogens can differ between patients with HIES and that the extent of the defective Th17 response determines their clinical phenotype.

Hyperimmunoglobulin E syndrome with a novel STAT3 mutation

A 35-year-old man with severe eczematous dermatitis and recurrent staphylococcal skin infections, some of which required hospitalization, is presented. Other medical concerns include recurrent oral staphylococcal infections, otitis media, ocular herpes simplex virus keratitis, asthma, steroid-induced gastritis, steroid-induced cataracts, recurrent upper respiratory infections, and acute pharyngitis. Past medical history includes retained dentition of six primary teeth, two episodes of childhood pneumonia that required hospitalization, and three wrist and ankle fractures. Laboratory data showed an eosinophil count of 2,400 cells/ml; the highest IgE level was 17,028 IU/mL. Considering the clinical and laboratory findings, the diagnosis of hyperimmunoglobulin E syndrome was made. DNA sequencing showed a novel signal transducer and activator of transcription 3 (STAT3) gene mutation within intron 12, specifically adenine to cytosine, two base pairs upstream of exon 13.

Hyper IgE syndrome: an update on clinical aspects and the role of signal transducer and activator of transcription 3

Hyper IgE syndrome (HIES) is a primary immunodeficiency characterized by eczema, recurrent skin and lung infections, elevated serum IgE, and connective tissue and skeletal abnormalities. We present newly recognized aspects of the clinical phenotype and discuss recent genetic and immunologic findings. In 2007, mutations in signal transducer and activator of transcription 3 (STAT3) were determined to be the cause of autosomal-dominant HIES. Mutations lead to disruption of STAT3-dependent pathways, which are crucial for signaling of many cytokines, including IL-6 and IL-10. On the one hand, cells from STAT3-defective patients have a proinflammatory profile with elevated TNFalpha and IFNgamma; on the other hand, STAT3 mutations result in the inability to produce IL-17 or form Th17 cells. HIES was previously defined on the basis of clinical manifestations and laboratory markers that were not specific to the disease. With the identification of STAT3 mutations as the cause of HIES, we can definitively characterize the disease at molecular and immunologic levels. Future study of HIES and STAT3 will help us understand eczema, IgE regulation, infection susceptibility, coronary artery disease, scoliosis, and bronchiectasis as well as provide mechanistic insights into treatment.