hyper-IgE Research Articles

REMOTE WORK. PROS AND CONS

The text is about remote work analyzed mainly in the context of the COVID-19 pandemic that took over the world in 2020 and, what is worse, is still ongoing, baffling by new mutations of this virus. Hence, research on remote work in this context is in statu nascendi. Therefore, the reflection on this subject are presented here in a form of an essay, based mainly on hermeneutics, empirical data, but to a large extent also on intuition. Thanks to the research we can find out that an especially important issue is an analysis of remote work in the context of redundant work, bullshit jobs syndrome, but also in the context of – growing in the modern world – loneliness syndrome. Therefore, these issues are presented against the background of the explosion of remote work, characteristic of the pandemic year 2020, and taking into account technological basis for its development. In addition, the views of employees and employers on this topic are presented. According to these opinions, remote work, to a much greater extent than before the pandemic, will become permanent in practice. This is mainly due to economic, social and environmental values of remote work. They are analyzed, but at the same time the analyzes show that such work is not free from various manifestations of degeneration. Hence optimizing proportion between remote and non-remote work is of fundamental importance. This is a difficult challenge mostly (but not only) for economists. It requires interdisciplinary knowledge and a holistic and non-extrapolative approach.

Stat3 loss in mesenchymal progenitors causes Job syndrome–like skeletal defects by reducing Wnt/β-catenin signaling

Job syndrome is a rare genetic disorder caused by STAT3 mutations and primarily characterized by immune dysfunction along with comorbid skeleton developmental abnormalities including osteopenia, recurrent fracture of long bones, and scoliosis. So far, there is no definitive cure for the skeletal defects in Job syndrome, and treatments are limited to management of clinical symptoms only. Here, we have investigated the molecular mechanism whereby Stat3 regulates skeletal development and osteoblast differentiation. We showed that removing Stat3 function in the developing limb mesenchyme or osteoprogenitor cells in mice resulted in shortened and bow limbs with multiple fractures in long bones that resembled the skeleton symptoms in the Job Syndrome. However, Stat3 loss did not alter chondrocyte differentiation and hypertrophy in embryonic development, while osteoblast differentiation was severely reduced. Genome-wide transcriptome analyses as well as biochemical and histological studies showed that Stat3 loss resulted in down-regulation of Wnt/β-catenin signaling. Restoration of Wnt/β-catenin signaling by injecting BIO, a small molecule inhibitor of GSK3, or crossing with a Lrp5 gain of function (GOF) allele, rescued the bone reduction phenotypes due to Stat3 loss to a great extent. These studies uncover the essential functions of Stat3 in maintaining Wnt/β-catenin signaling in early mesenchymal or osteoprogenitor cells and provide evidence that bone defects in the Job Syndrome are likely caused by Wnt/β-catenin signaling reduction due to reduced STAT3 activities in bone development. Enhancing Wnt/β-catenin signaling could be a therapeutic approach to reduce bone symptoms of Job syndrome patients.

Hyperimmunoglobulin E Syndrome (HIES) Treated with Thalidomide Plus Dexamethasone with Encouraging Results

Hyperimmunoglobulin E syndrome (HIES) is a rare and complex immunodeficiency disease that is characterized by recurrent skin abscesses caused by Staphylococcus aureus, recurrent pneumonia with formation of pneumatoceles, eosinophilia and serum immunoglobulin E > 2,000 IU / mL. Recent studies about the molecular changes in HIES include mutations in the gene encoding signal transducer and activator of transcription 3 (STAT3), which cause autosomal dominant form of the disease. Clinical diagnosis is established through Grimbacher criteria, because there is significant variation in the constellation of symptoms and signs among individual patients. There is no specific treatment of HIES, although therapeutic alternatives have been studied with controversial results. Several forms of treatment have been informed with bone marrow transplantation as well without benefit results. We present two cases of HiperIgE that received off - label treatment with thalidomide and dexamethasone achieving an excellent evolution, remission of symptoms and decline of IgE levels. To our knowledge this is the first report in which the disease natural history has changed with thalidomide and dexamethasone treatment with a rapid reduction of symptoms (pruritus) and IgE levels returned to normal. DisclosuresNo relevant conflicts of interest to declare.

Aautoimmune Hemolytic Anemia: Pattern of Clinical Presentation and Management Outcome — a Nine Year Observation from a Tertiary Care Hospital in Saudi Arabia

Introduction: Autoimmune hemolytic anemia (AIHA) is characterized by production of auto-antibodies that bind to antigen on the erythrocyte surface that leads to its premature destruction and removal from the circulation by macrophages. Occurrence of AIHA in children and adolescents is rare, exact incidence unknown. Objective of this retrospective study was to assess clinical and laboratory characteristics, and management outcome of patients diagnosed with AIHA seen at Pediatric Hematology/Oncology department of King Faisal specialist Hospital and Research Center ,Riyadh from 2005 to 2014. Method: Retrospective chart review of patients (1-14 yrs.) diagnosed with AIHA was conducted. Children were excluded if they have congenital hemolytic anemia, such as hemoglobinopathies, congenital membranopathy and erythrocyte enzyme deficiencies. Result: Thirty-one patients identified, 19(61%) female and 12(39%) male with a median age at diagnosis of 6 years (0.1-12.4). The direct Coombs test was positive in 23 (74%) patients. Underlying diseases observed as cause of AIHA in 14 (45%) patients: majority secondary to viral infections followed by severe combined immunodeficiency syndrome post bone marrow transplant GVHD complication, while systemic lupus erythematosus, antiphospholipid antibody syndrome, autoimmune hepatitis, hypereosinophilic syndrome, Hyper IgE syndrome, post-liver transplant, diabetes was observed in individual cases. Remaining 17 (55%) patients diagnosed as primary AIHA .Corticosteroids and/or immunoglobulin was given as first line of treatment to 64.5% (20) patients while 35.5% (11) required Rituximab and/or splenectomy as second line of treatment, of which 73%(8) were diagnosed as primary AIHA. Five-year overall survival (Kaplan-Meir) rate of 89% was observed with twenty-seven alive patients showing partial or complete response ,while four patients died due to underlying diseases.Conclusion: Our results demonstrates patients responding to first line of treatment, however serious cases required management through second line of treatment. Further, a regional multicenter observational study will enable better understanding of differences in disease presentation and treatment outcomes. DisclosuresNo relevant conflicts of interest to declare.

Rare Case of Adult Onset DOCK8 Mutated Hyper Ige Syndrome

Background: Autosomal dominant hyper IgE syndrome (AD-HIES) is a primary immune deficiency characterized by the classic triad of recurrent skin boils, cyst-forming pneumonias, and extreme elevations of serum IgE. AD-HIES is classically associated with mutations in the signal transducer and the activator of the transcription 3 gene (STAT3) gene. To date, the majority of cases have been caused by de novo pathogenic variants. The dedicator of the cytokinesis 8 gene (DOCK8) has been identified as the cause of many cases with autosomal recessive hyper-IgE syndrome (AR-HIES). The autosomal dominant hyper-IgE syndrome is associated with a cluster of facial, dental, skeletal, and connective tissue abnormalities which are not observable in the recessive type. Here we present a rare case of a patient meeting criteria for AD-HIES but with DOCK8 p.R83Q mutation.Methods: Case study involving retrospective chart review from May 2015 to present.Clinical case: Patient is a 49 yo female with past medical history of moderate eczema, innumerable recurrent sinopulmonary infections, 4 episodes of pneumonia, mild scoliosis, 8 digital fractures with minimal trauma, 5 skin abcesses, recurrent vulvovaginal candidiasis, monthly urinary tract infections who presented to the emergency room in May 2015 with left facial paralysis and progressive paralysis in left upper and lower extremity associated with numbness. Physical examination revealed diffuse scaly pruritic rash, high palate, left facial droop, left sided upper and lower extremity weakness and numbness (Figure 1). MRI of the brain with contrast May 2015 showing scattered periventricular, subcortical and deep white matter FLAIR signal hyperintensities (Figure 2). CSF for viral, fungal, bacterial cultures, Cryptococcus, west nile, flow cytometry, protein electropheresis at that time was normal. She was found to have low IGG 579 mg/dL, normal IGA 191 mg/dL, IGM 111mg/Dl IGD 2.09 mg/dL, and increased IGE (297 IU/mL, currently 807 IU/mL, peak 1171 IU/mL). She had a complete negative workup for infections: Blood cultures, HIV, TB, EBV, CMV, HTLV-1&2, Colorado Tick Fever, Tropheryma Whipplei, Stongyloides, Schistosoma, Toxocara Abs, Ascaris, Plasmodium, Trichinella, Influenza A B, HSV, Hepatitis A B C, Echinococcues, West Nile virus, Cystercercosis, Lyme Disease, Syphilis, Amoebic cultures, Aspergillus, Mucormycosis. Stool was negative for ova & parasites, Shigella, Yersenia, Clostridium, Giardia, E. Coli, Trichome stain. Malignancy evaluation was negative including: CT brain, chest, abdomen, and pelvis, flow cytometry, protein electrophoresis, tumor markers, bone marrow biopsy and aspirate (figure 3), upper & lower endoscopy. Electrolytes, metal screen (arsenic, copper, lead, mercury, zinc), complete chemistries were negative. A complete autoimmune and allergy panel was negative. Immunology profile showed normal CBC (normal PLT size), low CH 50 of 38 U/mL, normal helper CD3% 78%, 1884 cell/mcL, elevated helper CD4% 68.5%, 1601 cell/mcL, low suppressor CD8% of 11% with normal absolute number 249 cell/mcL. IL 6 = 3.1 pg/mL, IL 10 =11.5 pg/mL, IL 12 was undetectable. Genetic analysis revealed normal NOTCH3, SPINK5, STAT3, TYK2 genes. A heterozygous mutation in DOCK8 p.Arg83Gln (R83Q) was discovered in this patient. Based on a clinical scoring system developed by the National Institutes of Health patient has features suggestive of AD-HIES (> 40 is cutoff, our patient scored 52). The patient has been receiving IVIG 40 grams IV every 3 weeks with clinical improvement in infectious symptoms but continued progression of neurological symptoms. Due to rarity of this case the patient is currently being referred to the NIH for further management.Conclusion: Here we present a rare adult onset case with the patient meeting criteria for AD-HIES and symptoms of DOCK8 AR-HIES harboring R83Q variant DOCK8. This patient may likely harbor an undiscovered mutation in another allele. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature

Serine/threonine kinase-4 (STK4) deficiency is an autosomal recessive combined immunodeficiency. We aimed to define characteristic clinical and laboratory features to aid the differential diagnosis and determine the most suitable therapy. In addition to nine STK4 deficiency patients, we reviewed 15 patients from the medical literature. We compared B lymphocyte subgroups of the cohort with age-matched healthy controls. In the cohort, median age at symptom onset and age at diagnosis were 6 years 8 months (range, 6-248 months) and 7 years 5 months (range, 6-260 months), respectively. The main clinical findings were infections (in all nine patients [9 of 9]), autoimmune or inflammatory diseases (7 of 9), and atopy (4 of 9). CD4 lymphopenia (9 out 9), lymphopenia (7 out 9), intermittent eosinophilia (4 out 9), transient neutropenia (3 out 9), low IgM (4 out 9), and high IgE (4 out 9) were common. Decreased recent thymic emigrants, naive and central memory T cells, but increased effector memory T cells were present. The increase in plasmablasts (P= .003) and decrease in switched memory B cells (P= .022) were significant. When 24 patients are analyzed, cutaneous viral infections (n= 20), recurrent pneumonia (n= 18), Epstein Barr virus-associated lymphoproliferation (n= 11), atopic dermatitis (n= 10), autoimmune cytopenia (n= 7), and lymphoma (n= 6) were frequent. Lymphopenia, CD4 lymphopenia, high IgG, IgA, and IgE were common laboratory characteristics. The differential diagnosis with autosomal recessive hyper-IgE syndrome is crucial. Because, atopy and CD4 lymphopenia are common in both diseases. Immunoglobulins, antibacterial, and antiviral prophylaxis are the mainstays of treatment. Clinicians may use immunomodulatory therapies during inflammatory or autoimmune complications. However, more data are needed to recommend hematopoietic stem cell transplantation as a safe therapy.

A hungry Histiocyte, altered immunity and myriad of problems: Diagnostic challenges for Pediatric HLH.

Hemophagocytic lymphohistiocytosis (HLH) is an immune deregulation disorder with varied clinical presentation which clinically overlaps with widespread tropical infections. We conducted a retrospective chart review of children diagnosed with HLH at our center from February-2017 to October-2020. Out of the nine diagnosed patients, genetic predisposition was present in three children; two had identified infectious triggers. The mean age of presentation was 30months with male predominance. The most common clinical findings were fever, organomegaly, and pancytopenia. The median value of fibrinogen was-156mg/dL, ferritin-12957ng/mL and for triglycerides-349mg/dL, respectively. In children with identified genetic predisposition, serum ferritin levels were usually more than 10000ng/mL. The majority of our patients had evidence of hemophagocytosis on bone marrow examination. In our experience, although nonspecific, very high ferritin and serum triglycerides with low fibrinogen in a patient with bi-cytopenia, pancytopenia was the most suggestive evidence of HLH. Genetic evaluation in our series identified three children, one with primary HLH genetic mutation and two with underlying immune deficiency syndrome. The presence of HLH in the accelerated phase of Chediak-Higashi and AD Hyper IgE syndrome with HLH is extremely rare. Leishmaniasis (in nonendemic area) and Ebstein-Barr virus (EBV) was identified as an infectious trigger in two cases. Most of our cases received treatment as per HLH 2004 protocol. Three children died during the initial diagnosis and treatment. HLH with subcutaneous panniculitis-like T-cell lymphoma recovered well. HLH remains a life-threatening disorder associated with a variety of underlying illnesses as highlighted by our case series.

Treatment options for DOCK8 deficiency-related severe dermatitis.

Cutaneous manifestations of dedicator of cytokinesis 8 gene (DOCK8) deficiency, a combined type of T and B cell immunodeficiency, previously designated as autosomal recessive hyper IgE syndrome, includes dermatitis and skin infections. There are limited treatment options for dermatitis related to the syndrome. To describe a cohort of patients with DOCK8 deficiency with a focus on the treatment of their cutaneous manifestations. A retrospective study on all children with the genetic diagnosis of DOCK8 deficiency treated at the Sheba Medical Center between 1/1/2003 and 1/1/2021 was preformed. Collected data included: demographic features, family history, laboratory, genetic testing, skin manifestations, treatment, and disease course. Description of two cases of severe recalcitrant dermatitis treated with dupilumab is detailed. Nine children with a genetic diagnosis of DOCK8 deficiency were included, of whom six were girls (66%) with a median age of 8.5 (±2.2 SD) years. The median age at diagnosis was 2.8 (±2.6 SD) years. Six patients were born to consanguineous parents. Five out of six patients who received hematopoietic stem cell transplantation (HSCT) had a complete response, and one was recently transplanted. Of note, two patients, while awaiting HSCT, were treated with dupilumab for their severe dermatitis resulting in a marked improvement of the cutaneous manifestations and pruritus. Hematopoietic stem cell transplantation is the gold standard and most effective therapy for patients with DOCK8 deficiency. Dupilumab, a biological therapy indicated for atopic dermatitis and other Th2 derived dermatoses, is an excellent option for dermatitis in patients with DOCK8 deficiency and can be used as a bridge before HSCT. Larger studies are needed to confirm this observation.

Inborn errors of IL-6 family cytokine responses.

The IL-6 family of cytokines mediates functions in host protective immunity, development of multiple organs, tissue regeneration and metabolism. Inborn errors in cytokines or cytokine receptor units highlight specific roles for IL-6, IL-11, LIF, OSM, and CLC signaling whereas incomplete loss-of-function variants in the common receptor chain GP130 encoded by IL6ST or the transcription factor STAT3, as well as genes that affect either GP130 glycosylation (PGM3) or STAT3 transcriptional control (ZNF341) lead to complex phenotypes including features of hyper-IgE syndrome. Gain-of-function variants in the GP130-STAT3 signaling pathway cause immune dysregulation disorders. Insights into IL-6 family cytokine signaling inform on therapeutic application in immune-mediated disorders and potential side effects such as infection susceptibility.

Continuous MYD88 Activation Is Associated With Expansion and Then Transformation of IgM Differentiating Plasma Cells.

Activating mutations of MYD88 (MYD88L265P being the far most frequent) are found in most cases of Waldenström macroglobulinemia (WM) as well as in various aggressive B-cell lymphoma entities with features of plasma cell (PC) differentiation, such as activated B-cell type diffuse large B-cell lymphoma (DLBCL). To understand how MYD88 activation exerts its transformation potential, we developed a new mouse model in which the MYD88L252P protein, the murine ortholog of human MYD88L265P, is continuously expressed in CD19 positive B-cells together with the Yellow Fluorescent Protein (Myd88L252P mice). In bone marrow, IgM B and plasma cells were expanded with a CD138 expression continuum from IgMhigh CD138low to IgMlow CD138high cells and the progressive loss of the B220 marker. Serum protein electrophoresis (SPE) longitudinal analysis of 40 Myd88L252P mice (16 to 56 weeks old) demonstrated that ageing was first associated with serum polyclonal hyper gammaglobulinemia (hyper Ig) and followed by a monoclonal immunoglobulin (Ig) peak related to a progressive increase in IgM serum levels. All Myd88L252P mice exhibited spleen enlargement which was directly correlated with the SPE profile and was maximal for monoclonal Ig peaks. Myd88L252P mice exhibited very early increased IgM PC differentiation. Most likely due to an early increase in the Ki67 proliferation index, IgM lymphoplasmacytic (LP) and plasma cells continuously expanded with age being first associated with hyper Ig and then with monoclonal Ig peak. This peak was consistently associated with a spleen LP-like B-cell lymphoma. Clonal expression of both membrane and secreted µ chain isoforms was demonstrated at the mRNA level by high throughput sequencing. The Myd88L252P tumor transcriptomic signature identified both proliferation and canonical NF-κB p65/RelA activation. Comparison with MYD88L265P WM showed that Myd88L252P tumors also shared the typical lymphoplasmacytic transcriptomic signature of WM bone marrow purified tumor B-cells. Altogether these results demonstrate for the first time that continuous MYD88 activation is specifically associated with clonal transformation of differentiating IgM B-cells. Since MYD88L252P targets the IgM PC differentiation continuum, it provides an interesting preclinical model for development of new therapeutic approaches to both WM and aggressive MYD88 associated DLBCLs.

Rescue of STAT3 Function in Hyper-IgE Syndrome Using Adenine Base Editing.

STAT3-hyper IgE syndrome (STAT3-HIES) is a primary immunodeficiency presenting with destructive lung disease along with other symptoms. CRISPR-Cas9-mediated adenine base editors (ABEs) have the potential to correct one of the most common STAT3-HIES causing heterozygous STAT3 mutations (c.1144C>T/p.R382W). As a proof-of-concept, we successfully applied ABEs to correct STAT3 p.R382W in patient fibroblasts and induced pluripotent stem cells (iPSCs). Treated primary STAT3-HIES patient fibroblasts showed a correction efficiency of 29% ± 7% without detectable off-target effects evaluated through whole-genome and high-throughput sequencing. Compared with untreated patient fibroblasts, corrected single-cell clones showed functional rescue of STAT3 signaling with significantly increased STAT3 DNA-binding activity and target gene expression of CCL2 and SOCS3. Patient-derived iPSCs were corrected with an efficiency of 30% ± 6% and differentiated to alveolar organoids showing preserved plasticity in treated cells. In conclusion, our results are supportive for ABE-based gene correction as a potential causative treatment of STAT3-HIES.

Recurrent Anal Abscess in a Young Male Patient with Autosomal-Dominant Hyper IgE Syndrome

Here we present the case of a 17-year-old male patient affected by autosomal-dominant Hyper IgE Syndrome (AD-HIES) who underwent to incision and drainage of recurrent anterior anal abscess. To our knowledge, this is the first reported case about recurrent perianal infection in autosomal-dominant Hyper IgE Syndrome.

Job’s Syndrome With a Family History of Kawasaki Disease: A Case Presentation and Review of Literature

Background: Job’s syndrome or hyper-immunoglobulin E (IgE) syndrome (HIES) is an extremely rare primary immunodeficiency disease with an approximate annual incidence of less than 1/1000000. It is characterized by recurrent cold staphylococcal infections, unusual eczematous dermatitis, severe lung infections, and extensively high concentrations of the serum antibody IgE. Case Presentation: A typical case of Job’s syndrome with a family history of Kawasaki disease is presented in this study aiming at identifying the clinical features, investigational procedures, and management strategy, as well as evaluating the role of the ear, nose, and throat specialist and highlighting the probable relation between Job’s syndrome and Kawasaki disease. Conclusions: In general, early detection with proper care can prevent the progression of Job syndrome. In addition, the initiated treatment at the first signs of infection is mandatory for preventing long-term complications. There is a probable relation between Job and Kawasaki which requires more consideration.

Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome

Biallelic variants in IL6ST, encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6and IL-11 and variable oncostatin M (OSM) and IL-27levels but sparing leukemia inhibitory factor (LIF) signaling. Our aim was to understand the functional and structural impact of recessive HIES-associated IL6ST variants. We investigated a patient with HIES by using exome, genome, and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamics simulations and structural modeling of GP130 cytokine receptor complexes were performed. We identified a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro and the exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant resulted in a more profound IL-6- and IL-11-dominated signaling defect than did the previously identified recessive HIES IL6ST variants p.Asn404Tyr and p.Pro498Leu. Molecular dynamics simulations suggested that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane-proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilized the conformation of the hexameric cytokine receptor complexes, whereas the trimeric LIF-GP130-LIFR complex remained stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently caused additional defective LIF signaling and Stüve-Wiedemann syndrome. Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.

Peripheral immune profile of children with Talaromyces marneffei infections: a retrospective analysis of 21 cases

BackgroundTalaromyces marneffei (T. marneffei) is an opportunistic pathogen that infects immunodeficient children. The aim of the study is to determine the clinical features and peripheral immune state of Talaromyces marneffei (T. marneffei) infections in children for early detection and diagnosis.MethodsWe retrospectively reviewed 21 pediatric patients who were diagnosed with T. marneffei infections and were followed up in the Guangzhou Women and Children’s Medical Center from January 2010 to January 2020. For each patient, we collected and analyzed clinical characteristics, peripheral immunological results, genetic tests, complications and prognosis.ResultsCommon clinical features of the patients included fever (20/21, 95.24%), cough (17/21, 80.95%) and hepatomegaly (17/21, 80.95%). Severe complications included septic shock (12/21, 57.14%), hemophagocytic lymphohistiocytosis (HLH) (11/21, 52.38%), acute respiratory distress syndrome (ARDS) (10/21, 47.62%), multiple organ dysfunction syndrome (MODS) (9/21, 42.86%), and disseminated intravascular coagulation (DIC) (7/21, 33.33%). Eleven children (11/21, 52.38%) eventually died of T. marneffei infections. All patients were HIV negative. Seven cases revealed reduced antibody levels, especially IgG. Higher levels of IgE were detected in 9 cases with an obvious increase in two patients. Ten patients showed decreased complement C3 levels, some of whom had low C4 levels. Three patients displayed decreased absolute T lymphocyte counts, including the CD 4+ and CD 8+ subsets. A reduction in NK cells was present in most patients. No patient had positive nitro blue tetrazolium (NBT) test results. Nine patients were screened for common genetic mutations. Of the cases, one case had no disease-specific gene mutation. Four children had confirmed hyperimmunoglobulin M syndrome (HIGM) with CD40LG variation, one case had severe combined immunodeficiency (SCID), and one case had hyper-IgE syndrome (HIES). One patient was identified as having a heterozygous mutation in STAT3 gene; however, he showed no typical clinical manifestations of HIES at his age. One patient had a mutated COPA gene with uncertain pathogenic potential. Another patient was diagnosed with HIES that depended on her clinical features and the National Institutes of Health (NIH) scoring system.ConclusionsT. marneffei infections in HIV-negative children induced severe systemic complications and poor prognosis. Children with T. marneffei infections commonly exhibited abnormal immunoglobulin levels in peripheral blood, particularly decreased IgG or increased IgE levels, further suggesting possible underlying PIDs in these patients.

STAT Immunodeficiency Disorders and Fungal Infection Susceptibility

Invasive fungal diseases (IFD) or complicated mucocutaneous fungal infections can occur secondary to both primary and acquired immunodeficiency disorders. The signal transducer and activator of transcription (STAT) proteins are critical transcription factors involved in a wide range of processes including the immune response. This review highlights the immune pathways, clinical phenotypes and current management options of fungal infections in patient with mutations in STAT1 and STAT3, the most relevant STAT molecules involved in the host response to fungal pathogens. STAT1 gain of function (GOF) and STAT3 loss of function (LOF) (cause of autosomal dominant Hyper IgE syndrome) mutations have been associated with both chronic mucocutaneous candidiasis (CMC) and invasive fungal infections, not only inhaled moulds, mostly Aspergillus spp., but also Pneumocystis, Cryptococcus and other endemic dimorphic fungi. Significant progress has been made in the insights into the immunopathogenesis of fungal infections in these patients; nevertheless, the concrete mechanisms involved are still not fully elucidated. Early initiation of antifungal therapy followed by long-term secondary prophylaxis is normally required. Some adjunctive therapies have also been employed, although their use has not been completely established. Besides a developing knowledge in STAT1 GOF and STAT3 LOF mutations, additional research is needed. It should aim for a better understanding of the pathogenesis, diagnosis, and management of fungal infections in these patients. The identification of new therapeutic targets should help to improve patient quality of life and outcomes.

Clinical Profile of Hyper-IgE Syndrome in India.

Introduction: Hyper-IgE Syndrome (HIES) is a rare inborn error of immunity (IEI) characterized by a constellation of symptoms related to susceptibility to Staphylococcal skin and pulmonary infections, eczema, raised serum IgE (>2,000 IU/ml), craniofacial anomalies, and recurrent bone fractures. Data on HIES from the Indian subcontinent is scarce and restricted to small case series and case reports. This is the first compilation of national data on HIES.Materials and Methods: A total 103 cases clinically diagnosed and treated as HIES were analyzed from nine centers. Cases with clinical and/or molecular diagnosis of DOCK8 deficiency were not included. Patients were divided into two groups: group I for whom a heterozygous rare variant of STAT3 was identified, and group II, with clinical features similar to those of AD STAT3 deficiency, but without any genetic diagnosis.Results: Genetic diagnosis was available in 27 patients (26.2%) and all harbored rare variants in the STAT3 gene. Majority of these STAT3 HIES patients presented with recurrent skin abscesses (77.7%) or pneumonia (62.9%) or both (59.2%). Other features included eczema (37%), candidiasis (55.5%), facial dysmorphism (55.5%), recurrent fractures (11.1%), and retained primary teeth (7.4%). Mycobacterial infections were seen in a significant 18.5%. Mortality was seen in three subjects (11.1%). A similar trend in the clinical presentation was observed when all the 103 patients were analyzed together. Twenty percent of patients without a rare variant in the STAT3 gene had an NIH score of ≥40, whereas, 51.9% of STAT3 HIES subjects had scores below the cut off of ≥40. TH17 cell numbers were low in 10/11 (90.9%) STAT3 HIES tested. Rare variants observed were 8 in exon 21; 8 in exon 13; 3 in exon 10; 2 in exon 15, and one each in exon 6, 16, 17, 19, 22, and splice site downstream of exon 12. Seven variants were novel and included F174S, N567D, L404Sfs*8, G419 =, M329K, T714I, R518X, and a splice site variant downstream of exon 12.Conclusions: The report includes seven novel STAT3 variants, including a rare linker domain nonsense variant and a CC domain variant. Mycobacterial diseases were more frequent, compared to western literature.

Inborn Error of Immunity or Atopic Dermatitis: When to be Concerned and How to Investigate

Around 20% of all children worldwide suffer from atopic dermatitis. Therefore, eczematous skin lesions and elevated serum immunoglobulin E (IgE) levels are common findings. Inborn errors of immunity (IEI) may be missed in the context of atopic dermatitis, and management and prognosis of these conditions can be substantially different. Children suffering from IEIs such as hyper-IgE syndromes, Wiskott-Aldrich syndrome, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, Omenn syndrome, the atypical complete DiGeorge syndrome, and skin barrier disorders like Comèl-Netherton syndrome and severe dermatitis-multiple allergies and metabolic wasting syndrome may present with additional red flags, which should raise a clinical suspicion for an underlying IEI. These red flags may include eczematous skin lesion manifesting prior to two months of life, disseminated or recurrent viral, bacterial, or fungal infections, mucocutaneous candidiasis, purpura, chronic diarrhea, or abnormalities in development or of connective tissue. A differential blood count, as well as a lymphocyte subset analysis, total immunoglobulin levels, and vaccination titers can help the clinician to decide whether a patient with eczematous skin lesions and elevated serum IgE should be referred to a clinical immunologist for a full immunological work-up and broad genetic analysis.

Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome

Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.

Clinical and Immunological Heterogeneity in Japanese Patients with Gain-of-Function Variants in STAT3.

Germline loss-of-function variants in the signal transducer and activator of transcription 3 (STAT3) gene result in autosomal dominant hyper IgE syndrome, whereas somatic gain-of-function (GOF) variants in STAT3 are associated with some malignancies. In addition, germline GOF variants in STAT3 are linked to disorders involving autoimmunity and lymphoproliferation. In this study, we describe five Japanese families with germline GOF variants in STAT3, including three novel variants. We also present the clinical and immunological characteristics of these patients. Eight patients from five families were enrolled in this study. We performed genetic and immunological analyses, and collected the associated clinical information. We identified five heterozygous variants in STAT3 using whole-exome sequencing and target gene sequencing. Two of these (E286G and T716M) were previously reported and three (K348E, E415G, and G618A) were novel. A STAT3 reporter assay revealed that all of the variants were GOF. However, the immunological and clinical characteristics among the patients were highly variable. Patients with STAT3 GOF variants exhibited clinical and immunological heterogeneity with incomplete penetrance.