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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epstein-Barr virus (EBV) oncogenes exert potent B cell proliferative effects. EBV infection gives rise to B cell lines that readily proliferate in culture. This ability of EBV represents a powerful tool to study cell proliferation. In efforts to delineate the contribution of signal transducer and activator of transcription 3 (STAT3) toward EBV-driven cell proliferation, we have discovered that B cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES) resist such EBV oncogene-driven outgrowth of cells. Patients with AD-HIES have a dominant negative mutation in their STAT3 gene which renders most of the protein nonfunctional. Exposure of healthy subject-derived B cells to EBV resulted in early activation of STAT3, rapidly followed by increased expression of its mRNA and protein. STAT3 upregulation preceded the expression of EBNA2, temporally one of the first viral oncogenes to be expressed. We found that STAT3 was necessary for subsequent survival and for proliferation of EBV-infected cells past the S phase of the cell cycle. Consequently, B cells from AD-HIES patients were prone to dying and accumulated in the S phase, thereby accounting for impaired cell outgrowth. Of importance, we have now identified a cohort of patients with a primary immunodeficiency disorder whose B cells oppose EBV-driven proliferative signals. These findings simultaneously reveal how EBV manipulates host STAT3 even before expression of viral oncogenes to facilitate cell survival and proliferation, processes fundamental to EBV lymphomagenesis.
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PMID:B lymphocytes from patients with a hypomorphic mutation in STAT3 resist Epstein-Barr virus-driven cell proliferation. 2417 12

A significant number of contributions to our understanding of primary immunodeficiencies (PIDs) in pathogenesis, diagnosis, and treatment were published in the Journal in 2013. For example, deficiency of mast cell degranulation caused by signal transducer and activator of transcription 3 deficiency was demonstrated to contribute to the difference in the frequency of severe allergic reactions in patients with autosomal dominant hyper-IgE syndrome compared with that seen in atopic subjects with similar high IgE serum levels. High levels of nonglycosylated IgA were found in patients with Wiskott-Aldrich syndrome, and these abnormal antibodies might contribute to the nephropathy seen in these patients. New described genes causing immunodeficiency included caspase recruitment domain 11 (CARD11), mucosa-associated lymphoid tissue 1 (MALT1) for combined immunodeficiencies, and tetratricopeptide repeat domain 7A (TTC7A) for mutations associated with multiple atresia with combined immunodeficiency. Other observations expand the spectrum of clinical presentation of specific gene defects (eg, adult-onset idiopathic T-cell lymphopenia and early-onset autoimmunity might be due to hypomorphic mutations of the recombination-activating genes). Newborn screening in California established the incidence of severe combined immunodeficiency at 1 in 66,250 live births. The use of hematopoietic stem cell transplantation for PIDs was reviewed, with recommendations to give priority to research oriented to establish the best regimens to improve the safety and efficacy of bone marrow transplantation. These represent only a fraction of significant research done in patients with PIDs that has accelerated the quality of care of these patients. Genetic analysis of patients has demonstrated multiple phenotypic expressions of immune deficiency in patients with nearly identical genotypes, suggesting that additional genetic factors, possibly gene dosage, or environmental factors are responsible for this diversity.
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PMID:Advances in basic and clinical immunology in 2013. 2458 42

Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350.
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PMID:Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. 2561 33

The hyper-immunoglobulin E (IgE) syndrome (HIES), also known as Job's syndrome is a rare primary immunodeficiency characterized by the clinical triad of recurrent staphylococcal abscesses of skin, recurrent cyst-forming pneumonia, and an elevated serum IgE level of > 2000 IU/ml. Although, most cases are sporadic, families with autosomal dominant (AD-HIES) and recessive (AR-HIES) traits have been reported. Very few articles were published previously on central nervous system abnormalities with definite neurologic manifestations which may vary from partial facial nerve paralysis to hemiplegia in children but Acute Disseminated Encephalomyelitis (ADEM) in a child with HIES hitherto has not been reported. Here we describe a 5-year-old male child with HIES who presented with neurologic manifestations of ADEM.
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PMID:Acute disseminated encephalomyelitis: an uncommon presentation of hyper IgE syndrome. 2551 94

Hyper-IgE syndrome (HIES) is an immunodeficiency disorder that is characterized by distinctive immunologic and non-immunologic manifestations. Although mutations in signal transducer and activator of transcription 3 (STAT3) have been associated with HIES, the exact nature of the relationship is unknown. Here, we characterized the functional activity of STAT3 and its mutations in 11 Mexican patients with autosomal dominant HIES. STAT3 phosphorylation was evaluated by flow cytometry, and in silico analyses were performed to estimate the impact of allelic mutations on the DNA binding and SH2 domains of the STAT3 protein. Electrophoretic mobility shift assays were used to assess whether the STAT3 mutants could bind to the consensus oligonucleotide target in vitro. Two novel mutations [g.58891A>T (Asn395Tyr) and g.59078A>T (Asn425Tyr)] as well as one possible somatic mosaicism were found in several of the patients who bore some remarkable features. However, there were no direct correlations between genotypes and HIES clinical features. STAT3 phosphorylation was found to be lower in the patient cohort than in healthy controls. Moreover, the mutated STAT3 proteins could bind to the Sp1, but not to the STAT3, consensus sequence. From these functional studies, the STAT3 mutations found in our patient cohort were concluded to be deleterious for normal STAT3 function.
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PMID:Functional characterization of two new STAT3 mutations associated with hyper-IgE syndrome in a Mexican cohort. 2629 84

The recently described Mucosal Associated Invariant T (MAIT) cells mediate specific recognition of bacterial and fungal vitamin B2 metabolites. As innate T cells, they possess broad effector responses, including IFN- including Iproduction, that are comparable to conventional T cell responses. Immunodeficiencies associated with systemic Th17 deficiency may also be compounded by defects in MAIT immunity. We evaluated Th17 immunity in this innate T cell compartment in primary (AD-HIES) and secondary immunodeficiency (thymoma) patients with conventional Th17 deficiency and susceptibility to fungal and bacterial disease. Our results suggest that MAIT cells are both reduced and functional deficient in STAT3 deficiency and thymoma patients with IL-12/23 autoantibodies. In contrast, thymoma patients without autoantibodies preserved the normal number and functional MAIT cells.
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PMID:Mucosal-Associated Invariant T (MAIT) Cells Are Impaired in Th17 Associated Primary and Secondary Immunodeficiencies. 2716 80

Signal transducer and activator of transcription 3 (STAT3) deficiency is a primary immunodeficiency characterized by eczema, complicated recurrent infections, elevated serum immunoglobulin E (IgE), osteopenia, and minimal trauma fractures. Zoledronic acid (ZA) is a long-acting bisphosphonate that has been successfully used in children with secondary osteoporosis and osteogenesis imperfecta. We describe the case of a 7-year-old male with STAT3 deficiency and minimal trauma fractures, who also developed osteonecrosis of the hip. He responded well to intravenous ZA every 6 months for 18 months. Three years later, he walks independently and unaided, and has not suffered any other fractures. Although more studies are needed, ZA might help reduce minimal trauma fractures in patients with STAT3 deficiency.
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PMID:Zoledronate as effective treatment for minimal trauma fractures in a child with STAT3 deficiency and osteonecrosis of the hip. 2741 72

A deficiency in signal transducer and activator of transcription 3 (STAT3) is responsible for autosomal dominant hyperimmunoglobulin E syndrome, an immunodeficiency syndrome causing Staphylococcus aureus, Streptococcus pneumonia, Haemophilus influenzae, and, rarely, Pseudomonas aeruginosa and Aspergillus sp infections. Currently, intracellular pathogens are not targeted in the management of severe infections. The pathophysiologic mechanism of hyperimmunoglobulin E syndrome immunodeficiency has recently been linked to a disorder in the T helper 17 pathway and disruption of the interleukin -23/interleukin-17 axis. We report an unusual case of severe pleuropneumopathy by Ureaplasma urealyticum in a teenage girl with STAT3-deficient hyperimmunoglobulin E syndrome (STAT3 HIES). A previous case of severe lung infection by Mycoplasma pneumoniae has already been described in a STAT3-deficient patient, but U urealyticum has never been reported in patients with STAT3 HIES. After a review of the literature, it seems that the specific immunodeficiency pathway of STAT3 HIES exposes STAT3 HIES patients to Ureaplasma lung infections because the pathophysiology of STAT3 HIES and Ureaplasma is based on STAT3 and T helper 17 cells.
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PMID:Life-Threatening Pneumopathy and U urealyticum in a STAT3-Deficient Hyper-IgE Syndrome Patient. 2856 53

Autosomal dominant hyper IgE syndrome (AD-HIES) is a primary immunodeficiency caused by a loss-of-function mutation in the Signal Transducer and Activator of Transcription 3 (STAT3). This immune disorder is clinically characterized by increased susceptibility to cutaneous and sinopulmonary infections, in particular with Candida and Staphylococcus aureus. It has recently been recognized that the skin microbiome of patients with AD-HIES is altered with an overrepresentation of certain Gram-negative bacteria and Gram-positive staphylococci. However, these alterations have not been characterized at the species- and strain-level. Since S. aureus infections are influenced by strain-specific expression of virulence factors, information on colonizing strain characteristics may provide insights into host-pathogen interactions and help guide management strategies for treatment and prophylaxis. The aim of this study was to determine whether the immunodeficiency of AD-HIES selects for unique strains of colonizing S. aureus. Using multi-locus sequence typing (MLST), protein A (spa) typing, and PCR-based detection of toxin genes, we performed a detailed analysis of the S. aureus isolates (n = 13) found on the skin of twenty-one patients with AD-HIES. We found a low diversity of sequence types, and an abundance of strains that expressed methicillin resistance, Panton-Valentine leukocidin (PVL), and staphylococcal enterotoxins K and Q (SEK, SEQ). Our results indicate that patients with AD-HIES may often carry antibiotic-resistant strains that harbor key virulence factors.
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PMID:Molecular Typing of Staphylococcus aureus Isolated from Patients with Autosomal Dominant Hyper IgE Syndrome. 2858 12

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated downstream of many key cytokine receptors expressed by lymphocytes. As such, it plays a critical role in regulating B cells as well as CD4+ and CD8+ T cells. Patients with clinically significant immunodeficiency and immune dysregulation resulting from loss-of-function or gain-of-function mutations in STAT3 have been described. These individuals provide insight into the critical role of this transcription factor in the regulation of immune responses and the balance between effective immune protection and autoimmunity.
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PMID:Signal Transducer and Activator of Transcription 3 Control of Human T and B Cell Responses. 2947 24


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