Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Nef protein of human immunodeficiency virus-1 (HIV-1) is essential for the progression from human and simian immunodeficiency virus infection to full-blown AIDS. Recent studies indicate that Nef generates anti-apoptotic signals in HIV-infected T cells, suppressing cell death early in infection to allow productive viral replication. Previous work from our laboratory has shown that Nef also promotes proliferation of myeloid cells through a signal transducer and activator of transcription 3-dependent pathway. Here we demonstrate that Nef suppresses cell death induced by cytokine deprivation in the human macrophage precursor cell line, TF-1. Nef selectively induced up-regulation of Bcl-XL, an anti-apoptotic gene that is also regulated by granulocyte/macrophage-colony stimulating factor in this cell line. Activation of the extracellular signal-regulated kinase (Erk) mitogen-activated protein kinase pathway also correlated with the survival of TF-1/Nef cells. Using the selective mitogen-activated protein kinase kinase inhibitor PD98059, we found that Nef-induced Erk signaling is essential for Bcl-XL up-regulation and cell survival. In contrast, expression of Bcl-XL and TF-1 survival was not affected by dominant-negative signal transducer and activator of transcription 3. These data suggest that Nef produces survival signals in myeloid cells through Erk-mediated Bcl-XL induction, a pathway distinct from Nef survival pathways recently reported in T lymphocytes.
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PMID:HIV-1 Nef promotes survival of TF-1 macrophages by inducing Bcl-XL expression in an extracellular signal-regulated kinase-dependent manner. 1545 89

Hyper-immunoglobulin E (IgE) syndrome (HIES) is one of the primary immunodeficiency syndromes. Although the cytokine dysregulation is suggested to play a role in its pathophysiology, the causative gene has not yet been identified. To investigate the pathophysiology and candidate genes involved in this disease, we performed microarray analysis of unstimulated peripheral CD4+ T cells and CD14+ cells, as well as peripheral blood mononuclear cells (PBMNC) stimulated with Staphylococcus aureus isolated from HIES patients and healthy controls. By microarray analysis, 38 genes showed over 2-fold differences between the HIES patients and healthy controls in purified CD14+ cells, although only small differences in the gene expression profiles were observed between the two groups in purified CD4+ T cells. RGC32 expression levels showed the greatest difference between the two groups, and were significantly elevated in HIES compared with those in severe atopic dermatitis or healthy controls using real-time PCR. A significantly larger number of lysosome-related genes were up-regulated, and significantly larger number of genes related to cell growth and maintenance were down-regulated in HIES. After the stimulation of PBMNC with Staphylococcus aureus, 51 genes showed over 3-fold differences between HIES patients and healthy controls. A significantly large number of immunoglobulin-related genes were up-regulated in HIES. The distinct patterns of gene expression profiles and RGC32 expression levels will be useful for understanding the pathophysiology and for diagnosis of HIES, respectively.
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PMID:Distinct gene expression patterns of peripheral blood cells in hyper-IgE syndrome. 1593 15

Hyper IgE recurrent infection syndrome (HIES, or Job's syndrome) is a primary immunodeficiency characterized by recurrent skin and lung infections, eczema, elevated serum immunoglobulin E (IgE) levels, and various connective tissue and skeletal system abnormalities including characteristic facies, scoliosis, joint hyperextensibility, retained primary dentition, craniosynostosis, osteopenia, and pathologic fractures. We have identified two patients with aneurysmal coronary artery disease. One was a forty-three-year-old man with HIES and coronary artery aneurysms and ectasia identified on cardiac catheterization following myocardial infarction. The other was a 48-year-old man with coronary artery ectasia-aneurysm identified after cardiac catheterization for evaluation of chest pain. Although connective tissue abnormalities are common in HIES, this is the first report of coronary artery aneurysms in HIES. Further studies are necessary to determine the incidence, pathogenesis, and optimal therapy of these arterial abnormalities in HIES.
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PMID:Coronary artery aneurysms in patients with hyper IgE recurrent infection syndrome. 1709 78

Hyper-immunoglobulin E syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with disproportionately milder inflammatory responses, referred to as cold abscesses, and skeletal abnormalities. Although some cases of familial HIES with autosomal dominant or recessive inheritance have been reported, most cases of HIES are sporadic, and their pathogenesis has remained mysterious for a long time. Here we show that dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem HIES. We found that eight out of fifteen unrelated non-familial HIES patients had heterozygous STAT3 mutations, but their parents and siblings did not have the mutant STAT3 alleles, suggesting that these were de novo mutations. Five different mutations were found, all of which were located in the STAT3 DNA-binding domain. The patients' peripheral blood cells showed defective responses to cytokines, including interleukin (IL)-6 and IL-10, and the DNA-binding ability of STAT3 in these cells was greatly diminished. All five mutants were non-functional by themselves and showed dominant-negative effects when co-expressed with wild-type STAT3. These results highlight the multiple roles played by STAT3 in humans, and underline the critical involvement of multiple cytokine pathways in the pathogenesis of HIES.
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PMID:Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. 1767 33

Signal transducer and activator of transcription 3 (STAT3) is a DNA-binding transcription factor activated by multiple cytokines and interferons. High expression of STAT3 has also been implicated in cancer and lymphoma. Here, we show a case of B cell lymphoma in which a defective human immunodeficiency virus 1 (HIV-1) integrated upstream of the first STAT3 coding exon. The lymphoma cells with anaplastic large cell morphology formed multiple nodular lesions in the lung of an acquired immunodeficiency syndrome (AIDS) patient with Kaposi's sarcoma. The provirus had a 5' long terminal repeat (LTR) deletion, but the 3' LTR had stronger promoter activity than the STAT3 promoter in reporter assays. Immunohistochemistry showed increased expression of STAT3 in the nuclei of lymphoma cells. Transfection of STAT3 resulted in transient cell proliferation in primary B cells in vitro. Although this is a very rare case of HIV-1-integrated lymphoma, these data suggest that up-regulation of STAT3 caused by HIV-1 integration resulted in the development of B cell lymphoma in this special case.
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PMID:Integration of HIV-1 caused STAT3-associated B cell lymphoma in an AIDS patient. 1802 24

Hyper-IgE syndrome (HIES) is a complex primary immunodeficiency characterized by high serum IgE, chronic eczematoid dermatitis, and recurrent extracellular bacterial infections. Two types of HIES have been reported: type 1 and type 2. Type 1 HIES displays abnormalities in multiple systems, including the skeletal, dental, and immune systems, whereas type 2 shows abnormalities confined to the immune system. We recently identified hypomorphic mutations in the signal transducer and activator of transcription 3 (STAT3) gene in type 1 HIES and a null mutation in the tyrosine kinase 2 (Tyk2) gene, accompanied by susceptibility to intracellular bacteria in type 2 HIES. Analyses of cytokine responses in both types of HIES revealed that severe defects in the signal transduction for multiple cytokines, including interleukin-6 and interleukin-23, are leading to impaired T-helper type 17 function. These findings suggest that HIES is caused by the defects in multiple cytokine signals and that the susceptibility to various infections in HIES is associated with the T-helper type 17 defect.
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PMID:Genetic origins of hyper-IgE syndrome. 1868 2

Mutations in STAT3 (signal transducer and activator of transcription 3) have recently been found to cause the hyper-IgE syndrome (HIES) - a rare immunodeficiency syndrome including complex somatic features. We now tested whether STAT3 mutations or single-nucleotide polymorphisms (SNPs) within STAT3 may be responsible for increased IgE levels in asthmatic children. We genotyped DNA samples from 918 individuals of 217 core families by MALDI-TOF mass spectrometry. SNPs were selected from previous reports, by functional relevance and haplotype-tagging capacity. In 24 assays, including the recently described HIES mutations, no variant was detected. In another 27 SNP assays, there was no association of any STAT3 variant with asthma, allergic rhinitis or eczema. In addition, neither total and specific IgE and eosinophil count nor any lung function parameter showed any significant association. When combining high eosinophil counts and high total IgE levels to an HIES-like trait, four SNPs in the 5'-UTR of STAT3 were slightly overtransmitted. A minor fraction of asthmatic children may possibly have an alternate STAT3 promoter architecture influencing joined IgE and eosinophil upregulation. While an overall effect of STAT3 mutations on serum IgE is unlikely in asthma children.
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PMID:STAT3 single-nucleotide polymorphisms and STAT3 mutations associated with hyper-IgE syndrome are not responsible for increased serum IgE serum levels in asthma families. 1884 Nov 65

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by atopic manifestations and susceptibility to infections with extracellular bacteria and fungi, which frequently occur in the skin and lung. Atopic manifestations in HIES include extremely high serum IgE levels, eczema and eosinophilia. Most of the extracellular bacterial infections are associated with disproportionally milder inflammation than normal, which was originally described as having a 'cold abscess'. Non-immunological abnormalities are also observed in most patients with HIES, including a distinctive facial appearance, scoliosis, hyper-extensive joints and retained primary teeth. Recent studies have demonstrated that hypomorphic mutations in signal transducer and activator of transcription 3 result in the classical multisystem form of HIES, whereas a null mutation in tyrosine kinase 2 causes the autosomal recessive form of HIES that is associated with viral and mycobacterial infections. Analyses of cytokine responses in both types of HIES have revealed defects in signal transduction for multiple cytokines including IL-6 and IL-23, leading to impaired T(h)17 function. These results suggest that the defect in multiple cytokine signals is the molecular basis of the immunological and non-immunological abnormalities in HIES and that the susceptibility to infections with extracellular bacteria and fungi in HIES might be associated with the defect in T(h)17 cell differentiation.
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PMID:Defects in Jak-STAT-mediated cytokine signals cause hyper-IgE syndrome: lessons from a primary immunodeficiency. 1908 64

Autosomal dominant Hyper-IgE syndrome (AD-HIES) is a rare primary immunodeficiency characterized by eczema, recurrent skin and lung infections, elevated serum IgE, and various connective tissue, skeletal, and vascular abnormalities. Mutations in signal transducer and activator of transcription 3 (STAT3) have recently been found to account for most cases; however, the pathogenesis of the varied features remains poorly defined. A distinct syndrome, known as autosomal recessive HIES (AR-HIES) manifests as severe eczema, recurrent bacterial and viral skin infections, and sinopulmonary infections. As opposed to STAT3 deficient HIES, AR-HIES lacks the connective tissue and skeletal manifestations but has an increase in neurologic abnormalities. In this review, we discuss the clinical presentations, genetic etiologies, and immunologic abnormalities of these two syndromes. In addition, we discuss animal models of STAT3 deficiency that provide insight into the pathogenesis of HIES. Further understanding of how STAT3 results in the diverse manifestations of HIES will allow us to develop more specific therapies for HIES as well as for many of the manifestations, such as scoliosis, recurrent staphylococcal infections, and eczema, which are common in the general population.
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PMID:Clinical manifestations, etiology, and pathogenesis of the hyper-IgE syndromes. 1919 May 25

After activation by unique cytokines, CD4(+) naive T cells differentiate into lineages of helper/effector (T(H)) and regulatory T (Treg) cells that are characterized by distinct developmental pathways and unique biologic functions. The trusted binary system of T(H)1 and T(H)2 has been expanded to include the IL-17-producing T(H)17 cell lineage, which plays a role in immune responses to infectious agents and maintenance of autoimmune diseases. Acting as counterbalance, Treg cells maintain peripheral tolerance and protect the host from autoaggressive lymphocytes. T(H)1 cells produce IFN-gamma and are involved in cell-mediated immunity, T(H)2 cells produce IL-4 and contribute to humoral immunity, T(H)17 cells generate IL-17 and play an important role in immune responses to fungi and extracellular pathogens, and forkhead box protein 3-positive (FOXP3(+)) Treg cells secrete TGF-beta and IL-10 and downregulate effector T cells. Autosomal dominant hyper-IgE syndrome, a rare primary immunodeficiency disorder, is caused by hypomorphic heterozygous mutations of signal transducer and activator of transcription 3 (STAT3), preventing T(H)17 lineage differentiation and increasing susceptibility to Staphylococcus and Candida species infections. Mutations in the FOXP3 gene interfere with Treg cell development and cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Other single-gene defects resulting in reduced Treg cell function include CD25, signal transducer and activator of transcription 5b, autoimmune regulator, and Wiskott-Aldrich syndrome protein. These observations emphasize the importance of functionally distinct T-cell lineages in maintaining a balanced innate and cognate immune system.
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PMID:TH17 cells and regulatory T cells in primary immunodeficiency diseases. 1941 Jun 87


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