Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 homeostasis of the immune response requires tight regulation of the proliferation and apoptosis of activated lymphocytes. In humans, defects in immune homeostasis result in lymphoproliferation disorders including autoimmunity, haemophagocytic lymphohystiocytosis and lymphomas. The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency that is characterized by lymphohystiocytosis, hypogammaglobulinaemia and lymphomas, and that usually develops in response to infection with Epstein-Barr virus (EBV). Mutations in the signalling lymphocyte activation molecule (SLAM)-associated protein SAP, a signalling adaptor molecule, underlie 60% of cases of familial XLP. Here, we identify mutations in the gene that encodes the X-linked inhibitor-of-apoptosis XIAP (also termed BIRC4) in patients with XLP from three families without mutations in SAP. These mutations lead to defective expression of XIAP. We show that apoptosis of lymphocytes from XIAP-deficient patients is enhanced in response to various stimuli including the T-cell antigen receptor (TCR)-CD3 complex, the death receptor CD95 (also termed Fas or Apo-1) and the TNF-associated apoptosis-inducing ligand receptor (TRAIL-R). We also found that XIAP-deficient patients, like SAP-deficient patients, have low numbers of natural killer T-lymphocytes (NKT cells), indicating that XIAP is required for the survival and/or differentiation of NKT cells. The observation that XIAP-deficiency and SAP-deficiency are both associated with a defect in NKT cells strengthens the hypothesis that NKT cells have a key role in the immune response to EBV. Furthermore, by identifying an XLP immunodeficiency that is caused by mutations in XIAP, we show that XIAP is a potent regulator of lymphocyte homeostasis in vivo.
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PMID:XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. 1708 92

Profiling integral plasma membrane proteins is of particular importance for the identification of new biomarkers for diagnosis and for drug development. We report in this study the identification of surface markers by performing comparative proteomics of established human immunodeficiency virus-1 (HIV-1) latent cell models and parental cell lines. To this end we isolated integral membrane proteins using a biotin-directed affinity purification method. Isolated proteins were separated by two-dimensional gel electrophoresis and identified by matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) after in gel digestion. Seventeen different proteins were found to vary on the surface of T-cells due to HIV-1 infection. Of these proteins, 47% were integral membrane proteins, and 18% were membrane-associated. Through the use of complementary techniques such as Western blotting and fluorescent staining, we confirmed the differential expression of some of the proteins identified by MALDI-TOF including Bruton's tyrosine kinase and X-linked inhibitor of apoptosis. Finally, using phosphatidylinositol 3-kinase inhibitors and flavopiridol to inhibit Bruton's tyrosine kinase localization at the membrane and X-linked inhibitor of apoptosis protein expression, respectively, we showed that HIV-1 latently infected cells are more sensitive to these drugs than uninfected cells. This suggests that HIV-1 latently infected cells may be targeted with drugs that alter several pathways that are essential for the establishment and maintenance of latency.
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PMID:Identifying the membrane proteome of HIV-1 latently infected cells. 1723 30

The fatal immune dysregulation that sometimes follows EBV infection in boys has been linked to mutations in two X chromosome-encoded genes, SLAM-associated protein (SAP) and X-linked inhibitor of apoptosis (XIAP). In this study we describe 2 girls from a consanguineous Turkish family who died after developing severe immune dysregulation and therapy-resistant EBV-positive B cell proliferation following EBV infection. SNP array-based genome-wide linkage analysis revealed IL-2-inducible T cell kinase (ITK) as a candidate gene for this immunodeficiency syndrome. Both girls harbored a homozygous missense mutation that led to substitution of a highly conserved residue (R335W) in the SH2 domain of ITK. Characteristics of ITK deficiency in mouse models, such as absence of NKT cells and high levels of eomesodermin in CD8+ cells, were seen in either one or both of the girls. Two lines of evidence suggested that R335W caused instability of the ITK protein. First, in silico modeling of the mutant protein predicted destabilization of the SH2 domain. Additionally, Western blot analysis revealed that, unlike wild-type ITK, the R335W mutant was nearly undetectable when expressed in 293 T cells. Our results suggest that ITK deficiency causes what we believe to be a novel immunodeficiency syndrome that leads to a fatal inadequate immune response to EBV. Because ITK deficiency resembles EBV-associated lymphoproliferative disorders in boys, we suggest that this molecular cause should be considered during diagnosis and treatment.
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PMID:Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. 1942 69

Human immunodeficiency virus (HIV) infection-induced apoptosis of infected CD4 T cells as well as uninfected (bystander) CD4 T cells and other types of cells is a major factor in the pathogenesis of AIDS. Clinically, HIV-2 patients have a higher CD4 cell count at the time of an AIDS diagnosis, and generally have longer survival after development of symptoms. The mortality after an AIDS diagnosis has been reported to be more influenced by CD4 cell count than HIV type. Previous studies have shown significant variations in cytopathic effects following in vitro infection with primary isolates of HIV-1 or HIV-2 subtypes; however, the relative contributions of HIV-1 and HIV-2 infection leading to cell death remain unclear. Using a human cell line, Jurkat, we examined differences in key molecules involved in apoptotic signaling pathways during infection with either HIV-1 or HIV-2. HIV-1 infection generated more reactive oxygen species (ROS), increased the expression of a larger number of molecules involved in cell signaling such as p47, p38alpha, JNK, c-Yes, total PKC, and decreased the expression of molecules such as p38beta, ERK1/2, and XIAP relative to HIV-2 infection. HIV-1 induced a higher degree of cell death through stronger activation of both apoptotic pathways. HIV-1 infection downregulated both Bcl-X(L) and FLIP expressions at later time points postinfection, while HIV-2 infection dramatically upregulated both Bcl-X(L) and FLIP expression. We also found that the expression of Bcl-X(L) or FLIP resulted in significant inhibition of HIV replication in Jurkat cells. These findings suggest that HIV-1 infection with high levels of cytotoxicity results in a higher level of cell death through apoptosis during a short time postinfection. The longer period of infection observed with HIV-2 with a lower degree of cytotoxicity was accompanied by increased Bcl-X(L) and FLIP expression. High protein levels of Bcl-X(L) or FLIP inhibit HIV replication and may be one explanation for the clinical observation that HIV-2 infected patients generally tend to be long-term nonprogressors with high CD4 lymphocyte counts compared with HIV-1 infected persons.
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PMID:Changes in the level of apoptosis-related proteins in Jurkat cells infected with HIV-1 versus HIV-2. 1984 66

X-linked inhibitor of apoptosis (XIAP) deficiency, caused by BIRC4 mutations, is described to cause X-linked lymphoproliferative disease (XLP) phenotypes. However, compared with XLP caused by SLAM-Associated Protein deficiency (SH2D1A mutation), XIAP deficiency was originally observed to be associated with a high incidence of hemophagocytic lymphohistiocytosis (HLH) and a lack of lymphoma, suggesting that classification of XIAP deficiency as a cause of XLP may not be entirely accurate. To further characterize XIAP deficiency, we reviewed our experience with 10 patients from 8 unrelated families with BIRC4 mutations. Nine of 10 patients developed HLH by 8 years of age. Most patients presented in infancy, and recurrent HLH was common. There were no cases of lymphoma. Lymphocyte defects thought to contribute to HLH development in SLAM-Associated Protein deficiency were not observed in XIAP deficiency. We conclude that XIAP deficiency is a unique primary immunodeficiency that is more appropriately classified as X-linked familial hemophagocytic lymphohistiocytosis.
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PMID:XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. 2048 57

Inflammatory and innate immune signaling in response to recognition of pathogens is essential for immunity and host survival. However, deregulation may lead to detrimental pathologies including immunodeficiency, inflammatory diseases, and cancer. Inhibitor of apoptosis (IAP) proteins have emerged as important regulators of innate immune signaling downstream of pattern recognition receptors (PRRs) such as Toll-like receptor 4 (TLR4), the nucleotide-binding oligomerization domain 1 (NOD1) and NOD2 receptors, and the retinoic acid-inducible gene (RIG)-I receptor. Recent evidence suggests that cIAP1, cIAP2, and XIAP facilitate ubiquitin-dependent signaling activated by these PRRs and mediate activation of nuclear factor-kappa B (NF-kappaB) transcription factors as well as the MAP kinases p38 and JNK. Here, we review the current understanding of IAP-mediated PRR signaling and how IAP proteins might present as promising targets for anti-inflammatory therapies in PRR-dependent inflammatory diseases including Crohn's disease, Blau syndrome, and septic shock.
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PMID:Inhibitor of apoptosis (IAP) proteins in regulation of inflammation and innate immunity. 2144 81

The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency characterized by recurrent episodes of hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, and/or lymphomas. Recently, X-linked inhibitor of apoptosis (XIAP/BIRC4) gene defects, in families with XLP but without SH2D1A gene defects, has been defined. The distinction from primary immunodeficiencies with a defined genetic cause is mandatory. A six-year-old male patient was admitted with the complaints of persistent general lymphadenopathy, for two years had fever, bilateral cervical multiple microlymphadenopathy, hepatic/splenic enlargement with laboratory findings as decreased serum immunoglobulins, negative EBV VCA IgM (viral capsid antigen) and anti-EBV EA (antibody to early D antigen), positive EBV VCA IgG (viral capsid antigen) and EBV EBNA (antibody to nuclear antigen). SH2D1A gene analysis was negative. XIAP/BIRC4 sequencing revealed two novel single nucleotide variants (exon 7, 1978G > A, and 1996T > A) in the 3'UTR of the gene in both patient and mother which were not disease causing. XIAP protein expression was found to be normal. The clinical and laboratory resemblance, no gene mutations, and normal XIAP protein expression led us to think that there may be another responsible gene for XLP. The patient will to be followed up as CVID until he presents new diagnostic signs or until the identification of a new gene.
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PMID:X-Linked Lymphoproliferative Syndrome and Common Variable Immunodeficiency May Not Be Differentiated by SH2D1A and XIAP/BIRC4 Genes Sequence Analysis. 2154 Dec 8

The present study focuses on a large family with an X-linked immunodeficiency in which there are variable clinical and laboratory phenotypes, including recurrent viral and bacterial infections, hypogammaglobulinemia, Epstein-Barr virus-driven lymphoproliferation, splenomegaly, colitis, and liver disease. Molecular and genetic analyses revealed that affected males were carriers of a hypomorphic hemizygous mutation in XIAP (XIAP(G466X)) that cosegregated with a rare polymorphism in CD40LG (CD40 ligand(G219R)). These genes are involved in the X-linked lymphoproliferative syndrome 2 and the X-linked hyper-IgM syndrome, respectively. Single expression of XIAP(G466X) or CD40L(G219R) had no or minimal effect in vivo, although in vitro, they lead to altered functional activities of their gene products, which suggests that the combination of XIAP and CD40LG mutations contributed to the expression of clinical manifestations observed in affected individuals. Our report of a primary X-linked immunodeficiency of oligogenic origin emphasizes that primary immunodeficiencies are not caused by a single defective gene, which leads to restricted manifestations, but are likely to be the result of an interplay between several genetic determinants, which leads to more variable clinical phenotypes.
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PMID:Human X-linked variable immunodeficiency caused by a hypomorphic mutation in XIAP in association with a rare polymorphism in CD40LG. 2154 60

The replication of viruses involves control of some aspects of host cell homeostasis by modification of target cell metabolism and regulation of the apoptotic machinery. It is not well known whether molecules involved in apoptotic pathways affect human immunodeficiency virus type 1 (HIV-1) replication and regulate viral yields. Using the susceptible Jurkat cell line, we studied the relationship of apoptosis-associated molecules with HIV-1 virus production using a sensitive real-time RT-PCR assay. Here, we found that expression of proapoptotic proteins, including Fas ligand (FasL), FADD, or p53 significantly increased HIV-1 virus production. In contrast, the expression of antiapoptotic molecules, such as FLIP, Bcl-X(L), and XIAP, decreased HIV-1 virus production. Knockdown of Bax with siRNA and FADD with expression of its antisense mRNA also inhibited viral replication and the caspase-3 inhibitor, Z-DEVD, and decreased virus production. These data indicate that HIV-1 infection regulates the apoptosis process to facilitate viral replication and inhibition of apoptosis may inhibit HIV-1 replication and cytopathogenesis. We also discuss the effects of MAPK signaling pathways and apoptosis on HIV-1 replication.
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PMID:Molecules from apoptotic pathways modulate HIV-1 replication in Jurkat cells. 2194 13

Hepatitis E virus (HEV) causes an emerging autochthonous disease in developed countries where links with a viral porcine reservoir have been evidenced. Moreover, chronic HEV infection and associated-cirrhosis have been described in severely immunocompromized patients. Nonetheless, only few studies have focused on pediatric HEV infections worldwide and only four autochthonous cases have been reported in children in developed countries. We describe here acute hepatitis E in three immunocompromized children. Case no. 1 was a 9-year-old liver transplant recipient girl in whom H1N1 2009 flu infection was diagnosed concurrently with hepatitis E. Case no. 2 was a 12-year-old boy presenting early medullar relapse of lymphoblastic leukemia of type B and in whom HEV RNA was detected over a 29-week period. Case no. 3 was a 9-year-old boy with a rare primary immunodeficiency due to XIAP deficiency. HEV infections were all autochthonously acquired and involved different viruses classified as subtype f, c, and e of genotype 3, which are those described in autochthonous cases in Europe. These three observations prompt to consider HEV as a causative agent of hepatitis in children in developed countries, and to perform particularly HEV testing in those severely immunocompromized who may develop chronic hepatitis E.
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PMID:Hepatitis E in three immunocompromized children in southeastern France. 2217 88


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