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)

Major histocompatibility complex class II (MHC-II) molecules are of central importance for adaptive immunity. Defective MHC-II expression causes a severe immunodeficiency disease called bare lymphocyte syndrome (BLS). Studies of the molecular defects underlying BLS have been pivotal for characterization of the regulatory system controlling the transcription of MHC-II genes. The precisely controlled pattern of MHC-II gene expression is achieved by a very peculiar and highly specialized molecular machinery that involves the interplay between ubiquitous DNA-binding transcription factors and a highly unusual, tightly regulated, non-DNA-binding coactivator called the MHC class II transactivator (CIITA). CIITA single handedly coordinates practically all aspects of MHC-II gene regulation and has therefore been dubbed the master controller of MHC-II expression. Several of the unusual features of the MHC-II regulatory system may be a consequence of the fact that CIITA originated from an ancient family of cytoplasmic proteins involved in inflammation and innate immunity. The function of CIITA in transcriptional regulation of MHC-II genes could thus be a recent acquisition by an ancestral protein having a role in an unrelated system.
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PMID:Regulation of MHC class II expression, a unique regulatory system identified by the study of a primary immunodeficiency disease. 1657 55

Langerhans cells (LCs) play a sentinel role by initiating both adaptive and innate immune responses to antigens pertinent to the skin. With the discovery of various LCs markers including antibodies to major histocompatibility complex class II (MHC-II) molecules and CD1a, intracellular presence of racket-shaped "Birbeck granules," and very recently Langerin/CD207, LCs can be readily distinguished from other subsets of dendritic cells. Femtosecond two-photon laser scanning microscopy (TPLSM) in recent years has emerged as an alternative to the single photon-excitation based confocal laser scanning microscope (CLSM), particularly for minimally-invasive deep-tissue 3D and 4D vital as well as nonvital biomedical imaging. We have recently combined high resolution two-photon immunofluorescence (using anti MHC-II and Langerin/CD207 antibodies) imaging with microspectroscopy and advanced image-processing/volume-rendering modalities. In this work, we demonstrate the use of this novel state-of-the-art combinational approach to characterize the steady state 3D organization and spectral features of the mouse epidermis, particularly to identify the spatial distribution of LCs. Our findings provide unequivocal direct evidence that, in the mouse epidermis, the MHC-II and mLangerin/CD207 antigens do indeed manifest a high degree of colocalization around the nucleus of the LCs, while in the distal dendritic processes, mLangerin/CD207 antigens are rather sparsely distributed as punctuate structures. This unique possibility to simultaneously visualize high resolution 3D-resolved spatial distributions of two different immuno-reactive antigens, namely MHC-II and mLangerin/CD207, along with the nuclei of LCs and the adjacent epidermal cells can find interesting applications. These could involve aspects associated with pragmatic analysis of the kinetics of LCs migration as a function of immuno-dermatological responses during (1) human Immunodeficiency virus disease progression, (2) vaccination and targeted gene therapy, (3) skin transplantation/plastic surgery, (4) ultraviolet and other radiation exposure, (5) tissue-engineering of 3D skin constructs, as well as in (6) cosmetic industry, to unravel the influence of cosmeceuticals.
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PMID:Femtosecond two-photon high-resolution 3D imaging, spatial-volume rendering and microspectral characterization of immunolocalized MHC-II and mLangerin/CD207 antigens in the mouse epidermis. 1694 65

Although combination therapy allows the suppression of human immunodeficiency virus type 1 (HIV-1) viremia to undetectable levels, eradication has not been achieved because the virus persists in cellular reservoirs, particularly the latent reservoir in resting CD4(+) T lymphocytes. We previously established a simian immunodeficiency virus (SIV)/macaque model to study latency. We describe here a novel mechanism for the induction of SIV from latently infected resting CD4(+) T cells. Several human cell lines including CEMx174 and Epstein-Barr virus-transformed human B-lymphoblastoid cell lines mediated contact-dependent activation of resting macaque T cells and induction of latent SIV. Antibody-blocking assays showed that interactions between the costimulatory molecule CD2 and its ligand CD58 were involved, whereas soluble factors and interactions between T-cell receptors and major histocompatibility complex class II were not. Combinations of specific antibodies to CD2 also induced T-cell activation and virus induction in human resting CD4(+) T cells carrying latent HIV-1. This is the first demonstration that costimulatory signals can induce latent virus without the coengagement of the T-cell receptor, and this study might provide insights into potential pathways to target latent HIV-1.
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PMID:Novel pathway for induction of latent virus from resting CD4(+) T cells in the simian immunodeficiency virus/macaque model of human immunodeficiency virus type 1 latency. 1715 Nov 30

Major histocompatibility complex class II deficiency is an autosomal recessive primary combined immunodeficiency. The prevalence of this deficiency is highest in Mediterranean areas, especially north Africa. Early diagnosis is essential due to high mortality in the first 2 years of life and the possibility of bone marrow transplantation. We report four cases of major histocompatibility complex class II deficiency and describe their epidemiologic and clinical characteristics, diagnostic tests, treatment and outcome.
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PMID:[Major histocompatibility complex class II deficiency]. 1734 58

DC-SIGN, a C-type lectin expressed on dendritic cells (DCs), can sequester human immunodeficiency virus (HIV) virions in multivesicular bodies. Here, using large-scale gene expression profiling and tyrosine-phosphorylated proteome analyses, we characterized signaling mediated by DC-SIGN after activation by either HIV or a DC-SIGN-specific antibody. Activation of DC-SIGN resulted in downregulation of genes encoding major histocompatibility complex class II, Jagged 1 and interferon-response molecules and upregulation of the gene encoding transcription factor ATF3. Phosphorylated proteome analysis showed that HIV- or antibody-stimulated DC-SIGN signaling was mediated by the Rho guanine nucleotide-exchange factor LARG and led to increased Rho-GTPase activity. Activation of LARG in DCs exposed to HIV was required for the formation of virus-T cell synapses. Thus, HIV sequestration by and stimulation of DC-SIGN helps HIV evade immune responses and spread to cells.
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PMID:Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication. 1751 7

The human immunodeficiency virus type 1 (HIV-1) Vpu accessory protein is a transmembrane protein that down regulates CD4 expression and promotes the release of new virions. We screened a human leukocyte-specific yeast two-hybrid expression library to discover novel Vpu-interacting cellular proteins. The major histocompatibility complex class II (MHC II) invariant chain, also called Ii or CD74, was found to be one such protein. We show direct binding of Vpu and CD74 by using a yeast two-hybrid assay and coimmunoprecipitation from HIV-1-infected cells. The cytoplasmic region of Vpu was found to interact with the 30-amino-acid cytoplasmic tail of CD74. Human monocytic U937 cells infected with wild-type or Vpu-defective HIV-1 and transfected cells showed that Vpu down modulated the surface expression of mature MHC II molecules. The reduction in cell surface mature MHC II molecules correlated with decreased antigen presentation to T cells in culture. Thus, the Vpu protein also contributes to viral persistence by attenuating immune responses during HIV infection. This report further exemplifies the rich diversity and redundancy shown by HIV in immune evasion.
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PMID:Human immunodeficiency virus type 1 Vpu protein interacts with CD74 and modulates major histocompatibility complex class II presentation. 1795 59

The role of CD4(+) T cells in the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication is not well understood. Even though strong HIV- and SIV-specific CD4(+) T-cell responses have been detected in individuals that control viral replication, major histocompatibility complex class II (MHC-II) molecules have not been definitively linked with slow disease progression. In a cohort of 196 SIVmac239-infected Indian rhesus macaques, a group of macaques controlled viral replication to less than 1,000 viral RNA copies/ml. These elite controllers (ECs) mounted a broad SIV-specific CD4(+) T-cell response. Here, we describe five macaque MHC-II alleles (Mamu-DRB*w606, -DRB*w2104, -DRB1*0306, -DRB1*1003, and -DPB1*06) that restricted six SIV-specific CD4(+) T-cell epitopes in ECs and report the first association between specific MHC-II alleles and elite control. Interestingly, the macaque MHC-II alleles, Mamu-DRB1*1003 and -DRB1*0306, were enriched in this EC group (P values of 0.02 and 0.05, respectively). Additionally, Mamu-B*17-positive SIV-infected rhesus macaques that also expressed these two MHC-II alleles had significantly lower viral loads than Mamu-B*17-positive animals that did not express Mamu-DRB1*1003 and -DRB1*0306 (P value of <0.0001). The study of MHC-II alleles in macaques that control viral replication could improve our understanding of the role of CD4(+) T cells in suppressing HIV/SIV replication and further our understanding of HIV vaccine design.
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PMID:The major histocompatibility complex class II alleles Mamu-DRB1*1003 and -DRB1*0306 are enriched in a cohort of simian immunodeficiency virus-infected rhesus macaque elite controllers. 1798 78

Recent clinical trials have shown that the presence of a robust human immunodeficiency virus type 1 (HIV-1)-specific T-cell response may not be sufficient to prevent or control HIV-1 infection. Studies of antigen processing in the context of infectious HIV-1 are therefore warranted. Envelope-specific, major histocompatibility complex class II-restricted murine T-cell hybridomas were tested for responsiveness to splenic antigen-presenting cells exposed to HIV-1-infected GHOST cells. Interleukin-2 assays showed that the presence of a peptide within HIV-1 did not ensure the reactivation of peptide-specific T cells. Further experiments defined the impact of gamma interferon-induced thiol reductase and cysteine proteases on the processing of HIV-1 peptides. The results highlight potential influences of peptide context on T-cell reactivation by HIV-1 and encourage the continued study of antigen processing as support for improved vaccine design.
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PMID:Target peptide sequence within infectious human immunodeficiency virus type 1 does not ensure envelope-specific T-helper cell reactivation: influences of cysteine protease and gamma interferon-induced thiol reductase activities. 1823 43

The human immunodeficiency virus type 1 (HIV-1) Nef protein upregulates the expression of the invariant chain (Ii)/major histocompatibility complex class II (MHC-II) complex at the cell surface. This complex appears to reach the antigen-loading endosomal compartment at least in part via an indirect pathway in which it is internalized from the cell surface via the adaptor protein 2 (AP-2) complex. Here we provide evidence for a competition model to explain how Nef upregulates the expression of Ii at the cell surface. In this model, Nef and Ii compete for binding to AP-2. In support of this model, Nef decreased the rate of internalization of Ii from the cell surface. The AP-binding dileucine motif in Nef, ENTSLL(165), was necessary and sufficient for the upregulation of Ii. In addition, two leucine-based AP-binding motifs in the Ii cytoplasmic tail, DDQRDLI(8) and EQLPML(17), were critical for the efficient upregulation of Ii by Nef. Experiments using Nef variants in which the native dileucine-based sorting motif was replaced with similar motifs from cellular transmembrane proteins allowed modulation of AP-binding specificity. Analysis of these variants suggested that the binding of Nef to AP-2 is sufficient to upregulate Ii at the plasma membrane. Finally, interference with the expression of AP-2 caused an upregulation of Ii at the plasma membrane, and this decreased the effect of Nef. These data indicate that Nef usurps AP-2 complexes to dysregulate Ii trafficking and potentially interfere with antigen presentation in the context of MHC-II.
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PMID:Competition model for upregulation of the major histocompatibility complex class II-associated invariant chain by human immunodeficiency virus type 1 Nef. 1852 31

Human immunodeficiency virus-1-derived lentiviral vectors have been increasingly used for gene delivery in both pre-clinical and clinical models. Numerous studies have shown that dendritic cells (DC) transduced with concentrated lentiviral vectors can induce primary T-cell responses to viral and tumor antigens. In this study, we attempted to generate influenza hemagglutinin-specific CD4 T cells using lentiviral vectors containing the signal sequence and human lysosome-associated membrane protein to target hemagglutinin to the major histocompatibility complex class II processing pathway. Autologous dendritic cells were generated in serum-free medium and transduced with concentrated, high-titer lentiviruses to stimulate autologous T cells. Unexpectedly, we failed to generate influenza hemagglutinin-specific CD4 T cells rather than T cells specific for fetal calf serum (FCS). By limiting dilution, we established several FCS-specific CD4 T-cell clones restricted by human leukocyte antigen-DR1 and human leukocyte antigen-DR4. Lentiviruses produced in human serum-adapted 293 cells or in serum-free medium were unable to sensitize dendritic cells for recognition by FCS-specific CD4 T-cell clones. Our results indicate that residual FCS in concentrated lentiviral pellets is, in part, responsible for its immunogenicity. These FCS-specific CD4 T cells may be useful in testing clinical grade lentiviral vectors for the presence of contaminating FCS.
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PMID:High-titer lentiviral vectors stimulate fetal calf serum-specific human CD4 T-cell responses: implications in human gene therapy. 1934 17


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