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Berlin Brandenburg

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  • 1
    Language: English
    In: Molecular Immunology, December 2015, Vol.68(2), pp.85-88
    Description: Cells rely on multiple intracellular trafficking pathways to capture antigens for proteolysis. The resulting peptides bind to MHC class II molecules to promote CD4 T cell recognition. Endocytosis enhances the capture of extracellular and cell surface bound antigens for processing and presentation, while autophagy pathways shunt cytoplasmic and nuclear antigens for presentation in the context of MHC class II molecules. Understanding how physiological changes and cellular stress alter antigen trafficking and the repertoire of peptides presented by class II molecules remains challenging, yet important in devising novel approaches to boost immune responses to pathogens and tumors. An abundant, constitutively expressed cytoplasmic chaperone, HSC70 plays a central role in modulating antigen transport within cells to control MHC class II presentation during nutrient stress. HSC70 may serve as a molecular switch to modulate endocytic and autophagy pathways, impacting the source of antigens delivered for MHC class II presentation during cellular stress.
    Keywords: Hsc70 ; Antigen Presentation ; Cell Stress ; Mhc Class II Molecules ; Autophagy ; Medicine ; Biology ; Chemistry
    ISSN: 0161-5890
    E-ISSN: 1872-9142
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  • 2
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 15 February 2015, Vol.194(4), pp.1446-53
    Description: B lymphocytes exploit macroautophagy to capture cytoplasmic and nuclear proteins within autophagosomes. Fusion of autophagosomes with lysosomes and endosomes facilitates content proteolysis, with the resulting peptides selectively binding MHC class II (MHC II) molecules, which are displayed for recognition by T lymphocytes. Nutrient deprivation or stress amplified this pathway, favoring increased MHC II presentation of cytoplasmic Ags targeted to autophagosomes. By contrast, this stress diminished MHC II presentation of membrane Ags including the BCR and cytoplasmic proteins that use the chaperone-mediated autophagy pathway. Whereas intracellular protease activity increased with nutrient stress, endocytic trafficking and proteolytic turnover of the BCR was impaired. Addition of macronutrients such as high molecular mass proteins restored endocytosis and Ag presentation, evidence of tightly regulated membrane trafficking dependent on macronutrient status. Altering cellular levels of the cytosolic chaperone HSC70 was sufficient to overcome the inhibitory effects of nutritional stress on BCR trafficking and Ag presentation. Together, these results reveal a key role for macronutrient sensing in regulating immune recognition and the importance of HSC70 in modulating membrane trafficking pathways during cellular stress.
    Keywords: Antigen Presentation -- Immunology ; B-Lymphocytes -- Immunology ; Hsc70 Heat-Shock Proteins -- Immunology ; Lymphocyte Activation -- Immunology ; T-Lymphocytes -- Immunology
    ISSN: 00221767
    E-ISSN: 1550-6606
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 3
    Language: English
    In: The American Biology Teacher, 2017, Vol.79(8), p.661(7)
    Description: The use of primary scientific inquiry and experimentation to develop students' understanding of methodologies used by scientists and the nature of science is a key component of the Next-Generation Science Standards (NGSS). Introduction to inquiry-based experimentation also has been shown to improve students'...
    Keywords: Caenorhabditis Elegans – Research ; High School Students – Education ; Neurobiology – Analysis
    ISSN: 0002-7685
    E-ISSN: 19384211
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  • 4
    Language: English
    In: Immunology, April 2014, Vol.141(4), pp.531-9
    Description: Vaccinia virus (VV) has been used globally as a vaccine to eradicate smallpox. Widespread use of this viral vaccine has been tempered in recent years because of its immuno-evasive properties, with restrictions prohibiting VV inoculation of individuals with immune deficiencies or atopic skin diseases. VV infection is known to perturb several pathways for immune recognition including MHC class II (MHCII) and CD1d-restricted antigen presentation. MHCII and CD1d molecules associate with a conserved intracellular chaperone, CD74, also known as invariant chain. Upon VV infection, cellular CD74 levels are significantly reduced in antigen-presenting cells, consistent with the observed destabilization of MHCII molecules. In the current study, the ability of sustained CD74 expression to overcome VV-induced suppression of antigen presentation was investigated. Viral inhibition of MHCII antigen presentation could be partially ameliorated by ectopic expression of CD74 or by infection of cells with a recombinant VV encoding murine CD74 (mCD74-VV). In contrast, virus-induced disruptions in CD1d-mediated antigen presentation persisted even with sustained CD74 expression. Mice immunized with the recombinant mCD74-VV displayed greater protection during VV challenge and more robust anti-VV antibody responses. Together, these observations suggest that recombinant VV vaccines encoding CD74 may be useful tools to improve CD4⁺ T-cell responses to viral and tumour antigens.
    Keywords: Cd74 ; Mhc ; Class II ; Invariant Chain ; Virus ; Antigens, Differentiation, B-Lymphocyte -- Immunology ; Histocompatibility Antigens Class II -- Immunology ; Smallpox Vaccine -- Immunology ; Vaccinia -- Prevention & Control ; Vaccinia Virus -- Immunology ; Viral Proteins -- Immunology
    ISSN: 00192805
    E-ISSN: 1365-2567
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  • 5
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 15 March 2016, Vol.196(6), pp.2457-65
    Description: Cells use multiple autophagy pathways to sequester macromolecules, senescent organelles, and pathogens. Several conserved isoforms of the lysosome-associated membrane protein-2 (LAMP-2) regulate these pathways influencing immune recognition and responses. LAMP-2A is required for chaperone-mediated autophagy (CMA), which promotes Ag capture and MHC class II (MHCII) presentation in B cells and signaling in T cells. LAMP-2B regulates lysosome maturation to impact macroautophagy and phagocytosis. Yet, far less is known about LAMP-2C function. Whereas LAMP2A and LAMP2B mRNA were broadly detected in human tissues, LAMP2C expression was more limited. Transcripts for the three LAMP2 isoforms increased with B cell activation, although specific gene induction varied depending on TLR versus BCR engagement. To examine LAMP-2C function in human B cells and specifically its role in Ag presentation, we used ectopic gene expression. Increased LAMP-2C expression in B cells did not alter MHCII expression or invariant chain processing, but did perturb cytoplasmic Ag presentation via CMA. MHCII presentation of epitopes from exogenous and membrane Ags was not affected by LAMP-2C expression in B cells. Similarly, changes in B cell LAMP-2C expression did not impact macroautophagy. The gene expression of other LAMP2 isoforms and proteasome and lysosomal proteases activities were unperturbed by LAMP-2C ectopic expression. LAMP-2C levels modulated the steady-state expression of several cytoplasmic proteins that are targeted for degradation by CMA and diminished peptide translocation via this pathway. Thus, LAMP-2C serves as a natural inhibitor of CMA that can selectively skew MHCII presentation of cytoplasmic Ags.
    Keywords: Antigen Presentation -- Immunology ; Autophagy -- Immunology ; Histocompatibility Antigens Class II -- Immunology ; Lysosomal-Associated Membrane Protein 2 -- Immunology
    E-ISSN: 1550-6606
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 6
    Language: English
    In: Frontiers in Immunology, 01 September 2013, Vol.4
    Description: The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expressed in phagocytes is a multi-subunit enzyme complex that generates superoxide (O2.-). This radical is an important precursor of hydrogen peroxide (H2O2) and other reactive oxygen species (ROS) needed for microbicidal activity...
    Keywords: Antigen Presentation ; Autoimmunity ; Nadph Oxidase ; B Lymphocytes ; Chronic Granulomatous Disease ; Biology
    E-ISSN: 1664-3224
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  • 7
    In: Immunology, June 2017, Vol.151(2), pp.198-210
    Description: A major obstacle in predicting and preventing the development of autoimmune type 1 diabetes (T1D) in at‐risk individuals is the lack of well‐established early biomarkers indicative of ongoing beta cell stress during the pre‐clinical phase of disease. Recently, serum levels of the cytoplasmic isoform of heat‐shock protein 90 (hsp90) were shown to be elevated in individuals with new‐onset T1D. We therefore hypothesized that hsp90 could be released from beta cells in response to cellular stress and inflammation associated with the earliest stages of T1D. Here, human beta cell lines and cadaveric islets released hsp90 in response to stress induced by treatment with a combination of pro‐inflammatory cytokines including interleukin‐1, tumour necrosis factor‐ and interferon‐. Mechanistically, hsp90 release was found to be driven by cytokine‐induced endoplasmic reticulum stress mediated by c‐Jun N‐terminal kinase (JNK), a pathway that can eventually lead to beta cell apoptosis. Cytokine‐induced beta cell hsp90 release and JNK activation were significantly reduced by pre‐treating cells with the endoplasmic reticulum stress‐mitigating chemical chaperone tauroursodeoxycholic acid. The hsp90 release by cells may therefore be a sensitive indicator of stress during inflammation and a useful tool in assessing therapeutic mitigation of cytokine‐induced cell damage linked to autoimmunity. Exposure to pro‐inflammatory cytokines associated with type I diabetes can induce stress in pancreatic beta cells. Heat‐shock protein 90 (hsp90) is released by beta cells serving as a biomarker for cytokine stress. Disruption of c‐Jun N‐terminal kinase activation in beta cells blocks cytokine‐induced extracellular hsp90 release.
    Keywords: Endoplasmic Reticulum Stress ; Heat‐Shock Protein 90 ; Inflammation ; Jun N‐Terminal Kinase ; Type 1 Diabetes
    ISSN: 0019-2805
    E-ISSN: 1365-2567
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  • 8
    In: eLife, Vol.6
    Description: ADAR proteins alter gene expression both by catalyzing adenosine (A) to inosine (I) RNA editing and binding to regulatory elements in target RNAs. Loss of ADARs affects neuronal function in all animals studied to date. Caenorhabditis elegans lacking ADARs exhibit reduced chemotaxis, but the targets responsible for this phenotype remain unknown. To identify critical neural ADAR targets in C. elegans , we performed an unbiased assessment of the effects of ADR-2, the only A-to-I editing enzyme in C. elegans , on the neural transcriptome. Development and implementation of publicly available software, SAILOR, identified 7361 A-to-I editing events across the neural transcriptome. Intersecting the neural editome with adr-2 associated gene expression changes, revealed an edited mRNA, clec-41 , whose neural expression is dependent on deamination. Restoring clec-41 expression in adr-2 deficient neural cells rescued the chemotaxis defect, providing the first evidence that neuronal phenotypes of ADAR mutants can be caused by altered gene expression. eLife digest DNA is the blueprint that tells each cell in an organism how it should operate. It encodes the instructions to make proteins and other molecules. To make a protein, a section of DNA known as a gene is used as a template to make molecules known as messenger ribonucleic acids (or mRNAs for short). The message in RNA consists of a series of individual letters, known as nucleotides, that tell the cell how much of a protein should be produced (referred to as gene expression) as well as the specific activities of each protein. The letters in mRNAs can be changed in specific cells and at certain points in development through a process known as RNA editing. This process is essential for animals to grow and develop normally and for the brain to work properly. Errors in RNA editing are found in patients suffering from a variety of neuropathological diseases, including Alzheimer’s disease, depression and brain tumors. Humans have millions of editing sites that are predicted to affect gene expression. However, many studies of RNA editing have only focused on the changes that alter protein activity. The ADAR proteins carry out a specific type of RNA editing in animals. In a microscopic worm known as Caenorhabditis elegans the loss of an ADAR protein called ADR-2 reduces the ability of the worm to move in response to chemicals, a process known as chemotaxis. Deffit et al. found that loss of ADR-2 affected the expression of over 150 genes in the nervous system of the worm. To identify which letters in the mRNAs were edited in the nervous system, Deffit et al. developed a new publically available software program called SAILOR (software for accurately identifying locations of RNA editing). This program can be used to detect RNA editing in any cell, tissue or organism. By combining the experimental and computational approaches, Deffit et al. were able to identify a gene that was edited in normal worms and expressed at lower levels in the mutant worms. Increasing the expression of just this one of gene in the mutant worms restored the worms’ ability to move towards a chemical “scent”. Together, these findings suggest that when studying human neuropathological diseases we should consider the effect of RNA editing on the amount of gene expression as well as protein activity. Future work should investigate the importance of RNA editing in controlling gene expression in other diseases including cancers.
    Keywords: Research Article ; Chromosomes And Gene Expression ; Rna Editing ; Adar ; Gene Expression ; Rna Biology ; Post-Transcriptional Gene Regulation ; Inosine ; C. Elegans
    E-ISSN: 2050-084X
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  • 9
    In: Immunology, April 2014, Vol.141(4), pp.531-539
    Description: Vaccinia virus (VV) has been used globally as a vaccine to eradicate smallpox. Widespread use of this viral vaccine has been tempered in recent years because of its immuno‐evasive properties, with restrictions prohibiting VV inoculation of individuals with immune deficiencies or atopic skin diseases. VV infection is known to perturb several pathways for immune recognition including MHC class II (MHCII) and CD1d‐restricted antigen presentation. MHCII and CD1d molecules associate with a conserved intracellular chaperone, CD74, also known as invariant chain. Upon VV infection, cellular CD74 levels are significantly reduced in antigen‐presenting cells, consistent with the observed destabilization of MHCII molecules. In the current study, the ability of sustained CD74 expression to overcome VV‐induced suppression of antigen presentation was investigated. Viral inhibition of MHCII antigen presentation could be partially ameliorated by ectopic expression of CD74 or by infection of cells with a recombinant VV encoding murine CD74 (74‐VV). In contrast, virus‐induced disruptions in CD1d‐mediated antigen presentation persisted even with sustained CD74 expression. Mice immunized with the recombinant 74‐VV displayed greater protection during VV challenge and more robust anti‐VV antibody responses. Together, these observations suggest that recombinant VV vaccines encoding CD74 may be useful tools to improve CD4 T‐cell responses to viral and tumour antigens.
    Keywords: 74 ; Class ; Invariant Chain ; Mhc ; Virus
    ISSN: 0019-2805
    E-ISSN: 1365-2567
    Source: John Wiley & Sons, Inc.
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  • 10
    Language: English
    In: Cell Reports, 23 April 2019, Vol.27(4), pp.1244-1253.e4
    Description: A-to-I RNA editing, catalyzed by ADAR proteins, is widespread in eukaryotic transcriptomes. Studies showed that, in , ADR-2 can actively deaminate dsRNA, whereas ADR-1 cannot. Therefore, we set out to study the effect of each of the ADAR genes on the RNA editing process. We performed comprehensive phenotypic, transcriptomics, proteomics, and RNA binding screens on worms mutated in a single ADAR gene. We found that ADR-1 mutants exhibit more-severe phenotypes than ADR-2, and some of them are a result of non-editing functions of ADR-1. We also show that ADR-1 significantly binds edited genes and regulates mRNA expression, whereas the effect on protein levels is minor. In addition, ADR-1 primarily promotes editing by ADR-2 at the L4 stage of development. Our results suggest that ADR-1 has a significant role in the RNA editing process and in altering editing levels that affect RNA expression; loss of ADR-1 results in severe phenotypes. Ganem et al. report that the enzymatic-inactive ADR-1 regulates A-to-I RNA editing by directing editing by ADR-2, mainly at the L4 developmental stage. Changes in RNA editing levels severely affect normal development by changing RNA levels, but not protein levels.
    Keywords: Adar ; C. elegans ; Gene Expression ; Transcriptomics ; Organism Development ; Biology
    ISSN: 2211-1247
    E-ISSN: 2211-1247
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