| Suppression of dendritic cell activation by diabetes autoantigens linked to the cholera toxin B subunit. | |
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MedLine Citation:
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PMID: 20956025 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Antigen presenting cells, specifically dendritic cells (DCs) are a focal point in the delicate balance between T cell tolerance and immune responses contributing to the onset of type I diabetes (T1D). Weak adjuvant proteins like the cholera toxin B subunit when linked to autoantigens may sufficiently alter the balance of this initial immune response to suppress the development of autoimmunity. To assess adjuvant enhancement of autoantigen mediated immune suppression of Type 1 diabetes, we examined the cholera toxin B subunit (CTB)-proinsulin fusion protein (CTB-INS) activation of immature dendritic cells (iDC) at the earliest detectable stage of the human immune response. In this study, Incubation of human umbilical cord blood monocyte-derived immature DCs with CTB-INS autoantigen fusion protein increased the surface membrane expression of DC Toll-like receptor (TLR-2) while no significant upregulation in TLR-4 expression was detected. Inoculation of iDCs with CTB stimulated the biosynthesis of both CD86 and CD83 co-stimulatory factors demonstrating an immunostimulatory role for CTB in both DC activation and maturation. In contrast, incubation of iDCs with proinsulin partially suppressed CD86 co-stimulatory factor mediated DC activation, while incubation of iDCs with CTB-INS fusion protein completely suppressed iDC biosynthesis of both CD86 and CD83 costimulatory factors. The incubation of iDCs with increasing amounts of insulin did not increase the level of immune suppression but rather activated DC maturation by stimulating increased biosynthesis of both CD86 and CD83 costimulatory factors. Inoculation of iDCs with CTB-INS fusion protein dramatically increased secretion of the immunosuppressive cytokine IL-10 and suppressed synthesis of the pro-inflammatory cytokine IL12/23 p40 subunit protein suggesting that linkage of CTB to insulin (INS) may play an important role in mediating DC guidance of cognate naïve Th0 cell development into immunosuppressive T lymphocytes. Taken together, the experimental data suggests Toll like receptor 2 (TLR-2) plays a dominant role in CTB mediated INS inhibition of DC induced type 1 diabetes onset in human Type 1 diabetes autoimmunity. Further, fusion of CTB to the autoantigen was found to be essential for enhancement of immune suppression as co-delivery of CTB and insulin did not significantly inhibit DC costimulatory factor biosynthesis. The experimental data presented supports the hypotheses that adjuvant enhancement of autoantigen mediated suppression of islet beta cell inflammation is dependent on CTB stimulation of dendritic cell TLR2 receptor activation and co-processing of both CTB and the autoantigen in the same dendritic cell. |
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Authors:
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Oludare Odumosu; Kimberly Payne; Ineavely Baez; Jessica Jutzy; Nathan Wall; William Langridge |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-09-24 |
Journal Detail:
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Title: Immunobiology Volume: 216 ISSN: 1878-3279 ISO Abbreviation: Immunobiology Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-03-07 Completed Date: 2011-09-26 Revised Date: 2012-04-04 |
Medline Journal Info:
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Nlm Unique ID: 8002742 Medline TA: Immunobiology Country: Netherlands |
Other Details:
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Languages: eng Pagination: 447-56 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier GmbH. All rights reserved. |
Affiliation:
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Department of Biochemistry, Center for Health Disparities and Molecular Medicine, Loma Linda University, School of Medicine, Loma Linda, CA 92354, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Autoantigens
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genetics,
immunology,
pharmacology* Cells, Cultured Cholera Toxin / genetics, immunology, pharmacology* Dendritic Cells / drug effects*, immunology Gene Order Humans Immunosuppression Immunosuppressive Agents / pharmacology* Interleukin-10 / metabolism Proinsulin / genetics, immunology, pharmacology* Recombinant Fusion Proteins / genetics, immunology, metabolism, pharmacology* Toll-Like Receptor 2 / metabolism Up-Regulation / drug effects* |
| Grant Support | |
ID/Acronym/Agency:
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R21 DK-99-013/DK/NIDDK NIH HHS; R21 DK057206-02/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Autoantigens; 0/Immunosuppressive Agents; 0/Recombinant Fusion Proteins; 0/TLR2 protein, human; 0/Toll-Like Receptor 2; 130068-27-8/Interleukin-10; 9012-63-9/Cholera Toxin; 9035-68-1/Proinsulin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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