| Cells that produce deleterious autoreactive antibodies are vulnerable to suicide. | |
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MedLine Citation:
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PMID: 18641365 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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It is puzzling how autoreactive B cells that escape self-tolerance mechanisms manage to produce Abs that target vital cellular processes without succumbing themselves to the potentially deleterious effects of these proteins. We report that censorship indeed exists at this level: when the Ab synthesis in the cell is up-regulated in IL-6-enriched environments (e.g., adjuvant-primed mouse peritoneum), the cell dies of the increased intracellular binding between the Ab and the cellular autoantigen. In the case in which telomerase is the autoantigen, mouse hybridoma cells synthesizing such an autoantibody, which appeared to grow well in culture, could not grow in syngeneic BALB/c mice to form ascites, but grew nevertheless in athymic siblings. Culture experiments demonstrated that peritoneal cell-derived IL-6 (and accessory factors) affected the growth and functions of the hybridoma cells, including the induction of mitochondria-based apoptosis. Electron microscopy revealed an abundance of Abs in the nuclear chromatin of IL-6-stimulated cells, presumably piggy-backed there by telomerase from the cytosol. This nuclear presence was confirmed by light microscopy analysis of isolated nuclei. In two other cases, hybridoma cells synthesizing an autoantibody to GTP or osteopontin also showed similar growth inhibition in vivo. In all cases, Ab function was crucial to the demise of the cells. Thus, autoreactive cells, which synthesize autoantibodies to certain intracellular Ags, live delicately between life and death depending on the cytokine microenvironment. Paradoxically, IL-6, which is normally growth-potentiating for B cells, is proapoptotic for these cells. The findings reveal potential strategies and targets for immunotherapy. |
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Authors:
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Haitao Niu; Danny T M Leung; Chun Hung Ma; Eric C Y Law; Frankie C H Tam; Pak-Leong Lim |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 181 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2008-07-21 Completed Date: 2008-08-19 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 2246-57 Citation Subset: AIM; IM |
Affiliation:
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Clinical Immunology Unit, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibody Specificity / immunology Apoptosis / drug effects, immunology* Ascites / genetics, immunology Autoantibodies / biosynthesis*, genetics, immunology*, metabolism B-Lymphocytes / immunology*, pathology* Base Sequence Cell Nucleus / immunology, metabolism Cells, Cultured Humans Hybridomas Immunoglobulin G / immunology Immunoglobulin M / immunology Interleukin-6 / pharmacology Mice Microscopy, Immunoelectron Mitochondria / immunology, metabolism Molecular Sequence Data Telomerase / immunology, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Autoantibodies; 0/Immunoglobulin G; 0/Immunoglobulin M; 0/Interleukin-6; EC 2.7.7.49/Telomerase |
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