Proteolytic Cleavage of a Self-Antigen Following Xenobiotic-Induced Cell Death Produces a Fragment with Novel Immunogenic Properties

The heavy metal mercury elicits a genetically restricted autoantibody response in mice that targets the nucleolar autoantigen fibrillarin. HgCl2-induced cell death of macrophages resulted in the proteolytic cleavage of fibrillarin. A prominent feature of mercury-induced cell death was the generation...

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Veröffentlicht in:The Journal of immunology (1950) 2000-08, Vol.165 (4), p.2263-2270
Hauptverfasser: Pollard, K. Michael, Pearson, Deborah L, Bluthner, Martin, Tan, Eng M
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container_title The Journal of immunology (1950)
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creator Pollard, K. Michael
Pearson, Deborah L
Bluthner, Martin
Tan, Eng M
description The heavy metal mercury elicits a genetically restricted autoantibody response in mice that targets the nucleolar autoantigen fibrillarin. HgCl2-induced cell death of macrophages resulted in the proteolytic cleavage of fibrillarin. A prominent feature of mercury-induced cell death was the generation of a 19-kDa fragment of fibrillarin that was not found following apoptotic or nonapoptotic cell death induced by stimuli other than mercury. Proteolysis of fibrillarin lacking cysteines, and therefore unable to bind mercury, also produced the 19-kDa fragment, suggesting that a mercury-fibrillarin interaction was not necessary for the unique cleavage pattern of this self-Ag. In contrast to immunization with full-length fibrillarin, the 19-kDa fragment produced anti-fibrillarin Abs with some of the properties of the HgCl2-induced anti-fibrillarin response. We propose that cell death following exposure to an autoimmunity-inducing xenobiotic can lead to the generation of novel protein fragments that may serve as sources of antigenic determinants for self-reactive T lymphocytes.
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In contrast to immunization with full-length fibrillarin, the 19-kDa fragment produced anti-fibrillarin Abs with some of the properties of the HgCl2-induced anti-fibrillarin response. 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Michael</creatorcontrib><creatorcontrib>Pearson, Deborah L</creatorcontrib><creatorcontrib>Bluthner, Martin</creatorcontrib><creatorcontrib>Tan, Eng M</creatorcontrib><title>Proteolytic Cleavage of a Self-Antigen Following Xenobiotic-Induced Cell Death Produces a Fragment with Novel Immunogenic Properties</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>The heavy metal mercury elicits a genetically restricted autoantibody response in mice that targets the nucleolar autoantigen fibrillarin. HgCl2-induced cell death of macrophages resulted in the proteolytic cleavage of fibrillarin. A prominent feature of mercury-induced cell death was the generation of a 19-kDa fragment of fibrillarin that was not found following apoptotic or nonapoptotic cell death induced by stimuli other than mercury. Proteolysis of fibrillarin lacking cysteines, and therefore unable to bind mercury, also produced the 19-kDa fragment, suggesting that a mercury-fibrillarin interaction was not necessary for the unique cleavage pattern of this self-Ag. In contrast to immunization with full-length fibrillarin, the 19-kDa fragment produced anti-fibrillarin Abs with some of the properties of the HgCl2-induced anti-fibrillarin response. We propose that cell death following exposure to an autoimmunity-inducing xenobiotic can lead to the generation of novel protein fragments that may serve as sources of antigenic determinants for self-reactive T lymphocytes.</description><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Apoptosis - immunology</subject><subject>Autoantibodies - biosynthesis</subject><subject>Autoantigens - administration &amp; dosage</subject><subject>Autoantigens - genetics</subject><subject>Autoantigens - immunology</subject><subject>Autoantigens - metabolism</subject><subject>Cell Line</subject><subject>Chromosomal Proteins, Non-Histone - administration &amp; dosage</subject><subject>Chromosomal Proteins, Non-Histone - genetics</subject><subject>Chromosomal Proteins, Non-Histone - immunology</subject><subject>Chromosomal Proteins, Non-Histone - metabolism</subject><subject>fibrillarin</subject><subject>Hydrolysis</subject><subject>Injections, Subcutaneous</subject><subject>Macrophages - cytology</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - immunology</subject><subject>Macrophages - metabolism</subject><subject>Mercuric Chloride - pharmacology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Molecular Weight</subject><subject>Mutagenesis, Site-Directed</subject><subject>Peptide Fragments - administration &amp; dosage</subject><subject>Peptide Fragments - biosynthesis</subject><subject>Peptide Fragments - genetics</subject><subject>Peptide Fragments - immunology</subject><subject>Xenobiotics - pharmacology</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkM1u1DAURi1ERYfCEyAhr2CV4Tr-CV5WUwZGqmglQGJnOclNxpUTD3bSqPs-OB6mSF1Zss_3-d5DyDsGawFCf7pzwzCPwa-ZkmuxLkvFX5AVkxIKpUC9JCuAsixYpapz8jqlOwBQUIpX5JyBLiVnckUeb2OYMPiHyTV049He2x5p6KilP9B3xeU4uR5Hug3eh8WNPf2NY6hdyHyxG9u5wZZu0Ht6hXba01x3vEs5v422H3Cc6OLyw_dwj57u_o2cC_NvGT1gnBymN-Sssz7h26fzgvzafvm5-VZc33zdbS6vi0aAnoqu4Y2sgbdc15-trlu0supEU9cdbytQGpS0ef-uFApEV4O2ClALK5BrxhW_IB9OvYcY_syYJjO41OTh7YhhToZVUvGKywzyE9jEkFLEzhyiG2x8MAzMUb75L99k-UaYo_ycev9UP9cDts8yJ9sZ-HgC9q7fLy6iSYP1PuPMLMvyrOovt4iSHQ</recordid><startdate>20000815</startdate><enddate>20000815</enddate><creator>Pollard, K. 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subjects Animals
Apoptosis - drug effects
Apoptosis - genetics
Apoptosis - immunology
Autoantibodies - biosynthesis
Autoantigens - administration & dosage
Autoantigens - genetics
Autoantigens - immunology
Autoantigens - metabolism
Cell Line
Chromosomal Proteins, Non-Histone - administration & dosage
Chromosomal Proteins, Non-Histone - genetics
Chromosomal Proteins, Non-Histone - immunology
Chromosomal Proteins, Non-Histone - metabolism
fibrillarin
Hydrolysis
Injections, Subcutaneous
Macrophages - cytology
Macrophages - drug effects
Macrophages - immunology
Macrophages - metabolism
Mercuric Chloride - pharmacology
Mice
Mice, Inbred C57BL
Molecular Weight
Mutagenesis, Site-Directed
Peptide Fragments - administration & dosage
Peptide Fragments - biosynthesis
Peptide Fragments - genetics
Peptide Fragments - immunology
Xenobiotics - pharmacology
title Proteolytic Cleavage of a Self-Antigen Following Xenobiotic-Induced Cell Death Produces a Fragment with Novel Immunogenic Properties
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