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High Pathogenic Potential of Low-Affinity Autoantibodies in Experimental Autoimmune Hemolytic Anemia

To assess the potency of low-affinity anti–red blood cell (RBC) autoantibodies in the induction of anemia, we generated an immunoglobulin (Ig)G2a class-switch variant of a 4C8 IgM anti–mouse RBC autoantibody, and compared its pathogenic potential with that of its IgM isotype and a high-affinity 34-3...

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Autores principales: Fossati-Jimack, Liliane, Reininger, Luc, Chicheportiche, Yves, Clynes, Raphael, Ravetch, Jeffrey V., Honjo, Tasuku, Izui, Shozo
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 1999
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2195740/
https://www.ncbi.nlm.nih.gov/pubmed/10587359
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author Fossati-Jimack, Liliane
Reininger, Luc
Chicheportiche, Yves
Clynes, Raphael
Ravetch, Jeffrey V.
Honjo, Tasuku
Izui, Shozo
author_facet Fossati-Jimack, Liliane
Reininger, Luc
Chicheportiche, Yves
Clynes, Raphael
Ravetch, Jeffrey V.
Honjo, Tasuku
Izui, Shozo
author_sort Fossati-Jimack, Liliane
collection PubMed
description To assess the potency of low-affinity anti–red blood cell (RBC) autoantibodies in the induction of anemia, we generated an immunoglobulin (Ig)G2a class-switch variant of a 4C8 IgM anti–mouse RBC autoantibody, and compared its pathogenic potential with that of its IgM isotype and a high-affinity 34-3C IgG2a autoantibody. The RBC-binding activity of the 4C8 IgG2a variant was barely detectable, at least 1,000 times lower than that of its IgM isotype, having a high-binding avidity, and that of the 34-3C IgG2a monoclonal antibody (mAb). This low-affinity feature of the 4C8 mAb was consistent with the lack of detection of opsonized RBCs in the circulating blood from the 4C8 IgG2a–injected mice. However, the 4C8 IgG2a variant was highly pathogenic, as potent as its IgM isotype and the 34-3C IgG2a mAb, due to its capacity to interact with Fc receptors involved in erythrophagocytosis. In addition, our results indicated that the pentameric form of the low-affinity IgM isotype, by promoting the binding and agglutination of RBCs, is critical for its pathogenic activity. Demonstration of the remarkably high pathogenic potency of low-affinity autoantibodies, if combined with appropriate heavy chain effector functions, highlights the critical role of the Ig heavy chain constant regions, but the relatively minor role of autoantigen-binding affinities, in autoimmune hemolytic anemia.
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spelling pubmed-21957402008-04-16 High Pathogenic Potential of Low-Affinity Autoantibodies in Experimental Autoimmune Hemolytic Anemia Fossati-Jimack, Liliane Reininger, Luc Chicheportiche, Yves Clynes, Raphael Ravetch, Jeffrey V. Honjo, Tasuku Izui, Shozo J Exp Med Original Article To assess the potency of low-affinity anti–red blood cell (RBC) autoantibodies in the induction of anemia, we generated an immunoglobulin (Ig)G2a class-switch variant of a 4C8 IgM anti–mouse RBC autoantibody, and compared its pathogenic potential with that of its IgM isotype and a high-affinity 34-3C IgG2a autoantibody. The RBC-binding activity of the 4C8 IgG2a variant was barely detectable, at least 1,000 times lower than that of its IgM isotype, having a high-binding avidity, and that of the 34-3C IgG2a monoclonal antibody (mAb). This low-affinity feature of the 4C8 mAb was consistent with the lack of detection of opsonized RBCs in the circulating blood from the 4C8 IgG2a–injected mice. However, the 4C8 IgG2a variant was highly pathogenic, as potent as its IgM isotype and the 34-3C IgG2a mAb, due to its capacity to interact with Fc receptors involved in erythrophagocytosis. In addition, our results indicated that the pentameric form of the low-affinity IgM isotype, by promoting the binding and agglutination of RBCs, is critical for its pathogenic activity. Demonstration of the remarkably high pathogenic potency of low-affinity autoantibodies, if combined with appropriate heavy chain effector functions, highlights the critical role of the Ig heavy chain constant regions, but the relatively minor role of autoantigen-binding affinities, in autoimmune hemolytic anemia. The Rockefeller University Press 1999-12-06 /pmc/articles/PMC2195740/ /pubmed/10587359 Text en © 1999 The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Original Article
Fossati-Jimack, Liliane
Reininger, Luc
Chicheportiche, Yves
Clynes, Raphael
Ravetch, Jeffrey V.
Honjo, Tasuku
Izui, Shozo
High Pathogenic Potential of Low-Affinity Autoantibodies in Experimental Autoimmune Hemolytic Anemia
title High Pathogenic Potential of Low-Affinity Autoantibodies in Experimental Autoimmune Hemolytic Anemia
title_full High Pathogenic Potential of Low-Affinity Autoantibodies in Experimental Autoimmune Hemolytic Anemia
title_fullStr High Pathogenic Potential of Low-Affinity Autoantibodies in Experimental Autoimmune Hemolytic Anemia
title_full_unstemmed High Pathogenic Potential of Low-Affinity Autoantibodies in Experimental Autoimmune Hemolytic Anemia
title_short High Pathogenic Potential of Low-Affinity Autoantibodies in Experimental Autoimmune Hemolytic Anemia
title_sort high pathogenic potential of low-affinity autoantibodies in experimental autoimmune hemolytic anemia
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2195740/
https://www.ncbi.nlm.nih.gov/pubmed/10587359
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