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Thyroid Autoantibodies Display both “Original Antigenic Sin” and Epitope Spreading
Evidence for original antigenic sin in spontaneous thyroid autoimmunity is revealed by autoantibody interactions with immunodominant regions on thyroid autoantigens, thyroglobulin (Tg), thyroid peroxidase (TPO), and the thyrotropin receptor (TSHR) A-subunit. In contrast, antibodies induced by immuni...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2017
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742354/ https://www.ncbi.nlm.nih.gov/pubmed/29326719 http://dx.doi.org/10.3389/fimmu.2017.01845 |
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author | McLachlan, Sandra M. Rapoport, Basil |
author_facet | McLachlan, Sandra M. Rapoport, Basil |
author_sort | McLachlan, Sandra M. |
collection | PubMed |
description | Evidence for original antigenic sin in spontaneous thyroid autoimmunity is revealed by autoantibody interactions with immunodominant regions on thyroid autoantigens, thyroglobulin (Tg), thyroid peroxidase (TPO), and the thyrotropin receptor (TSHR) A-subunit. In contrast, antibodies induced by immunization of rabbits or mice recognize diverse epitopes. Recognition of immunodominant regions persists despite fluctuations in autoantibody levels following treatment or over time. The enhancement of spontaneously arising pathogenic TSHR antibodies in transgenic human thyrotropin receptor/NOD.H2(h4) mice by injecting a non-pathogenic form of TSHR A-subunit protein also provides evidence for original antigenic sin. From other studies, antigen presentation by B cells, not dendritic cells, is likely responsible for original antigenic sin. Recognition of restricted epitopes on the large glycosylated thyroid autoantigens (60-kDa A-subunit, 100-kDa TPO, and 600-kDa Tg) facilitates exploring the amino acid locations in the immunodominant regions. Epitope spreading has also been revealed by autoantibodies in thyroid autoimmunity. In humans, and in mice that spontaneously develop autoimmunity to all three thyroid autoantigens, autoantibodies develop first to Tg and later to TPO and the TSHR A-subunit. The pattern of intermolecular epitope spreading is related in part to the thyroidal content of Tg, TPO and TSHR A-subunit and to the molecular sizes of these proteins. Importantly, the epitope spreading pattern provides a rationale for future antigen-specific manipulation to block the development of all thyroid autoantibodies by inducing tolerance to Tg, first in the autoantigen cascade. Because of its abundance, Tg may be the autoantigen of choice to explore antigen-specific treatment, preventing the development of pathogenic TSHR antibodies. |
format | Online Article Text |
id | pubmed-5742354 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-57423542018-01-11 Thyroid Autoantibodies Display both “Original Antigenic Sin” and Epitope Spreading McLachlan, Sandra M. Rapoport, Basil Front Immunol Immunology Evidence for original antigenic sin in spontaneous thyroid autoimmunity is revealed by autoantibody interactions with immunodominant regions on thyroid autoantigens, thyroglobulin (Tg), thyroid peroxidase (TPO), and the thyrotropin receptor (TSHR) A-subunit. In contrast, antibodies induced by immunization of rabbits or mice recognize diverse epitopes. Recognition of immunodominant regions persists despite fluctuations in autoantibody levels following treatment or over time. The enhancement of spontaneously arising pathogenic TSHR antibodies in transgenic human thyrotropin receptor/NOD.H2(h4) mice by injecting a non-pathogenic form of TSHR A-subunit protein also provides evidence for original antigenic sin. From other studies, antigen presentation by B cells, not dendritic cells, is likely responsible for original antigenic sin. Recognition of restricted epitopes on the large glycosylated thyroid autoantigens (60-kDa A-subunit, 100-kDa TPO, and 600-kDa Tg) facilitates exploring the amino acid locations in the immunodominant regions. Epitope spreading has also been revealed by autoantibodies in thyroid autoimmunity. In humans, and in mice that spontaneously develop autoimmunity to all three thyroid autoantigens, autoantibodies develop first to Tg and later to TPO and the TSHR A-subunit. The pattern of intermolecular epitope spreading is related in part to the thyroidal content of Tg, TPO and TSHR A-subunit and to the molecular sizes of these proteins. Importantly, the epitope spreading pattern provides a rationale for future antigen-specific manipulation to block the development of all thyroid autoantibodies by inducing tolerance to Tg, first in the autoantigen cascade. Because of its abundance, Tg may be the autoantigen of choice to explore antigen-specific treatment, preventing the development of pathogenic TSHR antibodies. Frontiers Media S.A. 2017-12-20 /pmc/articles/PMC5742354/ /pubmed/29326719 http://dx.doi.org/10.3389/fimmu.2017.01845 Text en Copyright © 2017 McLachlan and Rapoport. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology McLachlan, Sandra M. Rapoport, Basil Thyroid Autoantibodies Display both “Original Antigenic Sin” and Epitope Spreading |
title | Thyroid Autoantibodies Display both “Original Antigenic Sin” and Epitope Spreading |
title_full | Thyroid Autoantibodies Display both “Original Antigenic Sin” and Epitope Spreading |
title_fullStr | Thyroid Autoantibodies Display both “Original Antigenic Sin” and Epitope Spreading |
title_full_unstemmed | Thyroid Autoantibodies Display both “Original Antigenic Sin” and Epitope Spreading |
title_short | Thyroid Autoantibodies Display both “Original Antigenic Sin” and Epitope Spreading |
title_sort | thyroid autoantibodies display both “original antigenic sin” and epitope spreading |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742354/ https://www.ncbi.nlm.nih.gov/pubmed/29326719 http://dx.doi.org/10.3389/fimmu.2017.01845 |
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