Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: McLachlan, Sandra M., Rapoport, Basil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
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
_version_ 1783288357125619712
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
work_keys_str_mv AT mclachlansandram thyroidautoantibodiesdisplaybothoriginalantigenicsinandepitopespreading
AT rapoportbasil thyroidautoantibodiesdisplaybothoriginalantigenicsinandepitopespreading