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Selective Silencing of Disease-Associated B Lymphocytes from Hashimoto’s Thyroiditis Patients by Chimeric Protein Molecules

Hashimoto’s thyroiditis is one of the most common endocrine disorders, affecting up to 20% of the adult population. No treatment or prevention exists except hormonal substitution for hypothyroidism. We hypothesize that it may be possible to selectively suppress anti-thyroglobulin (Tg) IgG antibody-p...

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Autores principales: Ralchev, Nikola Ralchev, Markovski, Aleksandar Mishel, Yankova, Inna Angelova, Manoylov, Iliyan Konstantinov, Doytchinova, Irini Atanas, Mihaylova, Nikolina Mihaylova, Shinkov, Alexander Dimitrov, Tchorbanov, Andrey Ivanov
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9738561/
https://www.ncbi.nlm.nih.gov/pubmed/36499407
http://dx.doi.org/10.3390/ijms232315083
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author Ralchev, Nikola Ralchev
Markovski, Aleksandar Mishel
Yankova, Inna Angelova
Manoylov, Iliyan Konstantinov
Doytchinova, Irini Atanas
Mihaylova, Nikolina Mihaylova
Shinkov, Alexander Dimitrov
Tchorbanov, Andrey Ivanov
author_facet Ralchev, Nikola Ralchev
Markovski, Aleksandar Mishel
Yankova, Inna Angelova
Manoylov, Iliyan Konstantinov
Doytchinova, Irini Atanas
Mihaylova, Nikolina Mihaylova
Shinkov, Alexander Dimitrov
Tchorbanov, Andrey Ivanov
author_sort Ralchev, Nikola Ralchev
collection PubMed
description Hashimoto’s thyroiditis is one of the most common endocrine disorders, affecting up to 20% of the adult population. No treatment or prevention exists except hormonal substitution for hypothyroidism. We hypothesize that it may be possible to selectively suppress anti-thyroglobulin (Tg) IgG antibody-producing B lymphocytes from HT patients by a chimeric protein molecule containing a monoclonal antibody specific for the human inhibitory receptor CR1, coupled to peptide epitopes derived from Tg protein. We expect that this treatment will down-regulate B-cell autoreactivity by delivering a strong inhibitory signal. Three peptides—two epitope-predicted ones derived from Tg and another irrelevant peptide—were synthesized and then coupled with monoclonal anti-human CR1 antibody to construct three chimeric molecules. The binding to CD35 on human B cells and the effects of the chimeric constructs on PBMC and TMC from patients with HT were tested using flow cytometry, ELISpot assay, and immunoenzyme methods. We found that after the chemical conjugation, all chimeras retained their receptor-binding capacity, and the Tg epitopes could be recognized by anti-Tg autoantibodies in the patients’ sera. This treatment downregulated B-cell autoreactivity and cell proliferation, inhibited Tg-specific B-cell differentiation to plasmablasts and promoted apoptosis to the targeted cells. The treatment of PBMCs from HT patients with Tg-epitope-carrying chimeric molecules affects the activity of Tg-specific autoreactive B lymphocytes, delivering to them a strong suppressive signal.
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spelling pubmed-97385612022-12-11 Selective Silencing of Disease-Associated B Lymphocytes from Hashimoto’s Thyroiditis Patients by Chimeric Protein Molecules Ralchev, Nikola Ralchev Markovski, Aleksandar Mishel Yankova, Inna Angelova Manoylov, Iliyan Konstantinov Doytchinova, Irini Atanas Mihaylova, Nikolina Mihaylova Shinkov, Alexander Dimitrov Tchorbanov, Andrey Ivanov Int J Mol Sci Article Hashimoto’s thyroiditis is one of the most common endocrine disorders, affecting up to 20% of the adult population. No treatment or prevention exists except hormonal substitution for hypothyroidism. We hypothesize that it may be possible to selectively suppress anti-thyroglobulin (Tg) IgG antibody-producing B lymphocytes from HT patients by a chimeric protein molecule containing a monoclonal antibody specific for the human inhibitory receptor CR1, coupled to peptide epitopes derived from Tg protein. We expect that this treatment will down-regulate B-cell autoreactivity by delivering a strong inhibitory signal. Three peptides—two epitope-predicted ones derived from Tg and another irrelevant peptide—were synthesized and then coupled with monoclonal anti-human CR1 antibody to construct three chimeric molecules. The binding to CD35 on human B cells and the effects of the chimeric constructs on PBMC and TMC from patients with HT were tested using flow cytometry, ELISpot assay, and immunoenzyme methods. We found that after the chemical conjugation, all chimeras retained their receptor-binding capacity, and the Tg epitopes could be recognized by anti-Tg autoantibodies in the patients’ sera. This treatment downregulated B-cell autoreactivity and cell proliferation, inhibited Tg-specific B-cell differentiation to plasmablasts and promoted apoptosis to the targeted cells. The treatment of PBMCs from HT patients with Tg-epitope-carrying chimeric molecules affects the activity of Tg-specific autoreactive B lymphocytes, delivering to them a strong suppressive signal. MDPI 2022-12-01 /pmc/articles/PMC9738561/ /pubmed/36499407 http://dx.doi.org/10.3390/ijms232315083 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ralchev, Nikola Ralchev
Markovski, Aleksandar Mishel
Yankova, Inna Angelova
Manoylov, Iliyan Konstantinov
Doytchinova, Irini Atanas
Mihaylova, Nikolina Mihaylova
Shinkov, Alexander Dimitrov
Tchorbanov, Andrey Ivanov
Selective Silencing of Disease-Associated B Lymphocytes from Hashimoto’s Thyroiditis Patients by Chimeric Protein Molecules
title Selective Silencing of Disease-Associated B Lymphocytes from Hashimoto’s Thyroiditis Patients by Chimeric Protein Molecules
title_full Selective Silencing of Disease-Associated B Lymphocytes from Hashimoto’s Thyroiditis Patients by Chimeric Protein Molecules
title_fullStr Selective Silencing of Disease-Associated B Lymphocytes from Hashimoto’s Thyroiditis Patients by Chimeric Protein Molecules
title_full_unstemmed Selective Silencing of Disease-Associated B Lymphocytes from Hashimoto’s Thyroiditis Patients by Chimeric Protein Molecules
title_short Selective Silencing of Disease-Associated B Lymphocytes from Hashimoto’s Thyroiditis Patients by Chimeric Protein Molecules
title_sort selective silencing of disease-associated b lymphocytes from hashimoto’s thyroiditis patients by chimeric protein molecules
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9738561/
https://www.ncbi.nlm.nih.gov/pubmed/36499407
http://dx.doi.org/10.3390/ijms232315083
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