Compensatory T-cell regulation in unaffected relatives of SLE patients, and opposite IL-2/CD25-mediated effects suggested by coreferentiality modeling.

In human systemic lupus erythematosus (SLE), diverse autoantibodies accumulate over years before disease manifestation. Unaffected relatives of SLE patients frequently share a sustained production of autoantibodies with indiscriminable specificity, usually without ever acquiring the disease. We stud...

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Autores principales:	Constantin Fesel, Marta Barreto, Ricardo C Ferreira, Nuno Costa, Lara L Venda, Clara Pereira, Claudia Carvalho, Maria Francisca Morães-Fontes, Carlos M Ferreira, Carlos Vasconcelos, João F Viana, Eugenia Santos, Berta Martins, Jocelyne Demengeot, Astrid M Vicente
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b57d91131cd641c2abb0d070e64828df
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spelling	oai:doaj.org-article:b57d91131cd641c2abb0d070e64828df2021-11-18T07:23:52ZCompensatory T-cell regulation in unaffected relatives of SLE patients, and opposite IL-2/CD25-mediated effects suggested by coreferentiality modeling.1932-620310.1371/journal.pone.0033992https://doaj.org/article/b57d91131cd641c2abb0d070e64828df2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22479496/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203In human systemic lupus erythematosus (SLE), diverse autoantibodies accumulate over years before disease manifestation. Unaffected relatives of SLE patients frequently share a sustained production of autoantibodies with indiscriminable specificity, usually without ever acquiring the disease. We studied relations of IgG autoantibody profiles and peripheral blood activated regulatory T-cells (aTregs), represented by CD4(+)CD25(bright) T-cells that were regularly 70-90% Foxp3(+). We found consistent positive correlations of broad-range as well as specific SLE-associated IgG with aTreg frequencies within unaffected relatives, but not patients or unrelated controls. Our interpretation: unaffected relatives with shared genetic factors compensated pathogenic effects by aTregs engaged in parallel with the individual autoantibody production. To study this further, we applied a novel analytic approach named coreferentiality that tests the indirect relatedness of parameters in respect to multivariate phenotype data. Results show that independently of their direct correlation, aTreg frequencies and specific SLE-associated IgG were likely functionally related in unaffected relatives: they significantly parallelled each other in their relations to broad-range immunoblot autoantibody profiles. In unaffected relatives, we also found coreferential effects of genetic variation in the loci encoding IL-2 and CD25. A model of CD25 functional genetic effects constructed by coreferentiality maximization suggests that IL-2-CD25 interaction, likely stimulating aTregs in unaffected relatives, had an opposed effect in SLE patients, presumably triggering primarily T-effector cells in this group. Coreferentiality modeling as we do it here could also be useful in other contexts, particularly to explore combined functional genetic effects.Constantin FeselMarta BarretoRicardo C FerreiraNuno CostaLara L VendaClara PereiraClaudia CarvalhoMaria Francisca Morães-FontesCarlos M FerreiraCarlos VasconcelosJoão F VianaEugenia SantosBerta MartinsJocelyne DemengeotAstrid M VicentePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 3, p e33992 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Constantin Fesel Marta Barreto Ricardo C Ferreira Nuno Costa Lara L Venda Clara Pereira Claudia Carvalho Maria Francisca Morães-Fontes Carlos M Ferreira Carlos Vasconcelos João F Viana Eugenia Santos Berta Martins Jocelyne Demengeot Astrid M Vicente Compensatory T-cell regulation in unaffected relatives of SLE patients, and opposite IL-2/CD25-mediated effects suggested by coreferentiality modeling.
description	In human systemic lupus erythematosus (SLE), diverse autoantibodies accumulate over years before disease manifestation. Unaffected relatives of SLE patients frequently share a sustained production of autoantibodies with indiscriminable specificity, usually without ever acquiring the disease. We studied relations of IgG autoantibody profiles and peripheral blood activated regulatory T-cells (aTregs), represented by CD4(+)CD25(bright) T-cells that were regularly 70-90% Foxp3(+). We found consistent positive correlations of broad-range as well as specific SLE-associated IgG with aTreg frequencies within unaffected relatives, but not patients or unrelated controls. Our interpretation: unaffected relatives with shared genetic factors compensated pathogenic effects by aTregs engaged in parallel with the individual autoantibody production. To study this further, we applied a novel analytic approach named coreferentiality that tests the indirect relatedness of parameters in respect to multivariate phenotype data. Results show that independently of their direct correlation, aTreg frequencies and specific SLE-associated IgG were likely functionally related in unaffected relatives: they significantly parallelled each other in their relations to broad-range immunoblot autoantibody profiles. In unaffected relatives, we also found coreferential effects of genetic variation in the loci encoding IL-2 and CD25. A model of CD25 functional genetic effects constructed by coreferentiality maximization suggests that IL-2-CD25 interaction, likely stimulating aTregs in unaffected relatives, had an opposed effect in SLE patients, presumably triggering primarily T-effector cells in this group. Coreferentiality modeling as we do it here could also be useful in other contexts, particularly to explore combined functional genetic effects.
format	article
author	Constantin Fesel Marta Barreto Ricardo C Ferreira Nuno Costa Lara L Venda Clara Pereira Claudia Carvalho Maria Francisca Morães-Fontes Carlos M Ferreira Carlos Vasconcelos João F Viana Eugenia Santos Berta Martins Jocelyne Demengeot Astrid M Vicente
author_facet	Constantin Fesel Marta Barreto Ricardo C Ferreira Nuno Costa Lara L Venda Clara Pereira Claudia Carvalho Maria Francisca Morães-Fontes Carlos M Ferreira Carlos Vasconcelos João F Viana Eugenia Santos Berta Martins Jocelyne Demengeot Astrid M Vicente
author_sort	Constantin Fesel
title	Compensatory T-cell regulation in unaffected relatives of SLE patients, and opposite IL-2/CD25-mediated effects suggested by coreferentiality modeling.
title_short	Compensatory T-cell regulation in unaffected relatives of SLE patients, and opposite IL-2/CD25-mediated effects suggested by coreferentiality modeling.
title_full	Compensatory T-cell regulation in unaffected relatives of SLE patients, and opposite IL-2/CD25-mediated effects suggested by coreferentiality modeling.
title_fullStr	Compensatory T-cell regulation in unaffected relatives of SLE patients, and opposite IL-2/CD25-mediated effects suggested by coreferentiality modeling.
title_full_unstemmed	Compensatory T-cell regulation in unaffected relatives of SLE patients, and opposite IL-2/CD25-mediated effects suggested by coreferentiality modeling.
title_sort	compensatory t-cell regulation in unaffected relatives of sle patients, and opposite il-2/cd25-mediated effects suggested by coreferentiality modeling.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/b57d91131cd641c2abb0d070e64828df
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Compensatory T-cell regulation in unaffected relatives of SLE patients, and opposite IL-2/CD25-mediated effects suggested by coreferentiality modeling.

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