Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.7/638
Título: Compensatory T-Cell Regulation in Unaffected Relatives of SLE Patients, and Opposite IL-2/CD25-Mediated Effects Suggested by Coreferentiality Modeling
Autor: Fesel, Constantin
Barreto, Marta
Ferreira, Ricardo C.
Costa, Nuno
Venda, Lara L.
Pereira, Clara
Carvalho, Claudia
Morães-Fontes, Maria Francisca
Ferreira, Carlos M.
Vasconcelos, Carlos
Viana, João F.
Santos, Eugenia
Martins, Berta
Demengeot, Jocelyne
Vicente, Astrid M.
Palavras-chave: Adolescent
CD4 Lymphocyte Count
Immunoglobulin G
Interleukin-2 Receptor alpha Subunit
Lupus Erythematosus, Systemic
Middle Aged
Protein Binding
T-Lymphocytes, Regulatory
Young Adult
Models, Immunological
Data: 29-Mar-2012
Editora: PLOS
Citação: Fesel C, Barreto M, Ferreira RC, Costa N, Venda LL, et al. (2012) Compensatory T-Cell Regulation in Unaffected Relatives of SLE Patients, and Opposite IL- 2/CD25-Mediated Effects Suggested by Coreferentiality Modeling. PLoS ONE 7(3): e33992. doi:10.1371/journal.pone.0033992
Resumo: 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.
Peer review: yes
URI: http://hdl.handle.net/10400.7/638
DOI: 10.1371/journal.pone.0033992
Versão do Editor: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033992
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Fesel_PlosOne.(2012).PDFmain article1,02 MBAdobe PDFVer/Abrir
Fesel_PlosOne.(2012)_SM_Table_S1.pdfsupplementary materials 131,36 kBAdobe PDFVer/Abrir
Fesel_PlosOne.(201)_SM_Figure_S2.pdf2supplementary materials 245,78 kBAdobe PDFVer/Abrir
Fesel_PlosOne.(2012)_SM_Figure_S3.pdfsupplementary materials 3261,21 kBAdobe PDFVer/Abrir
Fesel_PlosOne.(2012)_SM_Table_S1.pdfsupplementary materials 431,36 kBAdobe PDFVer/Abrir

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