Javier Rodríguez-Carrio1, Mercedes Alperi-López2, Patricia López1, Sara Alonso-Castro2, Francisco J Ballina-García2, Ana Suárez3. 1. Area of Immunology, Departament of Functional Biology, University of Oviedo, Asturias, Spain. 2. Department of Rheumatology, Hospital Universitario Central de Asturias, Asturias, Spain. 3. Area of Immunology, Departament of Functional Biology, University of Oviedo, Asturias, Spain. Electronic address: anasua@uniovi.es.
Abstract
BACKGROUND: Expansion of CD4(+)CD28(null), a common feature of immunosenescence, which has been reported in rheumatoid arthritis (RA) patients, may also be associated with a CD4(+) imbalance. Although the increase of CD4(+)CD28(null) cells has been related to TNFα exposure, nothing is known about the possible role of genetic variants of this cytokine. METHODS: Participants were genotyped for TNFA rs1800629 (-308 G>A) and frequency of the CD4(+)CD28(null), regulatory T cells and Th1 cells subsets were quantified in peripheral blood samples by flow cytometry in 129 RA patients and 33 healthy controls. RESULTS: The expansion of CD4(+)CD28(null) cells in RA patients was associated with TNFA genotype, even at diagnosis, and linked to markers of aggressive disease in patient carriers of the minor allele. Analysis of regulatory T cells and IFNγ-CD4(+) expression suggested that defective suppression and/or Th1-shift could underlie the expansion of this population in these patients. Finally, although treatment with TNFα-blockers reduced CD4(+)CD28(null) cells in most patients, only those carriers of the common GG genotype reached values within the range of HC and showed a disease activity improvement correlated to this decrease. CONCLUSIONS: Our results provide evidence for a genetic basis of the premature immunosenescence of RA patients and highlight its potential role in clinical outcome after TNFα blockade.
BACKGROUND: Expansion of CD4(+)CD28(null), a common feature of immunosenescence, which has been reported in rheumatoid arthritis (RA) patients, may also be associated with a CD4(+) imbalance. Although the increase of CD4(+)CD28(null) cells has been related to TNFα exposure, nothing is known about the possible role of genetic variants of this cytokine. METHODS:Participants were genotyped for TNFArs1800629 (-308 G>A) and frequency of the CD4(+)CD28(null), regulatory T cells and Th1 cells subsets were quantified in peripheral blood samples by flow cytometry in 129 RApatients and 33 healthy controls. RESULTS: The expansion of CD4(+)CD28(null) cells in RApatients was associated with TNFA genotype, even at diagnosis, and linked to markers of aggressive disease in patient carriers of the minor allele. Analysis of regulatory T cells and IFNγ-CD4(+) expression suggested that defective suppression and/or Th1-shift could underlie the expansion of this population in these patients. Finally, although treatment with TNFα-blockers reduced CD4(+)CD28(null) cells in most patients, only those carriers of the common GG genotype reached values within the range of HC and showed a disease activity improvement correlated to this decrease. CONCLUSIONS: Our results provide evidence for a genetic basis of the premature immunosenescence of RApatients and highlight its potential role in clinical outcome after TNFα blockade.
Authors: Javier Rodríguez-Carrio; Mercedes Alperi-López; Patricia López; Francisco Javier Ballina-García; Ana Suárez Journal: PLoS One Date: 2016-08-03 Impact factor: 3.240