Abstract
The study examined sex-specificities in age-related changes in BALB/c mice IgG antibody responses to immunisation with trivalent inactivated split-virus influenza bulk. Aging diminished the total serum IgG antibody responses to H1N1 and H3N2 and B influenza virus antigens in mice of both sexes, but they remained greater in aged females. This sex difference in aged mice correlated with the greater post-immunisation increase in the frequency of spleen germinal centre (GC) B cells and more favourable T follicular regulatory (Tfr)/GC B cell ratio, as Tfr cells are suggested to control antibody production through suppression of glycolysis. The greater post-immunisation GC B cell response in aged females compared with males correlated with the greater proliferation of B cells and CD4+ cells in splenocyte cultures from aged females restimulated with inactivated split-virus influenza from the bulk. To support the greater post-immunisation increase in the frequency GC B cell in aged females was more favourable Tfr/T follicular helper (Tfh) cell ratio. Additionally, compared with aged males, in age-matched females the greater avidity of serum IgG antibodies was found. However, in aged females IgG2a/IgG1 antibody ratio, reflecting spleen Th1/Th2 cytokine balance, was shifted towards IgG1 when compared with age-matched male mice. This shift was ascribed to a more prominent decline in the titres of functionally important IgG2a antibodies in females with aging. The study suggest that biological sex should be considered as a variable in designing strategies to manipulate with immune outcome of immunisation in aged animals, and possibly, at very long distance, humans.
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Acknowledgements
This study was funded by the Ministry of Education, Science and Technological Development of Republic of Serbia (Grant Number 175050). The authors would like to express appreciation to Katarina Ilić and Luka Dragačević from Institute of Virology, Vaccines and Sera ‘‘Torlak’’, Belgrade, Serbia, who kindly provided vaccine antigens in this study.
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10522_2019_9811_MOESM1_ESM.tif
Suppl. Fig. 1. Gating strategy for flow cytometry analysis of CD4/Foxp3/CXCR5/Bcl6 staining of splenocytes. Gating strategy based on fluorescence minus one (FMO) controls for setting cut off boundaries for analysis of Foxp3/CXCR5/Bcl6 expression on CD4+ splenocytes from mice immunised with trivalent inactivated split-virus influenza bulk and unimmunised mice. Flow cytometry dot plots represent FMO controls without anti-Foxp3 or anti- CXCR5 or anti-Bcl6 mAbs for setting gating boundaries in (A) immunised and (B) unimmunised mice. Please note that FMO controls were not shown for CD4 staining, as it exhibits clear bimodal staining (see Material and Methods). Supplementary material 1 (TIFF 283 kb)
10522_2019_9811_MOESM2_ESM.tif
Suppl. Fig. 2. Gating strategy for flow cytometry analysis of B220/CD95 staining of splenocytes. Gating strategy based on fluorescence minus one (FMO) controls for setting cut off boundaries for analysis of CD95 expression on B220+ splenocytes from mice immunised with trivalent inactivated split-virus influenza bulk and unimmunised mice. Flow cytometry dot plots represent FMO controls without anti-CD95 mAb for setting gating boundaries in (A) immunised and (B) unimmunised mice. Please note that FMO controls were not shown for B220 staining, as it exhibits clear bimodal staining (see Material and Methods). Supplementary material 2 (TIFF 113 kb)
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Arsenović-Ranin, N., Petrović, R., Živković, I. et al. Influence of aging on germinal centre reaction and antibody response to inactivated influenza virus antigens in mice: sex-based differences. Biogerontology 20, 475–496 (2019). https://doi.org/10.1007/s10522-019-09811-8
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DOI: https://doi.org/10.1007/s10522-019-09811-8