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• Research Paper Volume 11, Issue 13 pp 4367-4381

  Age-related changes in B cell metabolism

  Relevance score: 11.317712

  Raj K. Kurupati, Larissa H. Haut, Kenneth E. Schmader, Hildegund CJ. Ertl

  Keywords: vaccination, antibody responses, B cell metabolism

  Published in Aging on July 8, 2019

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  Antibody responses to vaccinations or infections decline upon aging. In this study we tested if metabolic changes in B cells may contribute to attenuation of responses to influenza vaccination in aged humans. Our data show that aging affects mitochondrial functions in B cells leading to increases in mitochondrial reactive oxygen species (MROS) and mitochondrial mass (MM) in some aged B cell subsets and decreases in expression levels of Sirtuin 1 (SIRT1), Forkhead box protein (FOX)O1 and carnitine palmitoyltransferase 1 (CPT-1). Seahorse analyses showed minor defects in glycolysis in the aged B cells after activation but a strong reduction in oxidative phosphorylation. The analyses of the transcriptome revealed further pronounced defects in one-carbon metabolism, a pathway that is essential for amino acid and nucleotide metabolism. Overall our data support the notion that the declining ability of aged B cells to increase their metabolism following activation contributes to the weakened antibody responses of the elderly.

  

  Antibody responses. Sera from younger (open squares) and older (closed squares) individuals were tested for VNAs and antibodies of different serotypes specific for H1N1 (upper graphs) or H3N2 viruses (lower graphs). The graphs show absolute values for VNA titers and fold increase over baseline (visit 1 [V1]) for IgA, IgG and IgM by dividing amounts of antibody in μg/ml (extrapolated from using standards for each isotype) after vaccination by those obtained at baseline. Graphs show data for individual samples with medians. Lines with star above indicate significant differences by Mann-Whitney. * p-value between <0.05-0.01, ** p-value between <0.01 and 0.001, *** p-value between <0.001 and 0.0001, **** p-value <0.0001.

  
  
  

  

  Metabolic phenotypes of B cells. (A) Graphs show mean fluorescent intensity (MFI) of stains for the indicated markers in or on different B cell subsets, i.e., naïve B cells (IgD⁺CD19⁺CD27^-CD38^-), unswitched memory B cells (IgD⁺CD19⁺CD27⁺CD38^-), switched memory B cells (IgD^-CD20⁺CD19⁺CD38⁺CD27^-) and ASCs (IgD^-CD20^-CD19⁺CD38⁺CD27⁺) of younger (open circles) or aged (grey squares) individuals. Graphs show results for individual samples with means. Statistical difference indicated with lines and stars above as in legend to Figure 1 were calculated with multiple type 1 error corrected t-tests. (B) Samples were separated into those with high antibody responses (~1/3 of samples) and low antibody responses (~1/3 of samples). To this end samples were sorted according to magnitude of increases of the different antibody responses (VNAs, IgA, IgM and IgG titer increases) after vaccination as compared to baseline. The top and bottom samples (~1/3 of all samples each) were selected and analyzed. Significant differences were seen for the MFI for the SIRT1 stain in ASCs in high versus low IgG responders to H1N1 and H3N2. Lines with stars above indicate significant differences as described in legend to Figure 1. Abbreviations: CPT-1: carnitine palmitoyltransferase 1; FOXO1: Forkhead box (FOX) protein O1; MROS: mitochondrial reactive oxygen species; SIRT1: Sirtuin 1.

  
  
  

  

  Energy production by naïve B cells undergoing activation. Naïve B cells isolated from PBMCs of younger (circles) or aged (squares) individuals were cultured for 24 hours with (closed symbols) or without (open symbols) polyclonal activators and then tested by Seahorse for glycolysis (A) or respiration (B). After 3 measurements at baseline oligomycin was added to determine glycolytic capacity and proton leak. After 3 measurements carbonyl cyanide-4-phenylhydrazone (FCCP) was added to maximal respiration. Thereafter Rotenone and Antimycin A were added to measure non-mitochondrial respiration. Data for oxygen consumption rates (OCR) were used to calculate ATP production as basal respiration minus proton leak (C) and spare respiratory capacity as maximal respiration minus non-mitochondrial respiration (D).

  
  
  

  

  Gene expression profiles of naïve B cells undergoing stimulation. Naïve B cells isolated from PBMCs of younger or aged individuals were cultured for 24 hours with (stimulated) or without (resting) polyclonal activators. cDNA was generated and probed with primers to the indicated factors (A) by comparative (c)PCR. (B) The heatmap to the left shows age-related differences in levels of transcripts between resting or stimulated B cells comparing younger to elderly individuals. The heatmap to the right shows activation induced changes in younger and aged B cells. Blue shows reduced levels and red shows enhanced levels of transcripts in the younger compared to aged B cells (left) or in stimulated compared to resting B cells (right). Color intensities indicate magnitude of differences as shown in the legend.