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. 2020 Jun 23:17:20.
doi: 10.1186/s12979-020-00191-z. eCollection 2020.

In-depth immune cellular profiling reveals sex-specific associations with frailty

Leonard Daniël Samson  1   2 , A Mieke H Boots  2 , José A Ferreira  1 , H Susan J Picavet  1 , Lia G H de Rond  1 , Mary-Lène de Zeeuw-Brouwer  1 , W M Monique Verschuren  1   3 , Anne-Marie Buisman  1 , Peter Engelfriet  1
Affiliations

In-depth immune cellular profiling reveals sex-specific associations with frailty

Leonard Daniël Samson et al. Immun Ageing. .

Abstract

Background: With advancing age, the composition of leukocyte subpopulations in peripheral blood is known to change, but how this change differs between men and women and how it relates to frailty is poorly understood. Our aim in this exploratory study was to investigate whether frailty is associated with changes in immune cell subpopulations and whether this differs between men and women. Therefore, we performed in-depth immune cellular profiling by enumerating a total of 37 subpopulations of T cells, B cells, NK cells, monocytes, and neutrophils in peripheral blood of 289 elderly people between 60-87 years of age. Associations between frailty and each immune cell subpopulation were tested separately in men and women and were adjusted for age and CMV serostatus. In addition, a random forest algorithm was used to predict a participant's frailty score based on enumeration of immune cell subpopulations.

Results: In the association study, frailty was found to be associated with increased numbers of neutrophils in both men and in women. Frailer women, but not men, showed higher numbers of total and CD16- monocytes, and lower numbers of both CD56+ T cells and late differentiated CD4+ TemRA cells. The random forest algorithm confirmed all the findings of the association studies in men and women. In men, the predictive accuracy of the algorithm was too low (5.5%) to warrant additional conclusions on top of the ones derived from the association study. In women however, the predictive accuracy was higher (23.1%), additionally revealing that total T cell numbers and total lymphocyte numbers also contribute in predicting frailty.

Conclusions: In-depth immune cellular profiling revealed consistent associations of frailty with elevated numbers of myeloid cell subpopulations in both men and women. Furthermore, additional associations were found between frailty and lower numbers of some T cell subpopulations, in women only. Thus, our study indicates sex-specific associations of immune subpopulations with frailty. We hope that our study will prompt further investigation into the sex-specific immune mechanisms associated with the development of frailty.

Keywords: Frailty; Healthy aging; Immune cellular profiling; Immune homeostasis; Immunosenescence; Sex-specific immune profile.

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Conflict of interest statement

Competing interestsThe authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Subpopulations of a T cells, b B cells, c NK cells, d Monocytes, and e Neutrophils, of which absolute cell numbers were determined. CM: central memory (CD4 or CD8 positive) T cells. Tem: effector memory (CD4 or CD8 positive) T cells. TemRA: effector memory T cells re-expressing CD45RA. See Table S1 for definition of all phenotypes. 1Additionally analyzed on expression of CD38 and HLA-DR. 2Additionally analyzed on expression of CD16
Fig. 2
Fig. 2
The numbers of cells per leukocyte subpopulations in men (n=145) and women (n=144) above 60 years of age. The boxplots show median values with interquartile range. CM: central memory (CD4 or CD8 positive) T cells. Tem: effector memory (CD4 or CD8 positive) T cells. TemRA: effector memory T cells re-expressing CD45RA. *: Outcomes of tests of the association between leukocyte numbers and sex (adjusted for age and CMV serostatus) which passed the Benjamini-Hochberg method at a false discovery rate of 15%
Fig. 3
Fig. 3
The numbers of CD4 and CD8 Tem and TemRA cells in men (n=145) and women (n=144) above 60 years of age. The boxplots show median values with interquartile range. CM: central memory (CD4 or CD8 positive) T cells. Tem: effector memory (CD4 or CD8 positive) T cells. TemRA: effector memory T cells re-expressing CD45RA. *: Outcomes of tests of the association between leukocyte numbers and sex (adjusted for age and CMV serostatus) which passed the Benjamini-Hochberg method at a false discovery rate of 15%
Fig. 4
Fig. 4
Variable importance plot showing the leukocyte subpopulations and other variables that are most helpful in predicting frailty in men (n=140) and women (n=137). Participants with missing frailty index score data (n=12) were excluded from analysis. The bold lines and dots represent the most important variables that show an increase in mean squared error (MSE) of >50%. See text for the meaning of variable importance
Fig. 5
Fig. 5
Partial dependence plots illustrating the role of the most important leukocyte phenotypes in predicting frailty in a random forest predictor for men (n=140) and women (n=137). Participants with missing frailty index score data (n=12) were excluded from analysis. The short vertical segments on the horizontal axis represent the deciles of the cell numbers in the data. Range of the figures is restricted to the part containing most of the data
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