Longitudinal analysis of the B-cell receptor repertoire across 30 years of ageing

Leenders, L.; van den Oetelaar, M. A. J. I.; Engelfriet, P.; Buisman, A.-M.; de Zeeuw-Brouwer, M.-L.; de Rond, L.; Verschuren, W. M. M.; Vermeulen, R. C. H.; Langerak, A. W.; Kolijn, P. M.

doi:10.64898/2026.08.18.745470

bioRxiv · 10.64898/2026.08.18.745470

Longitudinal analysis of the B-cell receptor repertoire across 30 years of ageing

Leenders, L.·van den Oetelaar, M. A. J. I.·Engelfriet, P.·Buisman, A.-M.·de Zeeuw-Brouwer, M.-L.·de Rond, L.·Verschuren, W. M. M.·Vermeulen, R. C. H.·Langerak, A. W.·Kolijn, P. M.

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Abstract

Background: The gradual decline in the functionality of the immune system during aging is commonly referred to as immunosenescence. This study aims to investigate changes in the B-cell receptor immunoglobulin heavy chain (BCR IGH) gene repertoire during natural aging and evaluate the dynamics of emergent low-level BCR IGH clonality in the elderly. We conduct a longitudinal study nested within the Doetinchem Cohort study, comprising 98 participants aged between 31 and 59 years old at study entry who had repeated blood samples drawn at 5 year intervals over a 30 year period (n=548 samples). We sequenced the IGH gene repertoire and evaluated the impact of aging on IGH gene repertoire clonality and diversity using linear mixed effects modeling. Results: Participants older than 60 years exhibited increased BCR IGH clonality and reduced IGH gene repertoire diversity. In a multivariable model, IGH gene repertoire diversity was significantly decreased for individuals with a dominant clonotype ratio greater than 10 (Beta=-0.57, p < 0.001). Additionally, a trend toward reduced IGH gene repertoire diversity was observed in participants aged 60-70 years (Beta =-0.19, p = 0.1) and those aged 70 years or older (Beta =-0.20, p = 0.13). IGH gene repertoire diversity was determined primarily by the naive and transitional B-cell pool, while BCR IGH clonality was influenced by switched memory and age-associated B-cell counts. Conclusions: In summary, our study indicates that IGH gene repertoire diversity decreases significantly after age 60, which coincides with an increased incidence of low-level BCR IGH clonality. This clonality may be driven largely by switched memory and age-associated B-cells. By providing deep insights into age-related dynamic changes in the IGH gene repertoire, these findings lay the groundwork for the molecular assessment and monitoring of incident clonality by clinicians and researchers alike.

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Leenders, L., van den Oetelaar, M. A. J. I., Engelfriet, P., Buisman, A.-M., de Zeeuw-Brouwer, M.-L., de Rond, L., Verschuren, W. M. M., Vermeulen, R. C. H., Langerak, A. W., Kolijn, P. M.. 2026-08-22. Longitudinal analysis of the B-cell receptor repertoire across 30 years of ageing. https://doi.org/10.64898/2026.08.18.745470

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