Longitudinal analysis of the B-cell receptor repertoire across 30 years of ageing
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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 (β =-0.57, p < 0.001). Additionally, a trend toward reduced IGH gene repertoire diversity was observed in participants aged 60-70 years (β =-0.19, p = 0.1) and those aged 70 years or older ( β =-0.20, p = 0.13). IGH gene repertoire diversity was determined primarily by the naïve 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.
