SUMMARYThe lower avidity and/or affinity of antibodies generated by an aged immune system could be attributed to two major changes in the antibody repertoire: a shift in germline gene usage and a decrease in the rate of immunoglobulin hypermutation. In an attempt to identify the mechanisms involved in the observed humoral immune deficiency in the elderly, we studied whether differences in the somatic diversity of a particular Vk region occurred with ageing. By using the polymerase chain reaction and sequencing, we analysed and compared Vk4-Jk rearrangements isolated from young (mean age 21 years) and aged (mean age 83 years) healthy adults. Mutations in the Vk4 gene compared with the germline sequence were determined as well as the length and structure of the CDR3 sequence. We analysed in detail various mechanisms contributing to CDR3 and Vk variability in rearrangements involving the Vk4 gene. Our data revealed that, despite strong individual variations, significantly lower levels of somatic mutation were found in the aged group, both for complementarity-determining regions (CDRs) and framework regions (FRs) encoding Vk4 sequences. This decrease mostly affected mutations responsible for replacements and thus resulted in a lowered somatic diversification of the encoded Vk4 proteins in aged individuals. Moreover, comparison of the CDR3 regions of the Vk4-Ck cDNA revealed changes in lightchain junctional diversity that correlated with age. Altogether these data suggest an impaired light-chain somatic diversity in connection with human senescence.

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