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Abstract:
The immune system protects us from foreign substances or pathogens by generating specific antibodies. The variety of
immunoglobulin (Ig) paratopes for antigen recognition is a result of the V(D)J rearrangement mechanism, while a fast and
efficient immune response is mediated by specific immunoglobulin isotypes obtained through class switch recombination
(CSR). To get a better understanding on how antibody-based immune protection works and how it changes with age, the
interdependency between these two parameters need to be addressed. Here, we have performed an in depth analysis of
antibody repertoires of 14 healthy donors representing different gender and age groups. For this task, we developed a
unique pyrosequencing approach, which is able to monitor the expression levels of all immunoglobulin V(D)J
recombinations of all isotypes including subtypes in an unbiased and quantitative manner. Our results show that donors
have individual immunoglobulin repertoires and cannot be clustered according to V(D)J recombination patterns, neither by
age nor gender. However, after incorporating isotype-specific analysis and considering CSR information into hierarchical
clustering the situation changes. For the first time the donors cluster according to age and separate into young adults and
elderly donors (.50). As a direct consequence, this clustering defines the onset of immune senescence at the age of fifty
and beyond. The observed age-dependent reduction of CSR ability proposes a feasible explanation why reduced efficacy of
vaccination is seen in the elderly and implies that novel vaccine strategies for the elderly should include the ‘‘Golden Agers’’.
