title: Onset of immune senescence defined by unbiased pyrosequencing of human immunoglobulin mRNA repertoires.
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".
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Rubelt
authors.forename: Volker
authors.initials: V
authors.lastname: Sievert
authors.forename: Florian
authors.initials: F
authors.lastname: Knaust
authors.forename: Christian
authors.initials: C
authors.lastname: Diener
authors.forename: Theam Soon
authors.initials: TS
authors.lastname: Lim
authors.forename: Karl
authors.initials: K
authors.lastname: Skriner
authors.forename: Edda
authors.initials: E
authors.lastname: Klipp
authors.forename: Richard
authors.initials: R
authors.lastname: Reinhardt
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Konthur
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D001666:Binding Sites, Antibody / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000276:immunology*; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007132:Immunoglobulin Isotypes / Q000235:genetics*; D008297:Male; D005810:Multigene Family; D012333:RNA, Messenger / Q000145:classification / Q000235:genetics / Q000276:immunology*; D060152:V(D)J Recombination / Q000276:immunology
chemical_list: D007132:Immunoglobulin Isotypes; D012333:RNA, Messenger