Micro-RNAs miR-155 and miR-16 decrease AID and E47 in B cells from elderly individuals1

Our research in the past few years has identified B cell-specific biomarkers able to predict optimal antibody responses in both young and elderly individuals. These biomarkers are activation-induced cytidine deaminase (AID), the enzyme of class switch recombination and somatic hypermutation; the transcription factor E47, crucial for AID expression; and the ability to generate optimal memory B cells. Moreover, we have found that the increased pro-inflammatory status of the elderly, both in sera and intrinsic to B cells, negatively impacts B cell function. We have now investigated whether particular inflammatory micro-RNAs (miRs) contribute to decreased E47 and AID in aged B cells. Our data indicate that E47 and AID mRNA stability is lower in stimulated B cells from elderly individuals. We measured the expression of two miRs crucial for CSR, miR-155 and miR-16, in human unstimulated B cells from young and elderly individuals with the rationale that increases in these before stimulation would decrease E47/AID upon cell activation. We found these miRs and B-cell intrinsic inflammation up-regulated in aged unstimulated B cells and negatively associated with AID in the same B cells after stimulation with CpG. We propose that the down-regulation of AID in aged human B cells may occur through binding of miR-155 to the 3′-UTR of AID mRNA and/or binding of miR-16 to the 3′-UTR of E47 mRNA as well as at the transcriptional level of less E47 for AID. Our results indicate novel molecular pathways leading to reduced B cell function with aging.