Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Mutations in activation induced deaminase (AID) lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated cytosine deamination has been proposed as mediating active demethylation, although evidences both support and cast doubt on such a role. We here made use of HIGM2 B cells to investigate direct AID involvement in active DNA demethylation. HIGM2 naive and memory B cells both display widespread DNA methylation defects, of which approximately 25% of these defects correspond to active events. For genes that undergo active demethylation that is impaired in HIGM2 individuals, we did not observe AID involvement but a participation of TET enzymes. DNA methylation alterations in HIGM2 naive B cells are related to premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data supports a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.