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

Abstract

Activation-induced deaminase (AID) initiates antibody diversification in germinal center B cells by deaminating cytosines, leading to somatic hypermutation and class-switch recombination. Loss-of-function mutations in AID lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated deamination has been proposed as leading to active demethylation of 5-methycytosines in the DNA, although evidence both supports and casts doubt on such a role. In this study, using whole-genome bisulfite sequencing of HIGM2 B cells, we investigated direct AID involvement in active DNA demethylation. HIGM2 naïve and memory B cells both display widespread DNA methylation alterations, of which ∼25% are attributable to active DNA demethylation. For genes that undergo active demethylation that is impaired in HIGM2 individuals, our analysis indicates that AID is not directly involved. We demonstrate that the widespread alterations in the DNA methylation and expression profiles of HIGM2 naïve B cells result from premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data support 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.

Epigenetic regulation of B cells and its role in autoimmune pathogenesis

“…These epigenetic effects of AID are dependent on TET2, as AID-mediated demethylation is markedly impaired in Tet2 -deficient GC B cells [ 63 ]. Interestingly, AID might be involved in the establishment of DNA methylation patterns even before the GC reaction [ 64 ]. AID induces DNA breaks and drives CSR in GC B cells.…”

DNA Methylation and Immune Memory Response

“…The absence of AID catalytic activity on these patients affected DNA methylation in naïve and memory B cells. The enzyme response for these active demethylation processes during the transition to memory is the TET [ 117 ].…”