Studies on Germinal Center Biology

Abstract

The germinal center reaction is at the heart of the humoral immune response; it comprises one major arm of the immune system, with the other arm being the cellular response. It is the site where B cells undergo somatic hyper-mutation, class switching, affinity maturation, and selection. The precise molecular regulation of germinal center development remains largely unknown. We isolated B cells from the mesenteric lymph node germinal center of a C57BL/6 mice and assessed their gene regulation programs by using ATAC-seq, a method for mapping open chromatin region, and RNA-seq, to determine global gene expression profiles with the aim of revealing new insights into the formation and maturation of germinal centers. We are also interested in the role of the germinal center in autoimmunity; using MRL/MpJ mice as a model, we found that there is an increase in 9-O-acetylation of sialic acid in MRL/MpJ germinal center B cells compared to C57BL/6 and BALB/c mice. MRL/MpJ mouse B-cells also show defect in BCR induced apoptosis. Ganglioside GD3 is a membranebound glycosphingolipid containing sialic acid, known to have a role in apoptosis induction by targeting the mitochondria. Interestingly, the pro-apoptotic effects of GD3 can be counteracted by 9-O-acetylation of the terminal sialic acid residue, giving 9-O-acetyl-GD3. We hypothesize that 9-O-acetylation of GD3 disrupts the apoptotic process of auto-reactive B cells in the germinal center, which ultimately results in autoimmunity.