This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding.

SUMMARY During the humoral immune response B-cells undergo a dramatic change in phenotype to enable antibody affinity maturation in germinal centers (GCs). Using genome-wide chromosomal conformation capture (Hi-C), we found that GCB-cells undergo massive reorganization of the genomic architecture that encodes the GCB-cell transcriptome. Coordinate expression of genes that specify the GCB-cell phenotype – most prominently, BCL6 – was achieved through a multilayered chromatin reorganization process involving i) increased promoter connectivity, ii) formation of enhancer networks, iii) 5’ to 3’ gene looping, and iv) merging of gene neighborhoods that share active epigenetic marks. BCL6, was an anchor point for the formation of GC-specific gene and enhancer loops on chromosome 3. Deletion of a GC specific, highly interactive locus control region, upstream of Bcl6 abrogated GC formation in mice. Thus, large-scale and multi-tiered genomic three-dimensional reorganization is required for coordinate expression of phenotype-driving gene sets that determine the unique characteristics of GCB-cells.