450 million years in the making: mapping the evolutionary foundations of germinal centers

Abstract

Germinal centers (GCs) are distinct microanatomical structures that form in the secondary lymphoid organs of endothermic vertebrates (i.e., mammals and some birds). Within GCs, B cells undergo a Darwinian selection process to identify clones which can respond to pathogen insult as well as affinity mature the B cell repertoire. The GC response ultimately generates memory B cells and bone marrow plasma cells which facilitate humoral immunological memory, the basis for successful vaccination programs. GCs have not been observed in the secondary lymphoid organs of ectothermic jawed vertebrates (i.e., fishes, reptiles, and amphibians). However, abundant research over the past decades has indicated these organisms can produce antigen specific B cell responses and some degree of affinity maturation. This review examines data demonstrating that the fundamentals of B cell selection may be more conserved across vertebrate phylogeny than previously anticipated. Further, research in both conventional mammalian model systems and comparative models raises the question of what evolutionary benefit GCs provide endotherms if they are seemingly unnecessary for generating the basic functional components of jawed vertebrate humoral adaptive immune responses.

BRWD1 establishes epigenetic states for germinal center initiation, maintenance, and function

“…These observations are consistent with what is known about GC evolutionary biology. GCs and affinity maturation convergently evolved only in endothermic mammals and birds approximately 200 million years ago 66 . In contrast, SHM arose approximately 450 million years ago in ectothermic cartilaginous fish, which can also generate MBCs and PCs [66][67][68] .…”

“…GCs and affinity maturation convergently evolved only in endothermic mammals and birds approximately 200 million years ago 66 . In contrast, SHM arose approximately 450 million years ago in ectothermic cartilaginous fish, which can also generate MBCs and PCs [66][67][68] . In cartilaginous fish, SHM functions to diversify antibody responses and only modestly enhances affinity 69,70 .…”

“…Efficient affinity maturation only developed with the advent of GCs. It has been argued that GCs evolved to deal with the more rapid cell proliferation of endotherms 66 . Indeed, we postulate that with higher proliferative rates, insulation between SHM and mitosis via specialization of GC subsets became an evolutionary imperative to diminish the risk of neoplastic transformation.…”

Conditional Requirement for Dimerization of the Membrane-Binding Module of BTK

“…Comparing BTK from zebrafish ( Danio rerio , of the class Actinopterygii, which lacks the PH– TH dimerization signature) and the frog ( Xenopus laevis , of the class Amphibia, which has the PH–TH dimerization signature) offers clues. In the zebrafish, there are no clearly defined regions of B and T-cell association that form in response to infection [64]. By contrast, in the frog, B-cell follicles form in the spleen and are surrounded by a peripheral layer of T-cells in a structure resembling the germinal center [65].…”