Abstract
It has long been believed that fish lack antibody affinity maturation, in part because they were thought to lack germinal centers. Recent research done on sharks and bony fishes indicates that these early vertebrates are able to affinity mature their antibodies. This article reviews the functionality of the fish homologue of the immunoglobulin (Ig) mutator enzyme activation-induced cytidine deaminase (AID). We also consider the protein and molecular evidence for Ig somatic hypermutation and antibody affinity maturation. In the context of recent evidence for a putative proto-germinal center in fishes we propose some possible reasons that observed affinity maturation in fishes often seems lacking and propose future work that might shed further light on this process in fishes.
Highlights
In the mammalian paradigm of antibody affinity maturation a few activated B-cells and TH-cells are sequestered to primary lymphoid follicles where the former cells proliferate and acquire “random” point mutations in their VDJ exons
B-cells, at a rate estimated to be 4- to 7-fold lower than that in mammalian Ig genes; (2) Increases in antibody affinity for DNP were only 5- to 10-fold 4 weeks after immunization; (3) Unlike mammals there was a strong GC bias for sites of mutation— in codons for serine (RGY/YCR); (4) There was evidence for clonal lineage accumulation of mutations; (5) The ratio of replacement to silent mutations (R/S) was not statistically above the rate expected for random mutations in the complementarity determining regions (CDRs), which suggested to them that there was not a germinal center-like selection process occurring. These studies in amphibians did not necessarily predict what might be occurring in the earlier divergent fishes, though the discovery in the 1990’s of a new Ig isotype (IgNAR) in sharks and rays, with a very limited number of V-elements did open the way for determining that Ig somatic hypermutation did exist before the divergence of bony fishes
Over the last 20 years it has been established that several features consistent with antibody affinity maturation were in place in early gnathostomes
Summary
In the mammalian paradigm of antibody affinity maturation a few activated B-cells (plasmablasts) and TH-cells are sequestered to primary lymphoid follicles where the former cells ( centroblasts) proliferate and acquire “random” point mutations in their VDJ exons. These newly modified daughter cells (centrocytes) compete for limited antigen, trapped in complex with antibody or complement, on the surface of follicular dendritic cells (FDCs). Though all gnathostomes have B-cells and develop memory responses to vaccines there has been considerable debate on whether ectothermic vertebrates have a complete antibody affinity maturation process. The characterization of the mutation processes initiated by AID, and technological advances in protein chemistry and sequencing have provided a clearer understanding of how affinity maturation operates in both homeotherms and ectothermic vertebrates, and it is these advances that we will consider in greater detail
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