Diverse Immunoglobulin Light Chain Organizations in Fish Retain Potential to Revise B Cell Receptor Specificities

Abstract

We have characterized the genomic organization of the three zebrafish L chain isotypes and found they all differed from those reported in other teleost fishes. Two of the zebrafish L chain isotypes are encoded by two loci, each carrying multiple V gene segments. To understand the derivation of these L chain genes and their organizations, we performed phylogenetic analyses and show that IgL organization can diverge considerably among closely related species. Except in zebrafish, the teleost fish IgL each contain only two to four recombinogenic components (one to three V, one J) and exist in multiple copies. BCR heterogeneity can be generated, but this arrangement apparently provides neither combinatorial diversification nor an opportunity for the secondary rearrangements that, in mammals, take place during receptor editing, a process crucial to the promotion of tolerance in developing lymphocytes. Examination of the zebrafish IgL recombination possibilities gave insight into how the suppression of self-reactivity by receptor editing might be managed, including in miniloci. We suggest that, despite the diverse IgL organizations in early and higher vertebrates, two elements essential to generating the Ab repertoire are retained: the numerous genes/loci for ligand-binding diversification and the potential for correcting unwanted specificities that arise.

Four primordial immunoglobulin light chain isotypes, including λ and κ, identified in the most primitive living jawed vertebrates

“…As pointed out in a recent analysis of teleost L chains [6], L1 and L3 are difficult to distinguish within teleosts much less among other vertebrates; in this new tree, however, they are both clearly shown to be j orthologs. This designation of j genes in Fig.…”

“…Xenopus tropicalis expressed sequence tags (EST) as well as genomic scaffolds identified the isotype in a second Xenopus species, separated by 50 million years from X. laevis. Additionally, an IgL expressed sequence tag was recently found [6] from the bony fish channel catfish with high homology to r and teleost L2 that was clearly not of the described catfish isotypes F or G, which are both in the j class [10,11]. No r sequences were detected in any of the eu-or metatherian mammal databases; thus this isotype arose early in vertebrate evolutionary history and has been maintained in all cold-blooded vertebrates examined.…”

“…Three criteria have been considered: amino acid identity, gene organization, and heptamer and nonamer spacing in the RSS (either 12 or 23 base pairs) [5]. Gene organization has recently been informative for resolving relationships among teleost (i.e., bony fish) L chain isotypes [6]. However, teleosts are amenable to such analyses since they have both phylogenetically informative cluster and translocon IgL arrangements and ample genomic data exist from several fish genome projects.…”

The Evolution of Multiple Isotypic IgM Heavy Chain Genes in the Shark

“…This is of some concern, as similar data obtained for bony fish IgL clusters proved to be misleadingly incomplete once a genomic overview was available. In the case of zebrafish IgL, multiple components could be found in L chain genes of all three isotypes, showing that the generally accepted simple IgL locus with 2-4 gene segments was neither the predominant nor sole possible organization in bony fishes (10).…”

Evidence for Ig Light Chain Isotype Exclusion in Shark B Lymphocytes Suggests Ordered Mechanisms

“…In bony fish, the IgL are organized as many small loci, each with varying small numbers of V, J, and C exons, some of which share enhancers (15,21). The tandem positioning of gene segments and the proximity of many loci offer the potential for removing unwanted VJ rearrangements (22).…”