Ig Light Chain Precedes Heavy Chain Gene Rearrangement during Development of B Cells in Swine

The current mammalian paradigm states that 1) rearrangements in the IgH locus precede those in IgL loci, 2) IgL lambda genes rearrange only when IgL kappa genes are consumed, and 3) the surrogate L chain is necessary for selection of productive IgH gene rearrangements. We show in swine that IgL rearrangements precede IgH gene rearrangements, resulting in the expression of naked IgL on a surface of precursor B cells. Findings also suggest that there is no dependency on the surrogate L chain, and thus the authentic IgL proteins may be used for selection of the IgH repertoire. Although rearrangement starts with IgL kappa genes, it is rapidly replaced by IgL lambda rearrangement. Fast replacement is characterized by occurrence of IgL lambda(1o) IgL kappa(1o) dual-expressing precursors in which IgL kappa expression is a remnant of a previous translation. Most IgL kappa(+) B cells are then generated later, indicating that there are two waves of IgL kappa synthesis in different developmental stages with IgL lambda gene rearrangements in between. In the absence of stromal cells, the stepwise order of rearrangements is blocked so that IgL lambda gene rearrangements predominate in early B cell development. To our knowledge, this is the first evidence that some mammals can use an inverted order of Ig loci rearrangement. Moreover, a situation in which the generation of BCR-bearing IgL kappa is delayed until after IgL lambda becomes the dominant isotype may help explain the extreme deviations in the IgL kappa/IgL lambda ratios among mammals.