Global analysis of B cell selection using an immunoglobulin light chain-mediated model of autoreactivity.

The important subtleties of B cell tolerance are best understood in a diverse immunoglobulin (Ig) repertoire context encoding a full spectrum of autoreactivity. To achieve this, we used mice expressing Igκ transgenes that confer varying degrees of autoreactivity within a diverse heavy chain (HC) repertoire. These transgenes, coupled with a biomarker to identify receptor-edited cells and combined with expression cloning of B cell receptors, allowed us to analyze tolerance throughout B cell development.

B cell receptor light chain repertoires show signs of selection with differences between groups of healthy individuals and SLE patients.

We have developed a microarray to study the expression of L-chain V genes (V(L) genes) in healthy and SLE patient peripheral κ- and λ-sorted B cells. In all repertoires tested, one V(L) gene accounts for over 10% of all gene V(L) expression, consistent with positive selection acting on L-chains. While a few V(L) genes were highly expressed in all individuals, most V(L) genes were expressed at different levels.

Anti-DNA B cells in MRL/lpr mice show altered differentiation and editing pattern.

We have studied the regulation of anti-DNA B cells in transgenic mice with a heavy chain transgene (3H9H/56R). This transgene codes for a heavy chain that forms anti-double-stranded DNA (dsDNA) antibody when paired with most members of the endogenous Vkappa repertoire, but certain L chains, referred to as Vkappa editors, do not sustain dsDNA binding in combination with 3H9H/56R. In the nonautoimmune 3H9H/56R BALB/c, most B cells generated do not bind DNA because the transgene itself is edited or is associated with a Vkappa editor.