Alterations in B cell development, CDR-H3 repertoire and dsDNA-binding antibody production among C57BL/6 <i>ΔD−iD</i> mice congenic for the lupus susceptibility loci <i>sle1, sle2</i> or <i>sle3</i>

<p>Systemic lupus erythematosus (SLE) is an autoimmune disease that reflects a failure to block the production of self-reactive antibodies, especially those that bind double-stranded DNA (dsDNA). Backcrossing the lupus-prone NZM2410 genome onto C57BL/6 led to the identification of three genomic intervals, termed <i>sle1, sle2</i> and <i>sle3</i>, which are associated with lupus susceptibility. We previously generated a C57BL/6 strain congenic for an immunoglobulin D_H locus (<i>ΔD–iD</i>) that enriches for arginine at dsDNA-binding positions. We individually introduced the <i>ΔD–iD</i> allele into the three <i>sle</i> strains to test whether one or more of these susceptibility loci could affect the developmental fate of B cells bearing arginine-enriched CDR-H3s, the CDR-H3 repertoire created by the D_H and the prevalence of dsDNA-binding antibodies. We found that the combination of the <i>ΔD–iD</i> allele and the <i>sle1</i> locus led to a decrease in mature, recirculating B cell numbers and an increase in marginal zone cell numbers while maintaining a highly charged CDR-H3 repertoire. <i>ΔD–iD</i> and <i>sle2</i> had no effect on peripheral B cell numbers, but the CDR-H3 repertoire was partially normalized. <i>ΔD–iD</i> and <i>sle3</i> led to an increase in marginal zone B cell numbers, with some normalization of hydrophobicity. Mice with <i>ΔD–iD</i> combined with either <i>sle1</i> or <i>sle3</i> had increased production of dsDNA-binding IgM and IgG by 12 months of age. These findings indicate that the peripheral CDR-H3 repertoire can be categorically manipulated by the effects of nonimmunoglobulin genes.