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

摘要

Systemic lupus erythematosus is an autoimmune disease that reflects a failure to block 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 sle1, sle2, and sle3, which are associated with lupus susceptibility. We previously generated a C57BL/6 strain congenic for an immunoglobulin DH locus (ΔD-iD) that enriches for arginine at dsDNA binding positions. We individually introduced the ΔD-iD allele into the three sle 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 DH, and the prevalence of dsDNA binding antibodies. We found that the combination of the ΔD-iD allele and the sle1 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. ΔD-iD and sle2 had no effect on peripheral B cell numbers, but the CDR-H3 repertoire was partially normalized. ΔD-iD and sle3 led to an increase in marginal zone B cell numbers, with some normalization of hydrophobicity. Mice with ΔD-iD combined with either sle1 or sle3 had increased production of dsDNA binding IgM and IgG by twelve months of age. These findings indicate that the peripheral CDR-H3 repertoire can be categorically manipulated by the effects of non-immunoglobulin genes.