科研之友
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摘要
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 sle1, sle2 and sle3, which are associated with lupus susceptibility. We previously generated a C57BL/6 strain congenic for an immunoglobulin D-H locus (D-iD) that enriches for arginine at dsDNA-binding positions. We individually introduced the D-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 D-H and the prevalence of dsDNA-binding antibodies. We found that the combination of the D-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. D-iD and sle2 had no effect on peripheral B cell numbers, but the CDR-H3 repertoire was partially normalized. D-iD and sle3 led to an increase in marginal zone B cell numbers, with some normalization of hydrophobicity. Mice with D-iD combined with either sle1 or sle3 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.
- 出版日期2017-2
