The lupus susceptibility locus sle-2 on mouse chromosome 4 leads to abnormal b-cell development and activation

Genetic studies have identified Sle-1, Sle-2, and SIe-3 on chromosomes 1,4, and 7, respectively, as lupus susceptibility loci in the NZM2410 murine lupus model. To unravel the pathogenic mechanisms underlying lupus, we are studying C57BL/6 mice made congenic for each of these 3 intervals. B6.NZMc4 mice (congenic for the NZM locus, Sle-2) show aberrant B-cell maturation and activation. One-month-old B6.NZMc4 bone-marrow bear increased percentages of B220"' cells, but significantly reduced mature B-cells (3.3% vs. 7.2%, pO.Ol). Likewise, their spleens have increased B-cells, compared to C57BL/6 (67.3% vs. 54.6%, p<0.001) and CD23^low B-cells (22.3% vs. 12.1%, p<0.001) that are CD5^-ve, IgD^-ve, CD43^-ve and J11d^hi. B6.NZMc4 B-cells show increased spontaneous, IgM-induced and Ipsinduced proliferation, and an age-dependent increase in splenic IgMproducing B-cells and spontaneous IgM secretion in culture. Finally, B6.NZMc4 mice exhibit increased total serum IgM with polyclonal antigenic reactivity, with the penetrance of this trait increasing from 10% at 5mo age to >90% at 12mo age. In conclusion, Sle-2 impacts B-cell maturation in the marrow, and controls a key event in B-cell activation.