ANALYSIS OF CENTRAL B-CELL TOLERANCE IN AUTOIMMUNE-PRONE MRL LPR MICEBEARING AUTOANTIBODY TRANSGENES/

The effect of the autoimmune prone MRL/lpr (H-2(k)) genetic background on central B cell tolerance was studied in mice hearing 3-83 (anti-H- 2K(k)) Ig heavy and light chain transgenes. B cells bearing the domina nt, transgene-encoded anti-H-2K(k) specificity were tolerized appropri ately on the MRL/lpr genetic background. Nevertheless, mice developed disease traits characteristic of the MRL/lpr strain, including lymphad enopathy and elevated levels of IgG dsDNA autoantibodies. Two transgen ic lines were examined in this analysis: 3-83 mu delta, which expresse s IgM and IgD forms of the 3-83 Ab, and Tol 1, which expresses only th e IgM form of 3-83. The results obtained differed somewhat between the two transgenic lines. Crosses using 3-83 mu delta mice never demonstr ated any defects in B cell self-tolerance to H-2K(k). Similarly, no K- k autoantibody production was seen in Tol 1 mice that were backcrossed onto the MRL/lpr genetic background and maintained in a specific path ogen-free facility. However, a subset of Tol 1/MRL/lpr mice that were housed in a conventional mouse facility demonstrated significant trans gene-derived anti-K-k autoantibodies. Overall, these results suggest t hat there is no general defect in central B cell tolerance in MRL/lpr mice, despite their defect in the fas gene. These findings suggest sim ilarities between the MRL/lpr T and B cell systems, because both fail to manifest clear central tolerance defects, but they nevertheless pro mote hyperplasia and autoimmunity in the peripheral immune system.