Introduction: Injection of HgCl 2 into BN rats induces systemic autoimmunity, involving high production of (auto-) antibodies and IgE, multi-organ inflammation, and proteinuria. Induction of disease is dependent on activation of Th2 cells. In contrast, Lewis rats develop generalized immunosuppression upon exposure to HgCl 2 , which probably involves activation of Th1 cells. In both rat strains, HgCl 2 induces an early and transient increase in expression of the MHC class II (MHCII) molecule RT1.B (HLA-DQ/H-2 I-A homolog) on B cells. In vitro, HgCl 2 was shown to induce enhanced expression of RT1.B but not of RT1.D (HLA-DR/H-2 I-E homolog) on splenic B cells from BN and Lewis rats, which was partially inhibited by anti-IL-4 only in cell cultures from BN rats. We compared the effects of HgCl 2 and IL-4 on expression of RT1.B and RT1.D.Materials and Methods: Expression of RT1.B and RT1.D was measured by dual colour flow cytometry on lymphnode (LN) B cells from BN and Lewis rats at day 4 after the first injection of HgCl 2 . Furthermore, expression of RT1.B and RT1.D on B cells was studied in vitro upon exposure of LN cells from BN and Lewis rats to HgCl 2 and to II-4 for 18 hours.Results: In vivo exposure to HgCl 2 induced a significant increase in expression of RT1.B (+55%, p < 0.002), but not of RT1.D, on B cells from BN rats only. However, in vitro exposure of LN cells from BN or Lewis rats to 4 μM HgCl 2 resulted in a significant increase of B cell expression of RT1.B as well as RT1.D (+40 to 50%, p < 0.002). This increase could not be inhibited by adding a blocking antibody against rat IL-4. Incubation of LN cells from BN and Lewis rats with recombinant rat IL-4 induced a strong enhancement of RT1.B expression in both cultures (+140 to 200%, p < 0.001), which could be totally inhibited by adding anti-IL-4. In contrast, IL-4 had only a slight although significant effect on RT1.D expression on B cells in cultures derived from BN rat LN (+23%, p < 0.005), and was totally ineffective in enhancing RT1.D expression in Lewis rat-derived cultures. This difference between BN and Lewis rats was statistically significant (p < 0.02). Since we were not able to demonstrate IL-4-dependence of the effect of HgCl 2 on B cell MHCII expression in an unfractionated LN cell culture, we hypothesized that this effect of HgCl 2 in vitro may be T cell-independent. Indeed, HgCl 2 enhanced RT1.B expression to a similar extent in a culture of purified B cells (>97% pure; <2% CD2 + , <0.2% CD4 + , <0.4% CD8 + cells).Conclusion: Exposure of BN rats to HgCl 2 specifically enhances B cell RT1.B expression in vivo, and thus resembles the effect of IL-4 in vitro. However, HgCl 2 enhances both RT1.B and RT1.D expression on B cells in vitro, which is probably IL-4- and T cell-independent. In vitro, IL-4 strongly induces RT1.B expression but has only a minor effect on RT1.D expression. The latter effect is strain dependent. Distinct regulation of expression of MHCII molecules may be involved in their differential involvement in autoimmune diseases.