B cells from autoimmune BXSB mice are hyporesponsive to signals provided by CD4+ T cells.

Male BXSB mice, unlike female BXSB mice, develop an early-onset, lupus-like disease characterized by high levels of anti-nuclear antibodies (Abs) and total Ig. It has recently been shown that the male BXSB mice contain an expanded population of large B cells which are hyperresponsive to stimulation by anti-CD40 mAb. The present study was undertaken to determine whether their potential for extra CD40 signaling enabled the B cells from male BXSB mice to hyper-respond to CD40L-expressing CD4+ T cells. In contrast to expectations, large B cells from male BXSB mice did not interact with CD4+ T cells in a positive manner; cultures of B cells from antigen (Ag)-primed male BXSB mice, unlike cultures of B cells from Ag-primed female mice, generated few antibody forming cells (AFC) following interaction with activated CD4+T cells. In addition, B cells from male BXSB mice, unlike B cells from female BXSB mice, failed to upregulate MHC class II molecules following interaction with activated CD4+ T cells. Subsequent experiments revealed that the inability of the B cells from the male mice to upregulate MHC class II molecules in response to T cell-mediated activation resided primarily in the population of large B cells. Large B cells from male BXSB mice were also defective in their ability to proliferate following stimulation with activated CD4+ T cells. Taken together, these findings demonstrated that similar to B cells in lupus patients, large B cells from male BXSB mice could function in a hyporesponsive manner, and that this hyporesponsiveness related to the inability of the B cells to interact in a positive manner with CD4+T cells.

Trichloroethylene accelerates an autoimmune response by Th1 T cell activation in MRL +/+ mice.

Trichloroethylene (1,1,2-trichloroethene) is a major environmental contaminant. There is increasing evidence relating exposure to trichloroethylene with autoimmunity. To investigate potential mechanisms, we treated the autoimmune-prone MRL +/+ mice with trichloroethylene in the drinking water at 0, 2.5 or 5.0 mg/ml and sacrificed them at 4, 8 and 22 weeks. As early as 4 weeks of treatment, Western blot analysis showed a dose-dependent increase in the level of trichloroethylene-modified proteins, indicating that a reactive metabolite of trichloroethylene was formed. Significant increases in antinuclear antibodies (ANA) and total serum immunoglobulins were found following 4-8 weeks of trichloroethylene treatment, indicating that trichloroethylene was accelerating an autoimmune response. Investigation into possible mechanisms of this autoimmune response revealed that trichloroethylene treatment dramatically increased the expression of the activation marker CD44 on splenic CD4+ T cells at 4 weeks. In addition, splenic T cells from mice treated for 4 weeks with trichloroethylene secreted more IFN-gamma and less IL-4 than control T cells, consistent of a T-helper type 1 (Th1) type immune or inflammatory response. A specific immune response directed against dichloroacetylated proteins was found at 22 weeks of trichloroethylene treatment. Taken collectively, the results suggest that trichloroethylene treatment accelerated an autoimmune response characteristic of MRL +/+ mice in association with nonspecific activation of Th1 cells. In addition, long-term treatment with trichloroethylene led to the initiation of a trichloroethylene-specific immune response.