Analysis of innate immune responses in a model of IgA nephropathy induced by Sendai virus

In a model of IgA nephropathy (IgAN) induced by Sendai virus (SeV) without Th1/Th2 polarizing immunization, Th2-prone BALB/c mice develop more severe nephritis with acute renal insufficiency than Th1-prone C3H mice. To determine whether Th1 or Th2 predominance influences the severity of experimental IgAN in mice, we employed polarizing immunizations in a SeV-induced IgAN model in Th1-prone C57Bl/6 mice and Th2-prone BALB/c mice. C57Bl/6 mice, immunized with SeV +CFA or +IFA, showed: (1) clear cytokine polarity by splenocytes in recall assays. (2) Total serum IgA and especially SeV-specific IgA from the IFA group showed a selective defect in galactosylation, not seen in the CFA group, and (3) serum creatinine in the IFA group was higher than in the CFA group or nonimmune controls. However, BALB/c mice did not show clear cytokine polarity with CFA/IFA adjuvant. Moreover, spleen cells from naive BALB/c mice produce IFN-gamma (but not IL-2, -4, -5, or -13) upon stimulation with inactivated SeV in vitro. By flow cytometry, IFN-gamma producing cells are CD3(-), CD19(-), CD49b(+) natural killer cells. IFN-gamma production by naive splenocytes is blocked partially by anti-IL12 blocking Abs, and completely by anti-IL18R blocking Abs. In conclusion, C57Bl/6 mice with polarizing priming with SeV showed clear cytokine polarity and distinct kidney injuries. However, BALB/c mice did not show clear cytokine polarity in the same immunizing system, presumably due to the effects of innate responses to SeV upon antigen-specific lymphocytes. Natural IFN-gamma production may influence the risk of renal failure in IgAN.