Abstract
It is well known that a part of mycotoxins induce various types of nephrotoxicity in livestocks and in humans. For example, ochratoxin A (OTA) is believed to induce Balkan endemic nephropathy (BEN). Fumonisin, citrinin, rubratoxin B and a few other mycotoxins are also considered to be nephrotoxic. It has been recently reported that nivalenol (NIV) and deoxynivalenol (DON), which belong to the trichothecene mycotoxin, experimentally, induce pathological changes in mouse kidney resembling human IgA nephropathy (IgAN), the most common chronic glomerulonephritis in Japan. Actually, we have created a reproducible IgAN model in mice which is orally induced by the mycotoxin, NIV, based on the hypothesis that IgAN is triggered by some exogenous antigen (s) which induces dysregulation of the mucosal immune system (the mucosal immunity-oriented hypothesis). Significant IgA deposition in glomeruli and remarkable elevation of serum IgA levels were reproducibly induced in all C3H/HeN, C3H/HeJ and BALB/c mice fed NIV 12 ppm for 8 wk (NIV model). The degree of pathological changes analogous to human IgAN and the elevation of serum IgA levels in mice were associated with the dose and duration of oral NIV presentation. Long-term administration of NIV for 12 months significantly increased serum IgA levels as well as the intensity of glomerular IgA deposition in mice over time. Furthermore, a significant increase in IgA-producing cells was demonstrated by an enzyme-linked immunospot procedure in Peyer' s patch (PP) lymphocytes (PPL) of the NIV model mice. Upregulation of CD4+ T cells was also revealed in PP of the model mice by a cytokinespecific reverse transcription-polymerase chain reaction which detected markedly high levels of mRNA specific for IL-4, IL-5, IL-6, IL-10 and TGF-β (Th2 type cytokines) as well as IFN-γ and IL-2 (Th1 type cytokines) in these cells. When NIV diluted in alcohol or saline phosphate buffer was injected into the duodenum in C3H/HeN mice to examine histopathological changes in the intestinal wall, 24 hours later not only the number of PAS-positive goblet cells (GC) looked decreased in the small intestine but also necrotic and degenerative damages were observed in Paneth cells and epithelial cells of the small intestinal villi especially around the crypts in the NIV-injected mice compared with those in controls. In conclusion, NIV reproducibly and strain-nonspecifically induces pathological changes in mice which resemble those in human IgAN. IgAN-like changes in mice were exacerbated over time in a period-dependent manner with NIV administration. It was suggested that PPL are immunologically dysregulated in NIV-induced IgAN, and that this kind of upregulation of the mucosal immune system might be associated with the pathogenesis of IgAN. We also suggest that mycotoxins such as NIV and DON might immunolocically and histopathologically damage the mucosal system such as the intestinal wall and have some etiologic role at least in some types of glomerulonephritis.
