The effect on the imnnme system of inorganic mercury (Hg), organic mercury (methyl mercury-MeHg), and silver was examined in mouse strains genetically susceptible or resistant to metal-induced systemic autoimmunity (MIA). The major aim was to study the cytokine mRNA expression in the immune system of metal-treated mice, and relate these findings to the different parameters of MIA.
Cytokine mRNA expression in lymphoid tissues was assessed using the ribonuclease protection assay (RPA) and phosphorimaging. The baseline expression of IL-2 and IFN-γ mRNA was higher in a strain (A.SW) susceptible to induction of MIA, compared with a resistant strain (A.TL). In A.SW mice Hg treatment caused early upregulation of IL-2 and IFN-γ mRNA expression, followed by substantial expression of IL-4 mRNA, and induction of antifibrillarin antibodies (AFA), lymphoproliferation and systemic immune-complex (IC) deposits. Hg treatment caused in MIA-resistant A.TL mice unchanged expression of IFN-γ mRNA, but reduced IL-2 expression. A major difference between A.SW and A.TL mice was the greatly increased IL-10 mRNA expression in the latter strain. Silver treatment of A.SW mice, which leads to a modified MIA with AFA, minimal lymphoproliferation, but no IC deposits, caused an early increase of IL-2 and IFN-γ mRNA, but only a slight increase of IL-4 mRNA.
The observation of a preferential expression of IL-10 mRNA in Hg-treated genetically MIA-resistant mice was further examined by using a strain with a targeted mutation for the IL-10 gene, as well as treatruent of genetically susceptible mice with recombinaot IL-10 (rIL-10). The IL-10 deficient strain did not develop AFA during Hg treatment, but showed a significant increase in antinuclear antibodies with a homogeneous pattern and a higher serum lgE concentration compared with Hg-treated resistant mice lacking the IL-10 mutation. The susceptible A.SW strain showed during intense treabnent with riL-10 and Hg a reduced induction of AFA, antichromalin antibodies (ACA), and serum IgE, as compared with A.SW mice only receiving Hg.
The paradigm of T helper cells type 1 (Th1) aod 2 (Th2) is often discussed in the pathogenesis of autoimmnne diseases. MIA has many characteristics of a Th2 type of reaction, but the disease induction is critically depeodent on the Th1 cytokine IFN-γ. In order to study the relevance of the Th1/Th2 concept for MIA, and to see if the disease could be aggravated by a strong deviation towards Th1, rIL-12 was given in combination with anti-IL-4 monoclonal aotibody (Mab) during treatmeut with Hg to the susceptible A.SW strain. The combined treatment reduced the Th2-dependent serum Ig isotypes, but increased the Th1-dependent IgG2a isotype. The IgG-AFA developed earlier and attained a higher titre. The renal IC deposits were severely reduced after combined treatment during the induction phase. Treatment with rIL-12 + Hg increased the Th1-dependent AFA of the IgG2a isotype, the polyclonal B-cell activation (PBA), and the IC deposits in renal and splenic vessel wall. Using only anti-IL-4 Mab during induction of MIA, the Th2-dependent serum IgG isotypes were reduced, while the development of AFA was not affected. The renal vessel wall IC deposits were reduced while the splenic vessel wall deposits were unaffected.
A previous study showed that the organic mercury compound MeHg causes a different MIA pattern than Hg. In order to examine the relation between cytokine expression and different MIA parameters, susceptible A.SW mice were treated with MeHg, which caused an initial immunosuppression especially with regard to B-cells. The immunosuppression was superseded by a modest induction of AFA and IL-4 mRNA, but a lack of increase in IL-2 and IFN-γ mRNA, PBA, and systemic IC deposits. While increasing the dose ofMeHg accelerated and increased AFA development, the immuno-stimulation or IC deposits could not be aggravated. Speciation of mercury showed that the organ content of MeHg and Hg gradually increased.
Linköping: Linköpings universitet , 2004. , 64 p.