Heavy metal-induced activation of the murine immune system and autoimmunity : a comparative study of mercury and silver

• The activation and proliferation ofT- and B-cells induced by treatment with mercuric chloride (HgC12) or silver·nitrate (AgN03) was studied in mouse strains genetically susceptible (SJL, A. SW, A.TH, BALE/C) or resistant (A.TL, BALB.B) to induction of antinucleolar antibodies (ANoA) and systemic immune-complex (I C) deposits. SJL mice homozygous for the nude (nu) mutation were severely T-cell deficient. Neither these athymic SJL mice, nor euthymic SJL mice in which T-helper (CD4+) cells were eliminated by antiCD4 MAb treatment, developed ANoA or systemic IC-deposits in response to HgCI2 . Once induced, serum ANoA were not suppressed by 7 weeks high-dose anti-CD4 MAb therapy. This shows that chronic autoantibody (ANoA) production is relatively independent of CD4+ cells, and indicates that anti-CD4 MAb therapy should be given early in the course of autoimmune conditions in order to be efficient. A single subcutaneous injections ofHgCl2 induced after 4-5 days in the susceptible strains a shortlived increase in cells producing IL-2, TNF-a., IFN-y and ll.,-4, but resulted in neither immune activation nor ANoA. Subcutaneous injections ofHgC12 every third day induced on day 4-5 in the A. SW strain an activation ofT-cells with upregulation of the IL-2 receptor, an increase in IL-2- producing cells (IL-2'), and proliferation of CD4' and CD8' cells. While TNF-a' and IFN-"( cells were modestly increased on day 4 -6, IL- 4' cells dominated on day 8-10. In the susceptible SJL strain, constitutionally deficient in early IL-4-producing, Th2-promoting CD4' NKl.l' cells, IFN-y cells dominated on day 8-10. TheA.SW strain showed a doubling ofB-cells on day 14, whereas theincrease in B-cells was smaller and did not appear until day 28 in the SJL strain. Serum levels of both Th1- and Th2-dependent Ig isotypes were significantly increased after 2-4 weeks HgC12 treatment. Serum anti-ssDNA and anti-DNP antibodies of the IgM and IgG class, which are indicators of a polyclonal B-cell activation, reached a maximum in A.SW and SJL mice after 2-4 weeks treatment and then decreased. Serum ANoA, exclusively of the IgG class, first appeared after 2 weeks HgCl2 treatment in these mice, reached a maximum titre after 4 weeks, but remained increased for the next 16 weeks in both A. SW and SJL mice. Since ANoA and systemic IC-deposits developed in response to HgC12 irrespectively if a strain showed a dominance of Th2/IL-4 or Thl/ IFN-y, we found no support for the hypothesis that murine mercury-induced autoimmunity is linked to a Th2-dorninant response. However, mice with a Th2-donrinant response showed a stronger and more rapid B-cell activation than mice with a Thl -dominated response. TheA.TL and BALB.B strains showed neither activation of the immune system, nor signs of systemic autoimmunity after treatment with HgCl2. AgN03 caused in the susceptible strains less activation and proliferation of T and B cells than HgC12, and no polyclonal B-cell activation. However, the ANoA titre was not significantly different from that in HgClrtreated mice. This shows that a strong activation of the immune system with a polyclonal B-cell response, as seen in mercury treatment, is no prerequisite for development of ANoA, lending support for the importance of autoantigen-specific mechanisms in mercury- and silver-induced autoimmunity. Implantation of silver amalgam fillings, dominated by silver and mercury, in the peritoneal cavity of SJL mice caused an accumulation of mercury and silver in the internal organs, chronic stimulation of the immune system, ANoA and systemic IC-deposits in a dose- and time-dependent manner.

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