Analysis of mercury-induced immune activation in nonobese diabetic (NOD) mice

Abstract

In susceptible mice, the heavy metal ion mercury is able to induce a strong immune activation, which resembles a T helper 2 (Th2) type of immune response and is characterized by a polyclonal B cell activation, formation of high levels of IgG1 and IgE antibodies, production of autoantibodies of different specificities and development of renal IgG deposits. In the present study, we analysed the in vivo effects of mercury in nonobese diabetic (NOD) mice, which is believed to develop a spontaneous Th1 cell-mediated autoimmune diabetes similar to type 1 diabetes in humans. Three weeks of treatment with mercury induced a strong Th2 like immune/autoimmune response in NOD mice. This response was characterized by an intensive increase in splenic IgG1 antibody secreting cells, a marked elevation in serum IgE levels, a substantial increase in splenic IL-4 mRNA, but a significant decrease in splenic IFN-gamma mRNA. Mercury-induced IgG1 antibodies were mainly against ssDNA, TNP and thyroglobulin, but not against nucleolar antigen. Moreover, mercury-injected NOD mice developed high titres of IgG1 deposits in the kidney glomeruli. We further tested if the generated Th2 response could interfere with the development of insulitis and diabetes in NOD mice. We found that three weeks of treatment with mercury was also able to significantly suppress the development of insulitis and postpone the onset of diabetes in these mice. Thus, mercury-induced immune activation can counter-regulate the Th1 cell-mediated autoimmune responses and confer a partial protection against autoimmune diabetes in NOD mice.

Trichloroethylene Does Not Accelerate Autoimmune Diabetes in NOD Mice

“…(Pollard et al, 1999). In NOD mice, on the first hand, treatment with mercury induced a strong TH 2 -like autoimmune response characterised by an increase in IgG 1 , IgG 2a , IgG 3 , and IgE serum levels associated with high levels of autoantibodies against ssDNA and thyroglobulin, and renal immune complex deposits (Brenden et al, 2001). On the other hand, HgCl 2 reduced the development of insulitis and delayed the onset of autoimmune diabetes in NOD mice with a down-regulation of IFN-γ .…”

Immunological effects of mercury (IUPAC Technical Report)

“…Mercury-induced autoimmunity in genetically susceptible strains is characterized by T-cell-induced polyclonal B-cell activation, increased levels of IgE and IgG1, production of autoantibodies to laminin, polyclonal production of antinuclear antibodies, and systemic deposits of immunocomplexes, especially in the renal vessels [45][46][47][48]. The biochemical pathomechanisms may include a B-cell-activating agent which belongs to the family of tumor necrosis factors [49], and disturbed signal transduction at the T-cell-receptor (TCR) [50] as well as T-cells and Fc-receptors [45].…”

“…The authors concluded that mercury may act as a cofactor, which favors autoimmune disease when combined with other factors, such as genetic disposition or certain infectious disease [71]. Paradoxically, mercury counterregulated the spontaneous autoimmune diabetes in nonobese diabetic mice [46].…”

Mercury Alters B-Cell Protein Phosphorylation Profiles

“…This view is supported by experiments in mouse models of autoimmune disease. In most genetically autoimmune prone mouse strains, exposure to low levels of Hg 2+ exacerbates disease 13-16 , and in mice not prone to autoimmunity low levels of Hg 2+ exacerbate disease in several models of induced (acquired) autoimmunity 6,17,18 .…”