Mercury induces polyclonal B cell activation, autoantibody production and renal immune complex deposits in young (NZB × NZW)F1 hybrids

Abstract

It is well established that in susceptible mouse strains, chronic treatment with subtoxic doses of mercuric chloride (HgCl2) induces a systemic autoimmune disease, which is characterized by increased serum levels of IgG1 and IgE antibodies, by the production of anti-nucleolar antibodies and by the development of immune complex-mediated glomerulonephritis. Susceptibility to mercury is partly under the control of major histocompatibility complex genes. To study the susceptibility to mercury further, we investigated the in vivo effects of mercury in young autoimmune disease prone (NZB x NZW)F1 (H-2d/z) mice prior to establishment of spontaneous autoimmune disease. Mercury-susceptible SJL (H-2s) mice and mercury low-responder BALB/c (H-2d) mice were used as positive and negative controls, respectively. In (NZB x NZW)F1 mice, treatment with mercury stimulated an intense antibody formation characterized by increased numbers of splenic IgG1 and IgG3 antibody-producing cells as well as by elevated serum IgE levels. Injection with mercury also induced an increased production of IgG1, IgG2b and IgE antibodies in SJL, but not in BALB/c mice. The mercury-induced IgG1 response in (NZB x NZW)F1 and SJL mice was found to be polyclonal and autoantibodies against double-stranded (ds)DNA, IgG, collagen, cardiolipin, phosphatidylethanolamine as well as antibodies against the hapten trinitrophenol were produced. In addition, SJL, but not (NZB x NZW)F1 or BALB/c mice, produced IgG1 anti-nucleolar antibodies after treatment with mercury. Further studies demonstrated that (NZB x NZW)F1 and SJL mice developed high titers of renal mesangial immune complex deposits containing IgG1 antibodies 3 weeks after injection with mercury. Thus, a mouse strain genetically prone to develop spontaneous autoimmune diseases is highly susceptible to mercury-induced immunopathological alterations.

Genetic Control of Resistance to Mercury‐Induced Immune/Autoimmune Activation

“…Total mouse serum IgE was determined by a sandwich ELISA assay as described previously [16]. We used a rat antimouse IgE monoclonal antibodies (MoAb), R35-72 (Pharmingen, San Diago, CA, USA) as the capture antibody and a biotinylated rat antimouse IgE MoAb, R35-92 (Pharmingen) as the detection antibody.…”

“…The presence of IgG1 ANolA in the sera was determined by an indirect immunofluorescence method. Rat liver sections and/or HEp/2 cells grown as monolayers on slides were used as substrates and FITCconjugated goat antimouse IgG1 (Southern Biotechnology, Birmingham, AL, USA) as the detecting antibody [16]. The initial dilution for the sera was 1 : 50.…”

“…The presence of glomerular deposits of IgG1 Igs was detected by a direct immunofluorescence method, as described previously [16]. Briefly, 5 mm-thick kidney cryostat sections were fixed in acetone and incubated with serial dilutions of FITC-conjugated goat antimouse IgG1 antibody (Southern Biotechnology, Birmingham, AL, USA).…”

Thiol compounds inhibit mercury-induced immunological and immunopathological alterations in susceptible mice

“…Total mouse serum IgE antibodies were determined by a sandwich ELISA assay as described previously [10], using a rat anti-mouse IgE MoAb, R35-72 (Pharmingen, San Diego, CA) as a primary antibody and a biotinylated rat anti-mouse MoAb, R35-79 (Pharmingen) as a secondary antibody.…”

“…The presence of glomerular deposits of IgG1 antibodies was detected by direct immunofluorescence as described previously [10]. Briefly, The acetone-fixed kidney cryostat sections were incubated with serial dilutions of FITC-conjugated goat antimouse IgG1 antibodies (Southern Biothechnology, Birmingham, AL).…”