Genetic Susceptibility to Silver-Induced Anti-fibrillarin Autoantibodies in Mice

• Published in: Clinical immunology and immunopathology 1995-12, Vol.77 (3), p.291-297
• Main Authors: Hultman, Per, Ganowiak, Katarzyna, Turley, Shannon J., Pollard, K.Michael
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Antinuclear - immunology; Autoimmunity - drug effects; Autoimmunity - genetics; Biological and medical sciences; Blood Vessels - immunology; Cell Nucleolus - immunology; Chromatin - immunology; Chromosomal Proteins, Non-Histone - immunology; Experimental and animal immunopathology. Animal models; Female; Fluorescent Antibody Technique, Indirect; Glomerular Mesangium - immunology; Histones - immunology; Immunoblotting; Immunopathology; Medical sciences; Mice; Mice, Inbred Strains; Silver Nitrate - toxicity
• ISSN: 0090-1229; 1090-2341
• DOI: 10.1006/clin.1995.1155

Similar to mercuric chloride, silver nitrate has recently been shown to induce IgG autoantibodies targeting the nucleolar 34-kDa protein fibrillarin i SJL (H-2 δ) mice. In the present study we show that the autoimmunogenic effect of silver is dependent on intact T-cell function since SJL/N mice homozygous for the nude mutation (athymic), in contrast to the functionally T-cell-intact SJL/N-nu/+ littermates, did not develop anti-nucleolar/anti-fibrillarin autoantibodies (ANoA/AFA). The genetic susceptibility for silver-induced AFA was localized to the H-2A locus using congenic and intra-H-2-recombinant strains. However, background (non-H-2) genetic factors substantially influenced both the response rate and the titer of ANoA/AFA attained. Strains bearing H-2A δ on the SJL and A backgrounds (SJL, A. SW, A. TH) showed 100% response rate and high ANoA titers (3750 ± 246, mean reciprocal titer ± SEM), whereas H-2A δ mice on the B10 background (B10.S) showed 60% response rate and significantly lower ANoA titers (1170 ± 305) in the responding mice. Expression of H-2E [B10.S(9R) mice] further reduced the response rate (22%) and the ANoA titer (640 ± 0). A suppressive effect on the B10 background has previously been observed in mercury treatment, but the effect was stronger in silver-treated mice. Two major differences were noted between silver- and mercury-induced murine autoimmunity. First, silver-treated mice did not show elevated titers of other autoantibody specificities, specifically not of anti-chromatin and anti-histone antibodies, which develop in mercury-treated SJL mice. Second, silver-treated mice totally lacked the systemic immune-complex deposits seen in mercury-induced murine autoimmunity. Our studies indicate that silver induces a highly specific (auto)antigen-driven reaction against the nucleolar antigen fibrillarin, whereas mercury causes a broader immune (B)-cell activation targeting nucleolar as well as nuclear components, although with fibrillatin as the major autoantigen. This broader immune activation appears to be required for development of the systemic immune-complex deposits seen in mercury treatment.