The effect of dose, gender, and non-H-2 genes in murine mercury-induced autoimmunity.
We have studied the effect of dose, treatment time, gender and non-H-2 genes on immune parameters and toxicokinetics in murine mercury-induced autoimmunity (HgAI). The partly-proven mechanism for HgAI is the modification of the autoantigen fibrillarin by mercury, followed by a T cell-dependent immune response driven by the modified fibrillarin. In the H-2 congenic (H-2(S)) mouse strains A.SW and B10.S given (203)HgCl(2) in a dose of 0.25-8 mg Hg/l drinking water for up to 10 weeks, the internal dose measured as the whole-body retention of mercury reached steady state within 5 weeks. Fifty percent of the steady state level was reached already after 2 days. Conditions therefore exist for a rapid modification of fibrillarin, followed by a T cell-dependent immune response, which is consistent with the presence of anti-fibrillarin antibodies (AFA) in serum after 2 weeks. AFA developed in a dose-dependent pattern. Serum IgE showed a dose-dependent increase with a maximum after 1-2.5 weeks followed by a distinct decline towards the baseline level. Substantial polyclonal B-cell activation (PBA) developed in the highest dose groups only. Since AFA developed using lower doses too, PBA can be excluded as a general mechanism for induction of AFA. Tissue immune-complex (IC) deposits were present in the highest dose groups only, indicating a possible causality between PBA and IC deposits. The substantially lower whole body and organ mercury level needed to induce AFA in the A.SW strain as compared with the H-2 congenic B10.S strain, demonstrates that genetic factors outside the H-2 region, and not related to toxicokinetics, modifies the autoimmune response. In contrast, the difference in mercury thresholds for induction of IgE was only slight between A.SW and B10.S mice, indicating basically different mechanisms for induction of AFA and serum IgE.
Hultman
P
P
Division of Molecular and Immunological Pathology, Department of Health and Environment, Linköping University, SE-581 85 Linköping, Sweden. perhu@pai.liu.se
Nielsen
J B
JB
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000097:blood; D000936:Antigen-Antibody Complex / Q000032:analysis; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects / Q000276:immunology; D002868:Chromosomal Proteins, Non-Histone / Q000276:immunology; D004277:DNA, Single-Stranded / Q000276:immunology; D004140:Dinitrophenols / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004326:Drinking / Q000187:drug effects; D005260:Female; D006183:H-2 Antigens / Q000235:genetics* / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood; D008297:Male; D008628:Mercury / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D009928:Organ Specificity / Q000187:drug effects / Q000276:immunology; D012727:Sex Characteristics
D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D002868:Chromosomal Proteins, Non-Histone; D004277:DNA, Single-Stranded; D004140:Dinitrophenols; D006183:H-2 Antigens; C047458:fibrillarin; D007073:Immunoglobulin E; D008628:Mercury