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Interactions between Th1-type of autoimmunity (induced by collagen) and Th2-type of autoimmunity (induced by mercuric chloride)
Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
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Article in journal (Refereed) Submitted
URN: urn:nbn:se:su:diva-23735OAI: diva2:194288
Part of urn:nbn:se:su:diva-47Available from: 2004-02-10 Created: 2004-02-10Bibliographically approved
In thesis
1. Mercury-induced autoimmunity: Genetics and immunoregulation
Open this publication in new window or tab >>Mercury-induced autoimmunity: Genetics and immunoregulation
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The existence of immune self-tolerance allows the immune system to mount responses against infectious agents, but not against self-molecular constitutes. Although self-tolerance is a robust phenomenon, in some individuals as well as in experimental models, the self-tolerance breaks down and as a result, a self-destructive autoimmune disease emerges. The underlying mechanisms for the development of autoimmune diseases are not known, but genetic, environmental and immunological factors are suggested to be involved. In this thesis, we used murine mercury-induced autoimmunity to test this suggestion.

In susceptible mice mercuric chloride induces a systemic autoimmune disease characterized by increased serum levels of IgG1 and IgE, production of anti-nucleolar autoantibodies (ANolA) and formation of renal IgG deposits. In contrast, in resistant DBA/2 (H-2d) mice, none of these characteristics develop after exposure to mercury. By crossing and backcrossing mercury-resistant DBA/2 mice to mercury susceptible strains, we found that the resistance was inherited as a dominant trait in F1 hybrids and that one gene or a cluster of genes located in the H-2 loci determined the resistance to ANolA production, whereas resistance to the other characteristics was found to be controlled by two or three non-H-2 genes.

We further put forward the “cryptic peptide hypothesis” to investigate whether mercury and another xenobiotic metal use similar pathway(s) to induce the H-2 linked production of ANolA. We found that while mercury stimulated ANolA synthesis in all H-2 susceptible (H-2s, H-2q and H-2f) mouse strains, silver induced only ANolA responses in H-2s and H-2q mice, but not in H-2f mice. Further studies showed that the resistance to silver-induced ANolA production in H-2f mice was inherited as a dominant trait.

We next tested the proposition that mercury induces more adverse immunological effects in mouse strains, which are genetically prone to develop autoimmune diseases, using tight-skin 1 mice, an animal model for human Scleroderma. It was found that in this strain, mercury induced a strong immune activation with autoimmune characteristics, but did not accelerate the development of dermal fibrosis, a characteristic in Tsk/1 mice.

Finally we addressed the Th1/Th2 cross-regulation paradigm by examining if a Th1-type of response could interact with a Th2-type of response if simultaneous induced in susceptible mice. Our findings demonstrated that mercury-induced autoimmunity (Th2-type) and collagen-induced arthritis (CIA) (Th1-type) can interact in a synergistic, antagonistic or additive fashion, depending on at which stage of CIA mercury is administered.

Place, publisher, year, edition, pages
Stockholm: Wenner-Grens institut för experimentell biologi, 2004. 44 p.
mercury, autoimmunity, collagen-induced arthritis, Th1/Th2, silver, tight-skin 1 mice
National Category
Immunology in the medical area
urn:nbn:se:su:diva-47 (URN)91-7265-813-4 (ISBN)
Public defence
2004-03-05, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00
Available from: 2004-02-10 Created: 2004-02-10Bibliographically approved

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