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Mercury-induced autoimmunity: Genetics and immunoregulation
Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
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.
Keyword [en]
mercury, autoimmunity, collagen-induced arthritis, Th1/Th2, silver, tight-skin 1 mice
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:su:diva-47ISBN: 91-7265-813-4 (print)OAI: oai:DiVA.org:su-47DiVA: diva2:194289
Public defence
2004-03-05, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00
Opponent
Supervisors
Available from: 2004-02-10 Created: 2004-02-10Bibliographically approved
List of papers
1. Genetic control of resistance to mercury-induced immune/autoimmune activation
Open this publication in new window or tab >>Genetic control of resistance to mercury-induced immune/autoimmune activation
2001 In: Scandinavian Journal of Immunology, Vol. 54, no Jul-Aug, 190-197 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-23732 (URN)
Note
Part of urn:nbn:se:su:diva-47Available from: 2004-02-10 Created: 2004-02-10Bibliographically approved
2. Xenobiotic metal-induced autoimmunity:mercury and silver differentially induce antinucleolar autoantibody production in susceptible H-2s, H-2q and H-2f mice
Open this publication in new window or tab >>Xenobiotic metal-induced autoimmunity:mercury and silver differentially induce antinucleolar autoantibody production in susceptible H-2s, H-2q and H-2f mice
2003 In: Clinical and Experimental Immunology, Vol. 131, no 3, 405-414 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-23733 (URN)
Note
Part of urn:nbn:se:su:diva-47Available from: 2004-02-10 Created: 2004-02-10Bibliographically approved
3. Mercuric chloride induces a strong immune activation, but does not accelerate the development of dermal fibrosis in tight-skin 1 (Tsk 1) mice
Open this publication in new window or tab >>Mercuric chloride induces a strong immune activation, but does not accelerate the development of dermal fibrosis in tight-skin 1 (Tsk 1) mice
2004 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 59, no 5, 469-477 p.Article in journal (Refereed) Published
Abstract [en]

In susceptible mice, mercuric chloride induces a systemic autoimmune disease characterized by increased serum levels of immunoglobulin (Ig) G1 and IgE, production of anti-nucleolar autoantibodies (ANolA) and formation of renal IgG deposits. We have previously hypothesized that mercury confers more adverse immunological effects on those mouse strains, which are genetically prone to develop spontaneous autoimmune diseases than on normal strains. In this study, we tested our hypothesis in tight skin 1 (Tsk1/+) mice, a murine model for human scleroderma. As a support for our hypothesis, we observed that in Tsk1/+ mice, B cells were spontaneously hyperactive and that treatment with mercury induced a strong immune/autoimmune response in these mice, but not in their non-Tsk (+/+) littermates. This response was characterized by the formation of high numbers of splenic IgG1, IgG2b and IgG3 antibody-secreting cells, increased serum levels of IgE, production of IgG1 antibodies against single-stranded DNA (ssDNA), trinitrophenol (TNP) as well as thyroglobulin and the development of renal IgG1 deposits. Neither Tsk1/+ mice nor F1 hybrid crosses between this strain, and mercury susceptible B10.S (H-2s) were able to produce IgG1-ANolA in response to mercury. Moreover, mercury-induced immune activation in Tsk1/+ was not able to potentiate the progression of skin fibrosis in this strain. Thus, exposure to mercury accelerates the immune dysregulation, but not the development of skin fibrosis in Tsk1/+ mice.

Place, publisher, year, edition, pages
John Wiley & Sons, Inc, 2004
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-23734 (URN)10.1111/j.0300-9475.2004.01415.x (DOI)
Note
Part of urn:nbn:se:su:diva-47Available from: 2004-02-10 Created: 2004-02-10 Last updated: 2010-09-16Bibliographically approved
4. Interactions between Th1-type of autoimmunity (induced by collagen) and Th2-type of autoimmunity (induced by mercuric chloride)
Open this publication in new window or tab >>Interactions between Th1-type of autoimmunity (induced by collagen) and Th2-type of autoimmunity (induced by mercuric chloride)
Show others...
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:su:diva-23735 (URN)
Note
Part of urn:nbn:se:su:diva-47Available from: 2004-02-10 Created: 2004-02-10Bibliographically approved

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