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Murine metal-induced systemic autoimmunity: baseline and stimulated cytokine mRNA expression in genetically susceptible and resistant strains
Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
2001 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 126, no 1, 157-164 p.Article in journal (Refereed) Published
Abstract [en]

Cytokines play an important and complex role in the pathogenesis of systemic autoimmune diseases. In susceptible H-2s mice, inorganic mercury (Hg) induces lymphoproliferation, antinucleolar antibodies against the 34-kDa-protein fibrillarin, and systemic immune-complex (IC) deposits. Here, we report extensive analysis of cytokine mRNA levels in susceptible A.SW (H-2s) and resistant A.TL (H-2tl) mice under unstimulated conditions and during oral treatment with Hg and/or silver nitrate (Ag). Cytokine mRNA expression in lymphoid tissues was assessed using the ribonuclease protection assay and phosphorimaging. Baseline expression of IL-2 and IFN-γ mRNA was higher in A.SW than in A.TL mice. In A.SW mice, Hg treatment caused early up-regulation of IL-2 and IFN-γ levels, followed by substantial expression of IL-4 mRNA, which was significant compared to control A.SW and Hg-treated A.TL mice. Hg-exposed A.TL mice exhibited unchanged IFN-γ, reduced IL-2 and greatly increased IL-10 mRNA expression. Ag-treated A.SW mice, which develop antifibrillarin antibodies (AFA) but exhibit minimal immune activation and no IC deposits, showed an early increase in IL-2 and IFN-γ mRNA, but only a small and delayed rise in IL-4 mRNA. In conclusion, H-2-linked resistance to Hg-induced AFA is characterized by low constitutive expression of IL-2 and IFN-γ mRNA, which is not increased by Hg, and a marked increase in IL-10 expression. Conversely, the key features of H-2-linked susceptibility to Hg- and Ag-induced AFA are up-regulation of IL-2, IFN-γ and IL-4 mRNA expression, and down-regulation of IL-10 expression.

Place, publisher, year, edition, pages
2001. Vol. 126, no 1, 157-164 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25960DOI: 10.1046/j.1365-2249.2001.01636.xLocal ID: 10408OAI: oai:DiVA.org:liu-25960DiVA: diva2:246508
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Studies on cytokines in experimental metal-induced systemic autoimmunity
Open this publication in new window or tab >>Studies on cytokines in experimental metal-induced systemic autoimmunity
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The effect on the imnnme system of inorganic mercury (Hg), organic mercury (methyl mercury-MeHg), and silver was examined in mouse strains genetically susceptible or resistant to metal-induced systemic autoimmunity (MIA). The major aim was to study the cytokine mRNA expression in the immune system of metal-treated mice, and relate these findings to the different parameters of MIA.

Cytokine mRNA expression in lymphoid tissues was assessed using the ribonuclease protection assay (RPA) and phosphorimaging. The baseline expression of IL-2 and IFN-γ mRNA was higher in a strain (A.SW) susceptible to induction of MIA, compared with a resistant strain (A.TL). In A.SW mice Hg treatment caused early upregulation of IL-2 and IFN-γ mRNA expression, followed by substantial expression of IL-4 mRNA, and induction of antifibrillarin antibodies (AFA), lymphoproliferation and systemic immune-complex (IC) deposits. Hg treatment caused in MIA-resistant A.TL mice unchanged expression of IFN-γ mRNA, but reduced IL-2 expression. A major difference between A.SW and A.TL mice was the greatly increased IL-10 mRNA expression in the latter strain. Silver treatment of A.SW mice, which leads to a modified MIA with AFA, minimal lymphoproliferation, but no IC deposits, caused an early increase of IL-2 and IFN-γ mRNA, but only a slight increase of IL-4 mRNA.

The observation of a preferential expression of IL-10 mRNA in Hg-treated genetically MIA-resistant mice was further examined by using a strain with a targeted mutation for the IL-10 gene, as well as treatruent of genetically susceptible mice with recombinaot IL-10 (rIL-10). The IL-10 deficient strain did not develop AFA during Hg treatment, but showed a significant increase in antinuclear antibodies with a homogeneous pattern and a higher serum lgE concentration compared with Hg-treated resistant mice lacking the IL-10 mutation. The susceptible A.SW strain showed during intense treabnent with riL-10 and Hg a reduced induction of AFA, antichromalin antibodies (ACA), and serum IgE, as compared with A.SW mice only receiving Hg.

The paradigm of T helper cells type 1 (Th1) aod 2 (Th2) is often discussed in the pathogenesis of autoimmnne diseases. MIA has many characteristics of a Th2 type of reaction, but the disease induction is critically depeodent on the Th1 cytokine IFN-γ. In order to study the relevance of the Th1/Th2 concept for MIA, and to see if the disease could be aggravated by a strong deviation towards Th1, rIL-12 was given in combination with anti-IL-4 monoclonal aotibody (Mab) during treatmeut with Hg to the susceptible A.SW strain. The combined treatment reduced the Th2-dependent serum Ig isotypes, but increased the Th1-dependent IgG2a isotype. The IgG-AFA developed earlier and attained a higher titre. The renal IC deposits were severely reduced after combined treatment during the induction phase. Treatment with rIL-12 + Hg increased the Th1-dependent AFA of the IgG2a isotype, the polyclonal B-cell activation (PBA), and the IC deposits in renal and splenic vessel wall. Using only anti-IL-4 Mab during induction of MIA, the Th2-dependent serum IgG isotypes were reduced, while the development of AFA was not affected. The renal vessel wall IC deposits were reduced while the splenic vessel wall deposits were unaffected.

A previous study showed that the organic mercury compound MeHg causes a different MIA pattern than Hg. In order to examine the relation between cytokine expression and different MIA parameters, susceptible A.SW mice were treated with MeHg, which caused an initial immunosuppression especially with regard to B-cells. The immunosuppression was superseded by a modest induction of AFA and IL-4 mRNA, but a lack of increase in IL-2 and IFN-γ mRNA, PBA, and systemic IC deposits. While increasing the dose ofMeHg accelerated and increased AFA development, the immuno-stimulation or IC deposits could not be aggravated. Speciation of mercury showed that the organ content of MeHg and Hg gradually increased.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2004. 64 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 863
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-22315 (URN)1510 (Local ID)91-7373-837-9 (ISBN)1510 (Archive number)1510 (OAI)
Public defence
2004-10-22, Eken, Hälsouniversitet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-22Bibliographically approved

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Häggqvist, BoHultman, Per

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