Mercuric chloride induced autoimmune disease in Brown‐Norway rats: sequential search for anti‐basement membrane antibodies and circulating immune complexes

Bellon, B; Capron, M; Druet, E; Verroust, P; Vial, M C; Sapin, Catherine; Girard, Jean; Foidart, J.M.; Mahieu, P.; Druet, Philippe

doi:10.1111/j.1365-2362.1982.tb00949.x

Cited by 85 publications

(29 citation statements)

References 16 publications

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“…In BN rats, there was up-regulation of IFN-y expression in both spleen and lymph node after HgCI2, reaching a peak at day 15, when spontaneous autoregulation of the autoimmune response is occurring [16] (Fig. 2).…”

Section: Ifny Gene Expressionmentioning

confidence: 96%

Th1/Th2 cytokine gene expression after mercuric chloride in susceptible and resistant rat strains

et al. 1996

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Mercuric chloride (HgCl2) has contrasting effects on different rat strains: susceptible strains, e.g. Brown Norway (BN) develop polyclonal B cell activation, multiple autoantibodies and widespread tissue injury. Lewis (LEW) rats are resistant: no autoimmune response occurs after HgCl2; instead, there is immunosuppression. We have previously shown, by fully quantitative polymerase chain reaction (PCR), up-regulation of interleukin-4 (IL-4) gene expression in HgCl2-treated BN rats, implicating Th2 cells in the autoimmune syndrome. Involvement of the reciprocal Th1 subset, producing interferon-gamma (IFN-gamma), in resistance of LEW rats to HgCl2 has been suggested. We now report extensive analysis of Th1 and Th2 cytokine gene expression in spleen and lymph nodes of susceptible (BN) and resistant (LEW) rats after HgCl2. IL-4 and IFN-gamma were analyzed by quantitative PCR, other cytokines were assessed using semiquantitative PCR: the relative merits of these two techniques are discussed. We show pronounced up-regulation of IL-4 and more modest up-regulation of IFN-gamma in BN rats, but no up-regulation of either in LEW rats. Baseline levels of IFN-gamma were higher in Lew rats. Semiquantitative PCR showed increased expression of IL-2, IL-6 and IL-10 in BN; in LEW rats only IL-10 was increased. There was no marked change in IL-5, IL-13 or transforming growth factor-beta (TGF-beta) in either strain. These data further support the key role of IL-4 in HgCl2-induced autoimmunity, and suggest that failure of up-regulation of IL-4, together with higher baseline IFN-gamma expression, accounts for resistance of LEW rats to HgCl2. However, neither IFN-gamma nor TGF-beta can be implicated in HgCl2-induced immunosuppression in the LEW rat in vivo: our data suggest a role for IL-10 in this phenomenon.

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Section: Ifny Gene Expressionmentioning

confidence: 96%

Th1/Th2 cytokine gene expression after mercuric chloride in susceptible and resistant rat strains

et al. 1996

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“…Experimental mercury disease damages multiple organs and causes diverse and variable clinical manifestations similar to SLE, including lymphoproliferation (6), hypergammaglobulinemia (7), autoantibody production (8), and immune glomerulonephritis (9) in the context of a susceptible genetic background. Experimental mercury disease is mediated by autoreactive, MHC class II-restricted, CD4…”

Section: F Ollowing Activation Naive Cd8mentioning

confidence: 99%

Regulatory CD8+ T Cells Control Neonatal Tolerance to a Th2-Mediated Autoimmunity

Field

Caccavelli

Bloch

et al. 2003

The Journal of Immunology

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Exposure of newborn animals to a foreign Ag may result in immunological tolerance to that specific Ag, a phenomenon called neonatal tolerance. We have previously reported that neonatal administration to Brown-Norway rats of mercury, a heavy metal toxicant, induces a dominant tolerance, specific for the chemical otherwise responsible for Th2 cell-mediated autoimmune responses in this susceptible strain of rats. Neonatal exposure to Ags can prime immunity, rather than inactivate or delete responses, and sustain regulatory functions effective against autoreactive T cells. Here, we address whether such a tolerant response is due to the generation of regulatory cells. The results suggest that the CD8+ T cell subset is involved in neonatal tolerance to mercuric salt-induced Th2 autoimmune disease. Thus, we demonstrate that in vivo CD8 depletion breaks tolerance following mercury recall in animals under a neonatal tolerance protocol. Furthermore, adoptive cotransfer of splenocytes from naive and tolerant rats as well as transfer of CD8+ T cells from tolerant animals prevent naive syngeneic rats from developing pathologic Th2 immune responses. These observations indicate that CD8+ T cells are endowed with regulatory functions in neonatal tolerance and mediate active suppression. Moreover, neonatal tolerance induced the expansion of CD8+CD45RChigh T cells and the emergence of a high percentage of IFN-γ-synthesizing CD8+ T cells, which probably reflects the implication of regulatory Tc1 cells. Thus, in vivo induction of neonatal tolerance suppresses Th2 autoimmune responses via generation of a CD8+ cell-mediated regulatory response.

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“…Relatively low doses of mercury have been found to be effective in both rats and mice; for example, the immunotoxic effects of If -HgCI2 occur in BN rats at doses (3-25 ,g/100 g body weight) that are much lower than those causing the common nephrotoxic effects (11,12,Bigazzi et al, unpublished data). However, in the experiments reported here, we used higher levels of HgCl2 (100 ,ug/100 g body weight) to replicate the doses used in previous studies of BN and LEW rats (17,18,20).…”

Section: Methodsmentioning

confidence: 99%

Mercury-induced renal autoimmunity: changes in RT6+ T-lymphocytes of susceptible and resistant rats.

Kosuda

Greiner

Bigazzi

1993

Environ Health Perspect

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The repeated administration of mercury to rats of the Brown Norway (BN) inbred strain results in a self-limiting production of autoantibodies to renal antigens (e.g., laminin) and autoimmune glomerulonephritis. In contrast, rats of the Lewis (LEW) strain do not develop renal autoimmunity after mercury treatment. Suppressor T-cells and/or the idiotype-anti-idiotype network have been implicated in the control of autoimmunity in susceptible (BN) rats as well as the "resistant" state of nonsusceptible (LEW) animals. In our investigations of the immune regulation of mercury-induced autoimmune glomerulonephritis, we have performed a phenotypic analysis of lymphocyte subpopulation in the spleens and lymph nodes of mercury-treated and control LEW, BN, and (BN x LEW) F1 hybrid rats. Of particular interest were RT6+ T-cells, a subpopulation of lymphocytes that may have immunoregulatory properties and show a relative decrease in mercury-treated BN rats concomitantly with the development of autoimmune responses to renal autoantigens. LEW rats did not develop renal autoimmunity after mercury treatment and had no significant change in the ratio of RT6+ to RT6- T-lymphocytes. Interestingly, the administration of mercury to (BN x LEW) F1 hybrid rats caused effects similar to those observed in the BN strain. Auto-immune responses to antigens of the kidney coincided with a change in the balance within the RT6 cell population, which was altered in favor of T-lymphocytes that do not express the RT6 phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

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Mercuric chloride induced autoimmune disease in Brown‐Norway rats: sequential search for anti‐basement membrane antibodies and circulating immune complexes

Cited by 85 publications

References 16 publications

Th1/Th2 cytokine gene expression after mercuric chloride in susceptible and resistant rat strains

Th1/Th2 cytokine gene expression after mercuric chloride in susceptible and resistant rat strains

Regulatory CD8+ T Cells Control Neonatal Tolerance to a Th2-Mediated Autoimmunity

Mercury-induced renal autoimmunity: changes in RT6+ T-lymphocytes of susceptible and resistant rats.

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