Autoreactive T cells in mercury‐induced autoimmunity. Demonstration by limiting dilution analysis

Rossert, Jérôme; Pelletier, Lucette; Pasquier, R. Du; Druet, Philippe

doi:10.1002/eji.1830181116

Cited by 59 publications

(48 citation statements)

References 30 publications

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“…It has been previously reported that Brown Norway (BN) rats receiving sublethal doses of HgCl 2 develop an inflammatory syndrome (Pelletier et al, 1986;Rossert et al, 1988;Pusey et al, 1990). Recently, we have demonstrated that at-RA treatment significantly reduces the inflammatory response observed during HgCl 2 -induced nephritis in BN rats by inhibiting the cell infiltration into the renal interstitium as well as the release of proinflammatory mediators (Escribese et al, 2007).…”

mentioning

confidence: 68%

Mononuclear Cell Extravasation in an Inflammatory Response Is Abrogated by All-Trans-Retinoic Acid through Inhibiting the Acquisition of an Appropriate Migratory Phenotype

Escribese¹,

Conde²,

Sáenz-Morales³

et al. 2007

J Pharmacol Exp Ther

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The inflammatory response is tightly regulated by several mediators that promote the adhesive and migratory capacities of different cell types, including peripheral blood mononuclear cells (PBMCs). Our laboratory has previously characterized the inflammatory response developed in the experimental model of mercuric chloride (HgCl 2 )-induced nephritis in Brown Norway rats as an acute inflammatory response dependent on very late antigen (VLA)-4. This response can be modulated by all-transretinoic acid (at-RA), a vitamin A metabolite that regulates a broad range of biological processes and exhibits anti-inflammatory properties. Based on this in vivo experimental model, we have established a VLA-4-dependent ex vivo system to study the effect of at-RA on PBMC polarization, adhesion, and migration and to elicit new mechanisms triggered by at-RA for abrogating an inflammatory response. We found that at-RA significantly reduces the VLA-4-dependent migration of PBMCs activated in vivo. In addition, we demonstrated by spreading assays that in vivo at-RA treatment abrogates the acquisition of a polarized cell phenotype. In fact, at-RA inhibits the actin polymerization required for cell morphology changes, and it alters the distribution of F-actin and VLA-4 integrin in focal contacts, essential for cell adhesion. Moreover, we describe that at-RA also abrogates the redistribution of Rac1 and RhoA, important proteins implicated in the dynamic process of cell movement. In summary, we demonstrate the capacity of at-RA to block the acquisition of an appropriate migratory phenotype in PBMCs as a new mechanism underlying the anti-inflammatory effects of this compound.Leukocytes extravasation from the bloodstream into the tissue is of key importance in several physiological and pathological processes (Tanaka, 2001). During infiltration, these cells show a polarized morphology essential for directional movement. This polarization is characterized by a flat lamella extending in the direction of migration, which ends in a lamellipodium (the leading edge) and by a narrow retracting tail at the rear of the cell (for review, see Fais and Malorni, 2003). Although migratory phenotypes and factors that promote migration vary greatly among cell types and infiltration stimuli, a universal mechanism triggered by chemotactic factors that underlies cell migration is actin polymerization (Pollard and Borisy, 2003).Retinoic acid has been described as a potent modulator of immune responses and inflammatory diseases (Perez de Lema et al., 2004;Adams et al., 2005) Additionally, at-RA exhibited effects on adhesion molecules, abolishing in vitro ␣4 integrindependent rolling in the acute promyelocytic leukemia cell line NB-4 (Brown et al., 1999) and down-regulating the expression and function of ␤2 integrins in primary human monocytes (Babina and Henz, 2003). These in vitro results support those described in experimental in vivo models and, more in particular, in experimental models of kidney diseases where at-RA

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confidence: 68%

Mononuclear Cell Extravasation in an Inflammatory Response Is Abrogated by All-Trans-Retinoic Acid through Inhibiting the Acquisition of an Appropriate Migratory Phenotype

Escribese¹,

Conde²,

Sáenz-Morales³

et al. 2007

J Pharmacol Exp Ther

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“…Recently, some progress has been made [39,40], in that bulk T cells of HgCl 2 -treated B10.S mice were found to react against a variety of different self proteins altered by Hg 2+ , in particular fibrillarin, a small ribonucleoprotein that is mainly located in the nucleolus and is the principal target of ANolA in these mice [41,42]. Moreover, in HgCl 2 -treated Brown Norway rats an activation of autoreactive CD4 + T cells has been described [43,44], albeit that the MHC II-associated self proteins recognized by them have not yet been identified; recent experimental evidence indicates that these cells are of the Th2 type [17] (P. Druet, personal communication). These and other findings [7,15,16,45,46] indicate that in animals susceptible to HgCl 2 -induced systemic autoimmune disease an activation of the immune system takes place that favours a Th2-like reaction.…”

Section: Discussionmentioning

confidence: 99%

Genetic differences in immune reactivity to mercuric chloride (HgCl2): immunosuppression of H-2d mice is mediated by interferon-gamma (IFN-γ)

Doth

Fricke

Nicoletti

et al. 1997

Clinical and Experimental Immunology

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SUMMARYUpon treatment with HgCl 2 , H-2 s mice, such as B10.S, develop an activation of B lymphocytes that depends, at least partially, on activation of T helper type 2 (Th2) cells and results in increased serum levels of IgG1 and IgE, appearance of IgG autoantibodies, and development of immune glomerulonephritis and vasculitis. Results of previous studies and of experiments presented here indicate that the B cell activation and systemic autoimmune disease fail to develop in MHC-congenic B10.D2 (H-2 d ) and B10.BR (H-2 k ) mice treated with HgCl 2 , although B10.D2 T cells showed signs of activation by and specificity for HgCl 2 comparable to those seen in strain B10.S. Here, we report that following HgCl 2 injections the antibody response to sheep erythrocytes is normal in B10.S, but suppressed in B10.D2 mice. This suppression was prevented by MoAb to mouse IFN-g. Conversely, treatment of B10.D2 mice with murine recombinant IFN-g (rIFN-g) was able to reproduce the immunosuppression seen after HgCl 2 treatment. In B10.S mice, it took administration of both rIFN-g and HgCl 2 to suppress the antisheep erythrocyte response. Although rIFN-g diminished the increase in IgE serum levels of HgCl 2 -treated B10.S mice, it failed to prevent their autoantibody production and immune glomerulonephritis. These findings further strengthen the concept that B10.S mice react to HgCl 2 by preferential activation of their Th2 cells producing IL-4, whereas B10.D2 mice react to HgCl 2 by preferential activation of their Th1 cells, which produce IFN-g and thus suppress antibody responses.

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“…While this is a theoretical possibility, it seems unlikely. In a study using limiting-dilution analysis for autoreactive T-lymphocytes in BN rats injected with HgCl 2 there was no further increase in the number of autoreactive T-lymphocytes from day 6 to day 14 after commencing injections of HgCl 2 suggesting that full recruitment of naïve cells had occurred by day 6 [38].…”

Section: Discussionmentioning

confidence: 97%

The Th2-response in mercuric chloride-induced autoimmunity requires continuing costimulation via CD28

MacPhee¹,

Turner²,

Yagita

et al. 2002

Clinical and Experimental Immunology

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SUMMARY Mercuric chloride (HgCl2)‐induced autoimmunity in Brown Norway (BN) rats is a highly polarized polyclonal Th2‐driven autoimmune response with increased IgE production, lymphoproliferation, vasculitis and proteinuria. The increase in serum IgE concentration is clearly measurable by day 4 after the first HgCl2 injection and peaks between days 15 and 20. Treatment with CD80 and CD86 antibodies prior to administration of HgCl2 completely suppresses the autoimmune process. To determine whether interruption of CD28 signalling after initial stimulation of the Th2‐response would be suppressive, antibody treatment was delayed. BN rats were given 5 doses of HgCl2 subcutaneously on alternate days. CD80 and CD86 antibodies, or an isotype control, were given daily for 3 days and then on alternate days until day 12 commencing either on the day of the first HgCl2 injection (day 0) or on days 4 or 8. Treatment from day 0 reduced serum IgE concentrations to below baseline (median 9·34μg/ml on day 0 versus 4·6μg/ml, on day 5, P = 0·03) suggesting that ongoing costimulation via CD28 is required to maintain basal serum IgE production. Delaying treatment until day 4 or day 8 after the first HgCl2 injection resulted in significant inhibition of IgE secretion, lymphoproliferation, and vasculitis, although less markedly than when treatment was commenced on day 0. These data indicate that CD28‐mediated costimulation is not only required for the initiation of the Th2‐response but is required for maintenance of a maximal response, making this an attractive therapeutic target for antibody‐mediated autoimmune diseases.

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Autoreactive T cells in mercury‐induced autoimmunity. Demonstration by limiting dilution analysis

Cited by 59 publications

References 30 publications

Mononuclear Cell Extravasation in an Inflammatory Response Is Abrogated by All-Trans-Retinoic Acid through Inhibiting the Acquisition of an Appropriate Migratory Phenotype

Mononuclear Cell Extravasation in an Inflammatory Response Is Abrogated by All-Trans-Retinoic Acid through Inhibiting the Acquisition of an Appropriate Migratory Phenotype

Genetic differences in immune reactivity to mercuric chloride (HgCl2): immunosuppression of H-2d mice is mediated by interferon-gamma (IFN-γ)

The Th2-response in mercuric chloride-induced autoimmunity requires continuing costimulation via CD28

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