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LETTERS TO THE EDITOR |
Institut National de la Santé et de la Recherche Médicale Unité 699 Bichat Medical School Paris, France
Hochegger et al. challenge our conclusion (1) that protection is mediated by the ability of mast cells (MCs) to engender repair mechanisms. Like Hochegger et al., we found in the glomeruli of wild-type mice decreased signs of inflammation and diminished numbers of inflammatory cells as compared with MC-deficient W/Wv mice. These findings were surprising to us, because in various inflammatory disease models, the presence of MC is rather known to promote an inflammatory response with leukocyte recruitment to the local site. We proposed a direct effector role of MC to explain these somewhat unexpected findings instead of an MC-mediated immunomodulatory action. This is supported by the kinetics of appearance of the thick fibrin- and collagen-containing subendothelial deposits that were increased in MC-deficient mice as compared with wild-type mice. Favored by the high doses of anti-GBM Abs used in our study, these differences in deposits appeared already during the Ab-dependent heterologous phase of the disease (2), even though at day 8 urine tissue-type plasminogen activator and urokinase-type plasminogen activator activity were also affected. The net fibrinolytic activity was in accord with the described multiple fibrinolytic effector functions of MCs. Our somewhat unexpected findings are also supported by the fact that fibrin deposits readily explain the enhancement of macrophages in the glomeruli of W/Wv mice. A strong reduction in glomerular macrophage recruitment was demonstrated in fibrinogen-deficient mice subjected to anti-GBM-induced glomerulonephritis (3). Concerning the point that P-selectin-deficient mice also show increased fibrin deposits, we think that these studies are not directly comparable because fibrin deposits are a general marker of disease aggravation. Furthermore, the effect of P-selectin deficiency on MC activation, for example through interference with complement activation, has not been evaluated.
As the role of MCs in inflammation is complex, we do not rule out an additional immunomodulatory role of MCs, especially during the late phase of the disease. However, in contrast to our results obtained in the early phase of the disease, MC-mediated enhanced infiltration with T cells, macrophages, and, accordingly, TGF-
production appear relatively late in the study of Hochegger et al., which agrees with previous findings in the literature that indicated a role of T cells rather during the autologous phase of the disease in the accelerated model of anti-GBM-induced glomerulonephritis (4).
In conclusion, although several mechanisms may be involved, we believe that the available evidence points to a direct effect of MC activation in anti-GBM-induced glomerulonephritis. It now becomes important to dissect which of the various mediators are involved.
References
RIII in the induction of accelerated nephrotoxic glomerulonephritis. Kidney Int. 64: 1406-1416. [Medline]
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