Kosuda L L, Hosseinzadeh H, Greiner D L, Bigazzi P E
Department of Pathology, University of Connecticut Health Center, Farmington 06030.
J Toxicol Environ Health. 1994 Jul;42(3):303-21. doi: 10.1080/15287399409531881.
Brown Norway (BN) rats, "susceptible" to the autoimmune effects of mercury, experience a decrease of peripheral RT6.2+ T lymphocytes after the injection of relatively low doses of mercuric chloride. This change coincides with the appearance of circulating autoantibodies to renal antigens (e.g., laminin). Lewis (LEW) rats, "resistant" to the autoimmune effects of mercury, do not show significant decreases of RT6+ T cells. It is possible that BN rats are particularly sensitive to stress induced by mercury and that secretion of adrenocortical hormones decreases levels of RT6+ T cells in this rat strain. Alternatively, mercury may induce a graft-versus-host-like syndrome in BN rats, resulting in higher levels of corticosteroids capable of affecting RT6+ lymphocytes. To eliminate the possible influence of adrenocortical hormones, we have adrenalectomized BN rats prior to administration of mercury. Autoimmune responses to renal antigens were not affected by this experimental manipulation. Similarly, adrenalectomized rats exposed to mercury showed a significant decrease of RT6+ T lymphocytes in cervical lymph nodes. Overall, these observations do not support the hypothesis that increases in adrenocortical hormones play a major role in mercury-induced changes of RT6+ T cells. We have also explored whether experimental depletion of RT6+ T lymphocytes would result in autoimmunity. Gamma irradiation of BN rats led to a decrease of RT6+ T splenocytes, but by itself (i.e., without exposure to mercury) did not cause autoimmune responses to renal antigens. In addition, gamma-irradiated BN rats treated with mercury had autoimmune responses similar to those observed in mercury-treated nonirradiated controls. Depletion of RT6+ T cells in LEW rats through the use of a monoclonal antibody against the RT6.1 alloantigen did not by itself cause renal autoimmunity in this "resistant" strain. Depletion followed by administration of mercury also failed to induce renal autoimmunity. The lack of autoimmune effects in RT6-depleted BN and LEW rats suggests that a combination of several factors may be necessary to break self-tolerance and cause mercury-induced autoimmunity. Such factors likely comprise both environmental (mercury) and endogenous, genetically determined components. The latter include regulatory T cells (possibly RT6+), major histocompatibility complex (MHC), and T-cell receptors (TCR). Thus, BN rats with decreased percentages of immunoregulatory RT6+ T lymphocytes require additional immunotoxic and/or toxic effects of mercury for autoimmunity to occur. On the other hand, LEW rats depleted of regulatory T cells may still be unable to develop renal autoimmunity after exposure to mercury because they lack the appropriate MHC and TCR.
对汞的自身免疫效应“敏感”的棕色挪威（BN）大鼠，在注射相对低剂量的氯化汞后，外周RT6.2 + T淋巴细胞数量减少。这一变化与针对肾抗原（如层粘连蛋白）的循环自身抗体的出现同时发生。对汞的自身免疫效应“有抗性”的刘易斯（LEW）大鼠，RT6 + T细胞没有显著减少。有可能BN大鼠对汞诱导的应激特别敏感，并且肾上腺皮质激素的分泌降低了该大鼠品系中RT6 + T细胞的水平。或者，汞可能在BN大鼠中诱发移植物抗宿主样综合征，导致能够影响RT6 +淋巴细胞的皮质类固醇水平升高。为了消除肾上腺皮质激素的可能影响，我们在给BN大鼠施用汞之前对其进行了肾上腺切除术。对肾抗原的自身免疫反应不受该实验操作的影响。同样，暴露于汞的肾上腺切除大鼠颈部淋巴结中的RT6 + T淋巴细胞显著减少。总体而言，这些观察结果不支持肾上腺皮质激素增加在汞诱导的RT6 + T细胞变化中起主要作用这一假设。我们还探讨了实验性消耗RT6 + T淋巴细胞是否会导致自身免疫。对BN大鼠进行γ射线照射导致RT6 + T脾细胞减少，但仅此一项（即不暴露于汞）不会引起对肾抗原的自身免疫反应。此外，用汞处理的γ射线照射BN大鼠的自身免疫反应与在未照射的汞处理对照中观察到的相似。通过使用针对RT6.1同种抗原的单克隆抗体耗尽LEW大鼠中的RT6 + T细胞，本身并不会在这个“有抗性”的品系中引起肾自身免疫。耗尽后再施用汞也未能诱导肾自身免疫。在RT6耗尽的BN和LEW大鼠中缺乏自身免疫效应表明，可能需要多种因素共同作用才能打破自身耐受性并导致汞诱导的自身免疫。这些因素可能包括环境（汞）和内源性的、由基因决定的成分。后者包括调节性T细胞（可能是RT6 +）、主要组织相容性复合体（MHC）和T细胞受体（TCR）。因此，免疫调节性RT6 + T淋巴细胞百分比降低的BN大鼠需要汞的额外免疫毒性和/或毒性作用才能发生自身免疫。另一方面，耗尽调节性T细胞的LEW大鼠在暴露于汞后可能仍然无法发生肾自身免疫，因为它们缺乏合适的MHC和TCR。
