Role of RT6+ T lymphocytes in mercury-induced renal autoimmunity: experimental manipulations of "susceptible" and "resistant" rats.
Role of RT6+ T lymphocytes in mercury-induced renal autoimmunity: experimental manipulations of "susceptible" and "resistant" rats.
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RT6 T 淋巴细胞在汞诱导的肾自身免疫中的作用：“易感”和“耐药”大鼠的实验操作。
DOI：
10.1080/15287399409531881
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Bigazzi,PE
中科院分区：
文献类型：
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作者：
Kosuda,LL;Hosseinzadeh,H;Greiner,DL;Bigazzi,PE
棕色挪威(BN)大鼠易受汞的自身免疫影响，注射相对较低剂量的氯化汞后，外周血RT6.2+T淋巴细胞减少。这一变化与肾脏抗原(如层粘连蛋白)的循环自身抗体的出现相一致。刘易斯(Lew)大鼠对汞的自身免疫效应具有抵抗力，没有表现出明显的RT6+T细胞减少。BN大鼠可能对汞引起的应激特别敏感，肾上腺皮质激素的分泌降低了该品系大鼠的RT6+T细胞水平。或者，汞可能会在BN大鼠中诱导移植物抗宿主样综合征，导致能够影响RT6+淋巴细胞的更高水平的皮质类固醇。为了消除肾上腺皮质激素的可能影响，我们在给药前切除了BN大鼠的肾上腺。对肾脏抗原的自身免疫反应不受此实验操作的影响。同样，肾上腺切除大鼠暴露于汞后，颈淋巴结中的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的假设。我们还探讨了实验性耗尽RT6+T淋巴细胞是否会导致自身免疫。BN大鼠经CAMMA照射后，其外周血中RT6+T细胞减少，但其本身(即不接触汞)不能引起对肾脏抗原的自身免疫反应。此外，用汞处理过的伽马射线照射的BN大鼠的自身免疫反应与用汞处理的未照射的对照组相似。通过使用抗RT6.1同种异体抗原的单抗去除LEW大鼠的RT6+T细胞本身并不会导致这种“耐药”品系的肾脏自身免疫。耗尽汞后给药也不能诱导肾脏自身免疫。缺乏RT6的BN和LEW大鼠缺乏自身免疫效应，这表明几种因素的组合可能是打破自身耐受和导致汞诱导的自身免疫所必需的。这些因素可能既包括环境因素(汞)，也包括基因决定的内生因素。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大鼠需要额外的免疫毒性和/或汞的毒性效应才能发生自身免疫。另一方面，缺乏调节性T细胞的LEW大鼠在暴露于汞后可能仍然无法发展出肾脏自身免疫，因为它们缺乏适当的MHC和TCR。
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. Camma 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.