Amirhosseini Mehdi, Alkaissi Hammoudi, Hultman Per A, Havarinasab Said
Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden; Department of Clinical Pathology, Linköping University, Linköping, Sweden.
Toxicol Appl Pharmacol. 2021 Feb 1;412:115379. doi: 10.1016/j.taap.2020.115379. Epub 2020 Dec 24.
Exposure to heavy metals may have toxic effects on several human organs causing morbidity and mortality. Metals may trigger or exacerbate autoimmunity in humans. Inbred mouse strains with certain H-2 haplotypes are susceptible to xenobiotic-induced autoimmunity; and their immune response to metals such as mercury, gold, and silver have been explored. Serum antinuclear antibodies (ANA), polyclonal B-cell activation, hypergammaglobulinemia and tissue immune complex deposition are the main features of metal-induced autoimmunity in inbred mice. However, inbred mouse strains do not represent the genetic heterogeneity in humans. In this study, outbred Swiss Webster (SW) mice exposed to gold or mercury salts showed immune and autoimmune responses. Intramuscular injection of 22.5 mg/kg.bw aurothiomalate (AuTM) induced IgG ANA in SW mice starting after 5 weeks that persisted until week 15 although with a lower intensity. This was accompanied by elevated serum levels of total IgG antibodies against chromatin and total histones. Exposure to gold led to development of serum IgG autoantibodies corresponding to H1 and H2A histones, and dsDNA. Both gold and mercury induced polyclonal B-cell activation. Eight mg/L mercuric chloride (HgCl) in drinking water, caused IgG antinucleolar antibodies (ANoA) after 5 weeks in SW mice accompanied by immune complex deposition in kidneys and spleen. Serum IgG antibodies corresponding to anti-fibrillarin, and anti-PM/Scl-100 antibodies, were observed in mercury-exposed SW mice. Gold and mercury trigger systemic autoimmune response in genetically heterogeneous outbred SW mice and suggest them as an appropriate model to study xenobiotic-induced autoimmunity.
接触重金属可能会对人体多个器官产生毒性作用，导致发病和死亡。金属可能会引发或加剧人类的自身免疫。具有特定H-2单倍型的近交系小鼠易受外源性物质诱导的自身免疫影响；并且已经对它们对汞、金和银等金属的免疫反应进行了研究。血清抗核抗体（ANA）、多克隆B细胞活化、高球蛋白血症和组织免疫复合物沉积是近交系小鼠中金属诱导的自身免疫的主要特征。然而，近交系小鼠并不代表人类的遗传异质性。在本研究中，接触金盐或汞盐的远交系瑞士韦伯斯特（SW）小鼠表现出免疫和自身免疫反应。肌肉注射22.5mg/kg体重的硫代苹果酸金钠（AuTM）在5周后开始诱导SW小鼠产生IgG ANA，并持续到第15周，尽管强度较低。这伴随着血清中针对染色质和总组蛋白的总IgG抗体水平升高。接触金导致产生对应于H1和H2A组蛋白以及双链DNA的血清IgG自身抗体。金和汞都诱导多克隆B细胞活化。饮用水中8mg/L的氯化汞（HgCl）在5周后导致SW小鼠产生IgG抗核仁抗体（ANoA），同时伴有肾脏和脾脏中的免疫复合物沉积。在接触汞的SW小鼠中观察到对应于抗纤维蛋白原和抗PM/Scl-100抗体的血清IgG抗体。金和汞在遗传异质性的远交系SW小鼠中引发全身性自身免疫反应，并表明它们是研究外源性物质诱导的自身免疫的合适模型。
