Kuroda Yoshiki, Akaogi Jun, Nacionales Dina C, Wasdo Scott C, Szabo Nancy J, Reeves Westley H, Satoh Minoru
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Florida, Gainesville, Florida 32610-0221, USA.
Toxicol Sci. 2004 Apr;78(2):222-8. doi: 10.1093/toxsci/kfh063. Epub 2004 Jan 12.
Although mineral oils are generally considered nontoxic and have a long history of use in humans, the mineral oil Bayol F (incomplete Freund's adjuvant, IFA) and certain mineral oil components (squalene and n-hexadecane) induce lupus-related anti-nRNP/Sm or -Su autoantibodies in nonautoimmune mice. In the present study, we investigated whether medicinal mineral oils can induce other types of autoantibodies and whether structural features of hydrocarbons influence autoantibody specificity. Female 3-month-old BALB/c (16-45/group) mice each received an i.p. injection of pristane (C19), squalene (C30), IFA, three medicinal mineral oils (MO-F, MO-HT, MO-S), or PBS. Sera were tested for autoantibodies and immunoglobulin levels. Hydrocarbons were analyzed by gas chromatography/mass spectrometry. IFA contained mainly C15-C25 hydrocarbons, whereas MO-HT and MO-S contained C20-C40, and MO-F contained C15-C40. Pristane and n-hexadecane were found in IFA (0.17% and 0.10% w/v, respectively) and MOs (0.0026-0.027%). At 3 months, pristane and IFA induced mainly IgG2a, squalene IgG1, and MOs IgG3 and IgM in sera. Anti-cytoplasmic antibodies were common in mice treated with MO-F, as well as those treated with pristane, squalene, and IFA. Anti-ssDNA and -chromatin antibodies were higher in MO-F and MO-S than in untreated/PBS, squalene-, or IFA-treated mice, suggesting that there is variability in the induction of anti-nRNP/Sm versus -chromatin/DNA antibodies. The preferential induction of anti-chromatin/ssDNA antibodies without anti-nRNP/Sm/Su by MO-S and MO-F is consistent with the idea that different types of autoantibodies are regulated differently. Induction of autoantibodies by mineral oils considered nontoxic also may have pathogenetic implications in human autoimmune diseases.
尽管矿物油通常被认为无毒且在人类中使用历史悠久,但矿物油Bayol F(不完全弗氏佐剂,IFA)和某些矿物油成分(角鲨烯和正十六烷)可在非自身免疫小鼠中诱导产生狼疮相关的抗nRNP/Sm或-Su自身抗体。在本研究中,我们调查了药用矿物油是否能诱导其他类型的自身抗体,以及碳氢化合物的结构特征是否会影响自身抗体的特异性。3个月大的雌性BALB/c小鼠(每组16 - 45只)分别腹腔注射降植烷(C19)、角鲨烯(C30)、IFA、三种药用矿物油(MO - F、MO - HT、MO - S)或PBS。检测血清中的自身抗体和免疫球蛋白水平。通过气相色谱/质谱分析碳氢化合物。IFA主要含有C15 - C25碳氢化合物,而MO - HT和MO - S含有C20 - C40,MO - F含有C15 - C40。在IFA(分别为0.17%和0.10% w/v)和矿物油(0.0026 - 0.027%)中发现了降植烷和正十六烷。3个月时,降植烷和IFA在血清中主要诱导产生IgG2a,角鲨烯诱导产生IgG1,矿物油诱导产生IgG3和IgM。抗细胞质抗体在接受MO - F治疗以及接受降植烷、角鲨烯和IFA治疗的小鼠中很常见。MO - F和MO - S组小鼠的抗单链DNA和 - 染色质抗体水平高于未处理/ PBS、角鲨烯或IFA处理的小鼠,这表明抗nRNP/Sm与 - 染色质/DNA抗体的诱导存在差异。MO - S和MO - F优先诱导产生抗染色质/单链DNA抗体而不产生抗nRNP/Sm/Su抗体,这与不同类型的自身抗体受不同调节的观点一致。被认为无毒的矿物油诱导自身抗体产生这一现象在人类自身免疫性疾病中可能也具有致病意义。