Susceptibility of lupus-prone NZM mouse strains to lead exacerbation of systemic lupus erythematosus symptoms
Susceptibility of lupus-prone NZM mouse strains to lead exacerbation of systemic lupus erythematosus symptoms
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DOI：
10.1080/15287390306456
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发表时间：
2003-05-23
影响因子：
2.6
通讯作者：
Lawrence, DA
中科院分区：
文献类型：
--
作者：
Hudson, CA;Cao, L;Lawrence, DA
研究表明，重金属汞可诱导或加重易感品系大鼠和小鼠的狼疮样自身免疫反应。这种自身免疫诱导的一个特点是伴随着免疫转变，在这种转变中，通常最初会向Th2样的免疫环境倾斜。另一种重金属铅(铅)也被发现会引起小鼠Th2细胞的变化。然而，正常小鼠品系暴露于铅似乎并不能诱导自身免疫。为了研究遗传易感性的小鼠系统性红斑狼疮(SLE)是否易受铅致狼疮加重的易感性，4个新西兰混合(NZM)品系的雄性和雌性小鼠以及BALB/c和C57BL/6对照组，每周三次100-MUL的腹腔注射1.31 mM铅或醋酸钠，共3wk。四株NZM菌株NZM391、NZM2328、NZM88和NZM2758对SLE具有不同的遗传外显性，但这些菌株都会自然发展为肾小球肾炎，并产生高滴度的抗核自身抗体。小鼠在注射后(D1)直接放血，此后每月放血5个月。检测血清中抗双链DNA滴度、尿素氮水平和肌酸激酶活性，以及总免疫球蛋白(1g)G2a和IgG1水平。记录小鼠的死亡率和发病率。所有NZM菌株在d1都表现出对铅的急性、非性别敏感性，但对照菌株未受影响。随着时间的推移，很明显，这些菌株出现了分化：NZM391菌株表现出对铅的性别独立敏感性，狼疮症状和死亡率增加；NZM2328菌株表现出性别独立的铅敏感性，尽管只有女性增加了死亡率；NZM2758菌株显示出尿素氮和肌酸激酶活性水平的非性别升高；以及NZM88菌株显示出男性对抗DNA的敏感性和寿命。令人惊讶的是，铅延长了NZM88和NZM2758雌性的寿命。这些结果表明，铅确实可以加重狼疮易感小鼠的系统性红斑狼疮；然而，即使在狼疮易感品系之间，遗传差异也决定了恶化的程度。利用已知的表型和遗传差异，可以识别和表征与铅易感性相关的可能的性状和基因座。
It has been repeatedly shown that the heavy metal mercury can induce or exacerbate lupuslike autoimmunity in susceptible strains of rats and mice. A hallmark of such autoimmune induction is the accompaniment of an immune shift, in which there is usually an initial skewing toward a Th2-like immune environment. Another heavy metal, lead (Pb), has also been found to induce a Th2 shift in mice. However, exposure of normal mouse strains to Pb does not appear to induce autoimmunity. In order to investigate whether mice genetically predisposed to murine systemic lupus erythematosus (SLE) are susceptible to a Pb-induced exacerbation of lupus, males and females of four New Zealand mixed (NZM) mouse strains, along with BALB/c and C57Bl/6 controls, were administered three 100-mul intraperitoneal injections of either 1.31 mM lead or sodium acetate per week for 3 wk. The four NZM strains chosen, NZM391, NZM2328, NZM88, and NZM2758, have differential genetic penetrance for SLE with variances in certain manifestations of the disease, but all of these strains naturally develop glomerulonephritis and produce high titers of anti-nuclear autoantibodies. The mice were prebled for baseline values and were bled directly after the injection period (d 1) and monthly thereafter for 5 mo. Sera were assessed for anti-double-stranded DNA titers, urea nitrogen levels, and creatine kinase activity, as well as for total immunoglobulin (1g) G2a and IgG1 levels. Mortality and morbidity of the mice were also recorded. All NZM strains showed an acute, non-gender-based, susceptibility to Pb at d 1, but the control strains were unaffected. Over time, it became apparent that the strains diverged: The NZM391 strain showed gender-independent susceptibility to Pb enhancement of lupus manifestations and mortality; the NZM2328 strain exhibited gender-independent Pb susceptibility to manifestations, although only females had increased mortality; the NZM2758 strain exhibited non-gender-based elevations in urea nitrogen and creatine kinase activity levels; and the NZM88 strain displayed male susceptibility to anti-DNA and life span. Surprisingly, Pb increased the longevity of NZM88 and NZM2758 females. These results indicate that Pb indeed can exacerbate SLE in lupus-prone mice; however, even among lupus-prone strains, genetic differences determine the degree of exacerbation. Using the known phenotype and genetic differences, one can identify and characterize possible traits and loci associated with Pb susceptibility.