Gestational Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Disrupts B-Cell Lymphopoiesis and Exacerbates Autoimmune Disease in 24-Week-Old SNF1 Mice
Gestational Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Disrupts B-Cell Lymphopoiesis and Exacerbates Autoimmune Disease in 24-Week-Old SNF1 Mice
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DOI：
10.1093/toxsci/kfp177
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发表时间：
2009-11-01
影响因子：
3.8
通讯作者：
Gogal, Robert M., Jr.
中科院分区：
文献类型：
--
作者：
Mustafa, Amjad;Holladay, Steven D.;Gogal, Robert M., Jr.
雌性SNF 1杂交小鼠早在24周龄就自发地发展免疫复合物介导的肾小球肾炎，而雄性的疾病发作要慢得多。此外，通过自身反应性B细胞的肾小球特异性自身抗体浓度的升高对该菌株中疾病的进展至关重要。导致这种自身免疫的发病或程度的环境因素是令人感兴趣的，但知之甚少。在本研究中，时间怀孕的SWR x NZB母鼠（10/治疗）在妊娠12日用40或80 mg/kg的2，3，7，8-四氯二苯并-p-二恶英（TCDD）灌胃，并在24周龄时对SNF 1后代进行评价。TCDD可使雌性子代的骨髓B220（low-）CD 24（-）AA 4.1（+）定向B系祖细胞增多，而雄性子代的定向祖细胞和前B细胞减少。通过产前TCDD，不同性别的脾脏边缘区B细胞（CD 21（hi）CD 24（low-int））减少，滤泡B细胞（CD 21（int）CD 24（low））增加，而仅雄性动物的过渡型2 B细胞（CD 21（int）CD 24（hi））和（CD 23（low-int）CD 1（low-int））减少。双链DNA抗体显着增加跨性别的TCDD。抗IgG和抗C3免疫复合物肾沉积明显恶化的女性，并存在于TCDD治疗的男性。这些数据表明，发育暴露于TCDD永久性和差异性改变体液免疫功能的性别，并加剧了III型超敏性狼疮样自身免疫性疾病的遗传易感小鼠。
Female SNF1 hybrid mice spontaneously develop an immune complex-mediated glomerulonephritis as early as 24 weeks of age, whereas the disease onset in males is much slower. Further, a rise in concentration of glomerulus-specific autoantibodies via autoreactive B cells is critical to progression of the disease in this strain. Environmental factors contributing to the onset or degree of such autoimmunity are of interest yet poorly understood. In the present study, time-pregnant SWR x NZB dams (10/treatment) were gavaged on gestational 12 with 40 or 80 mg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and the SNF1 offspring were evaluated at 24 weeks of age. Bone marrow B220(low-) CD24(-)AA4.1(+) committed B lineage progenitors were increased in female offspring by TCDD, however, committed progenitors and pro-B cells were decreased in males. Splenic marginal zone B cells (CD21(hi)CD24(low-int)) were decreased and follicular B cells (CD21(int)CD24(low)) were increased across sex by prenatal TCDD, whereas transitional-2 B cells (CD21(int)CD24(hi)) and (CD23(low-int)CD1(low-int)) were decreased in males only. Antibodies to double-stranded DNA were significantly increased across sex by TCDD. Anti-IgG and anti-C3 immune complex renal deposition was visibly worsened in females, and present in TCDD-treated males. These data suggest that developmental exposure to TCDD permanently and differentially alters humoral immune function by sex, and exacerbates a type III hypersensitivity lupus-like autoimmune disease in genetically predisposed mice.