TCDD attenuates EAE through induction of FasL on B cells and inhibition of IgG production.
TCDD attenuates EAE through induction of FasL on B cells and inhibition of IgG production.
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DOI：
10.1016/j.tox.2020.152646
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发表时间：
2021-01-30
期刊：
影响因子：
4.5
通讯作者：
Kaplan BLF
中科院分区：
文献类型：
--
作者：
Kummari E;Rushing E;Nicaise A;McDonald A;Kaplan BLF
先前我们证明了2，3，7，8-四氯二苯并对二恶英(TCDD)通过诱导调节性T细胞(Tregs)和抑制脾内效应T细胞功能来抑制实验性自身免疫性脑脊髓炎(EAE)，EAE是一种研究多发性硬化(MS)的模型。由于B细胞，特别是调节性B细胞(Bregs)在与EAE和MS相关的病理过程中起着至关重要的作用，我们想要确定TCDD是否也能诱导Bregs。我们特别假设TCDD会在EAE中诱导Fas配体(FasL)+Breg群体，从而触发Fas表达的效应T细胞的凋亡，这是TCDD抑制T细胞功能的机制之一。TCDD0.1~2.5FasL/kg/d灌胃给药12天后，可轻度增加实验性脑脊髓炎小鼠脾和脊髓中μ+B细胞的百分率。然而，我们没有发现在体外使用TCDD的小鼠脾细胞或人外周血单核细胞(PBMC)中FasL+B细胞的百分比显著增加。TCDD的温和作用部分可能与FasL的局部表达有关；例如，在脾中，IgMhiIgDlo边缘区(MZ)B细胞更高表达FasL，而IgMloIgDhi滤泡(FO)B细胞对TCDD更敏感。与我们观察到的适度上调FasL一致，我们还观察到与分离的总B细胞或来自TCDD处理的EAE小鼠的IgM耗竭(即富含FO)的B细胞共同培养的T细胞线粒体膜电位的轻微变化。这些数据表明，虽然TCDD处理的B细胞可能会在T细胞中发生小的凋亡微环境，但这并不是TCDD在EAE中损害T细胞功能的主要机制。TCDD在全身性和终末期对脾和脊髓B细胞的免疫球蛋白G产生有明显的抑制作用。因此，这些研究表明，TCDD对EAE中B细胞的主要作用是抑制免疫球蛋白的产生，而不是诱导FasL+Breg。
Previously we demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppressed experimental autoimmune encephalomyelitis (EAE), a model to study multiple sclerosis (MS), through induction of regulatory T cells (Tregs) and suppression of effector T cell function in the spleen. Since B cells and specifically regulatory B cells (Bregs) have been shown to be so critical in the pathology associated with EAE and MS, we wanted to determine whether TCDD could also induce Bregs. We specifically hypothesized that a Fas ligand (FasL)+ Breg population would be induced by TCDD in EAE thereby triggering apoptosis in Fas-expressing effector T cells as one mechanism to account for inhibition of T cell function by TCDD. TCDD (0.1–2.5 μg/kg/day administered orally for 12 days) modestly increased the percentage of FasL+ B cells in the spleen and spinal cord in TCDD-treated EAE mice. However, we did not detect significant increases in percentages of FasL+ B cells using TCDD in vitro in mouse splenocytes or human peripheral blood mononuclear cells (PBMCs). Part of the modest effect by TCDD was likely related to the localized expression of FasL; for instance, in the spleen, FasL was more highly expressed by IgMhiIgDlo marginal zone (MZ) B cells, but IgMloIgDhi follicular (FO) B cells were more responsive to TCDD. Consistent with our observation of modest upregulation of FasL, we also observed modest changes in mitochondrial membrane potential in T cells co-cultured with isolated total B cells or IgM-depleted (i.e., FO-enriched) B cells from TCDD-treated EAE mice. These data suggest that while small microenvironments of apoptosis might be occurring in T cells in response to TCDD-treated B cells, it is not a major mechanism by which T cell function is compromised by TCDD in EAE. TCDD did robustly suppress IgG production systemically and in spleen and spinal cord B cells at end stage disease. Thus these studies show that TCDD’s primary effect on B cells in EAE is compromised IgG production but not FasL+ Breg induction.
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影响因子：
3.8
作者：
Fullerton, Aaron M.;Roth, Robert A.;Ganey, Patricia E.
通讯作者：
Ganey, Patricia E.
影响因子：
3.7
作者：
Duarte JH;Di Meglio P;Hirota K;Ahlfors H;Stockinger B
通讯作者：
Stockinger B
影响因子：
4.6
作者：
Fling, Russell R.;Doskey, Claire M.;Zacharewski, Tim R.
通讯作者：
Zacharewski, Tim R.
DOI：
10.1080/15287399009531449
发表时间：
1990-01-01
期刊：
JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH
影响因子：
--
作者：
HOUSE, RV;LAUER, LD;DEAN, JH
通讯作者：
DEAN, JH
影响因子：
3.8
作者：
Lawrence, BP;Vorderstrasse, BA
通讯作者：
Vorderstrasse, BA