Normalization of the lymph node T cell stromal microenvironment in lpr/lpr mice is associated with SU5416-induced reduction in autoantibodies.
Normalization of the lymph node T cell stromal microenvironment in lpr/lpr mice is associated with SU5416-induced reduction in autoantibodies.
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DOI：
10.1371/journal.pone.0032828
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lu TT
中科院分区：
文献类型：
--
作者：
Chyou S;Tian S;Ekland EH;Lu TT
淋巴结的血管基质成分在调节淋巴细胞的活动中起重要作用。在模型免疫应答期间，已显示血管-基质隔室经历增殖性扩张和功能改变。在自发的慢性自身免疫模型中，血管间质区室的状态和该区室的潜在重要性尚未得到很好的研究。在这里，我们描述了血管扩张在MRL-lpr/lpr淋巴结，并试图问是否抑制这种扩张可以干扰自身抗体的产生。我们发现，在扩大MRL-lpr/lpr淋巴结血管扩张的特点类似于模型免疫后野生型小鼠中发生的VEGF依赖性扩张。令人惊讶的是，用SU 5416（VEGF和其他受体酪氨酸激酶的抑制剂）治疗在抑制血管生长方面没有持续作用，但减弱了抗dsDNA应答并改变了在这些小鼠中扩增的双阴性T细胞的表型。在检查这些免疫学变化的解剖学相关性时，我们发现双阴性T细胞位于中央B细胞斑周围的异位滤泡内，并且这些富含T细胞的区域缺乏T区基质蛋白ER-TR 7以及正常T区微环境的其他元素。SU 5416处理破坏了这些卵泡，并使T区微环境元素和富含T细胞区域之间的关联正常化。最近的研究表明，T区基质元素的调节作用。因此，我们的抗dsDNA反应，双阴性T细胞表型，和改变淋巴细胞微环境的关联的研究结果表明，异位卵泡中的淋巴细胞定位的可能性，保护他们从调节T区基质元素和功能，以维持自身免疫反应。潜在地，改变由血管-基质隔室建立的淋巴细胞微环境可以是控制不期望的自身免疫应答的手段。
The vascular-stromal elements of lymph nodes can play important roles in regulating the activities of the lymphocytes within. During model immune responses, the vascular-stromal compartment has been shown to undergo proliferative expansion and functional alterations. The state of the vascular-stromal compartment and the potential importance of this compartment in a spontaneous, chronic model of autoimmunity have not been well studied. Here, we characterize the vascular expansion in MRL-lpr/lpr lymph nodes and attempt to ask whether inhibiting this expansion can interfere with autoantibody generation. We show that characteristics of vascular expansion in enlarging MRL-lpr/lpr lymph nodes resemble that of the VEGF-dependent expansion that occurs in wild-type mice after model immunization. Surprisingly, treatment with SU5416, an inhibitor of VEGF and other receptor tyrosine kinases, did not have sustained effects in inhibiting vascular growth, but attenuated the anti-dsDNA response and altered the phenotype of the double negative T cells that are expanded in these mice. In examining for anatomic correlates of these immunologic changes, we found that the double negative T cells are localized within ectopic follicles around a central B cell patch and that these T cell-rich areas lack the T zone stromal protein ER-TR7 as well as other elements of a normal T zone microenvironment. SU5416 treatment disrupted these follicles and normalized the association between T zone microenvironmental elements and T cell-rich areas. Recent studies have shown a regulatory role for T zone stromal elements. Thus, our findings of the association of anti-dsDNA responses, double negative T cell phenotype, and altered lymphocyte microenvironment suggest the possibility that lymphocyte localization in ectopic follicles protects them from regulation by T zone stromal elements and functions to maintain autoimmune responses. Potentially, altering the lymphocyte microenvironment that is set up by the vascular-stromal compartment can be a means by which to control undesired autoimmune responses.
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DOI：
10.1084/jem.194.1.45
发表时间：
2001-07-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hargreaves DC;Hyman PL;Lu TT;Ngo VN;Bidgol A;Suzuki G;Zou YR;Littman DR;Cyster JG
通讯作者：
Cyster JG
影响因子：
158.5
作者：
Eremina, Vera;Jefferson, J. Ashley;Quaggin, Susan E.
通讯作者：
Quaggin, Susan E.
影响因子：
32.4
作者：
JACOBSON, BA;PANKA, DJ;MARSHAKROTHSTEIN, A
通讯作者：
MARSHAKROTHSTEIN, A
影响因子：
32.4
作者：
Kataru, Raghu P.;Kim, Honsoul;Koh, Gou Young
通讯作者：
Koh, Gou Young
DOI：
10.1073/pnas.1100567108
发表时间：
2011-05-24
影响因子：
11.1
作者：
Kumamoto, Yosuke;Mattei, Lisa M.;Iwasaki, Akiko
通讯作者：
Iwasaki, Akiko