Suppression of established experimental autoimmune encephalomyelitis and formation of meningeal lymphoid follicles by lymphotoxin β receptor-Ig fusion protein
Suppression of established experimental autoimmune encephalomyelitis and formation of meningeal lymphoid follicles by lymphotoxin β receptor-Ig fusion protein
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DOI：
10.1016/j.jneuroim.2006.06.015
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发表时间：
2006-10-01
影响因子：
3.3
通讯作者：
Aloisi, Francesca
中科院分区：
文献类型：
--
作者：
Columba-Cabezas, Sandra;Griguoli, Marilena;Aloisi, Francesca
我们最近的研究表明，在继发性进行性多发性硬化症患者和复发缓解型实验性自身免疫性脑脊髓炎（EAE）的SJL小鼠中，炎症的中枢神经系统（CNS）脑膜中重新形成类似B细胞滤泡的淋巴结构。由于光毒素（LT）α（1）β（2）对淋巴组织的组织是必不可少的，我们使用实时PCR检测了用PLP 139-151肽免疫的SJL小鼠CNS中LT β和LT β受体（LT β R）基因的表达。此外，我们使用诱饵受体LT β R-免疫球蛋白融合蛋白来阻断已确诊EAE小鼠中的视网膜光毒素（LT）α（1）β（2）与LT β受体（LT β R）的相互作用，并评估融合蛋白全身和局部治疗对疾病进展、CNS淋巴细胞浸润和脑膜B细胞滤泡形成的影响。目前的研究结果表明，LT β和LT β R在EAE发作时和随后的复发期间上调，并且用LT β R-Ig全身和局部阻断LT途径分别导致EAE临床体征的持久和短暂抑制。LT β R-Ig治疗还可减少T细胞和B细胞浸润，防止趋化因子CXCL 10和CXCL 13的诱导以及在EAE影响的CNS中形成有组织的异位卵泡。靶向参与淋巴器官发生的分子可能是抑制CNS炎症和异位卵泡形成的有效策略，这可能在维持CNS自身免疫性疾病的异常鞘内体液免疫应答中发挥作用。
We have recently shown that de novo formation of lymphoid structures resembling B-cell follicles occurs in the inflamed central nervous system (CNS) meninges in a subset of patients with secondary progressive multiple sclerosis and in SJL mice with relapsing-remitting experimental autoimmune encephalomyelitis (EAE). Because lymphotoxin (LT) alpha(1)beta(2) is essential for lymphoid tissue organization, we used real-time PCR to examine LT beta and LT beta receptor (LT beta R) gene expression in the CNS of SJL mice immunized with PLP 139-151 peptide. Moreover, we used the decoy receptor LT beta R- immunoglobulin fusion protein to block the interaction of lymphotoxin (LT) alpha(1)beta(2) with the LT beta receptor (LT beta R) in mice with established EAE and evaluate the effect of systemic and local treatments with the fusion protein on disease progression, CNS lymphocytic infiltration and formation of meningeal B-cell follicles. The present findings indicate that both LT beta and LT beta R are upregulated at EAE onset and during subsequent relapses and that systemic and local blockade of the LT pathway with LT beta R-Ig results in protracted and transient inhibition of EAE clinical signs, respectively. LT beta R-Ig treatment also reduces T- and B-cell infiltration and prevents the induction of the chemokines CXCL10 and CXCL13 and the formation of organized ectopic follicles in the EAE-affected CNS. Targeting of molecules involved in lymphoid organogenesis could represent a valid strategy to inhibit CNS inflammation and formation of ectopic follicles, which may play a role in maintaining an abnormal, intrathecal humoral immune response in CNS autoimmune disease.