Kinetics and cellular origin of cytokines in the central nervous system: Insight into mechanisms of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis
Kinetics and cellular origin of cytokines in the central nervous system: Insight into mechanisms of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis
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DOI：
10.4049/jimmunol.164.1.419
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发表时间：
2000-01-01
影响因子：
4.4
通讯作者：
Ruddle, NH
中科院分区：
文献类型：
--
作者：
Juedes, AE;Hjelmstrom, P;Ruddle, NH
C57BL/6 （H-2(b)）小鼠髓鞘少突胶质细胞糖蛋白（MOG）诱导的实验性自身免疫性脑脊髓炎的特征是早期（第12天）急性瘫痪，随后是持续的慢性临床过程，逐渐稳定。广泛的炎症和脱髓鞘与疾病的临床症状一致。为了确定这些过程的机制，研究了个体促炎和抗炎细胞因子和趋化因子。利用敏感的单细胞试验来确定中枢神经系统中细胞因子产生的细胞来源和动力学，MOG（35-55）肽免疫导致脾脏中Th1（淋巴素、ifn - γ和tnf - α）和Th2 （IL-4）细胞的启动。然而，只有Th1细胞在中枢神经系统中可见，在MOG免疫后第7天，中枢神经系统中出现了产生ifn - γ或tnf - α的CD4 T细胞（35-55），在第20天达到峰值，然后减弱。Mac-1（+）细胞也在中枢神经系统中产生tnf - α。免疫后第7天和第10天，产生tnf - α的Mac1（+）细胞以小胶质细胞为主，到第14天发生转变，产生tnf - α的Mac1（+）细胞具有浸润性巨噬细胞的表型，免疫后第8天在中枢神经系统中检测到RANTES、ifn诱导蛋白10 （IP-10）和单核细胞趋化蛋白1趋化因子mRNA。单核细胞趋化蛋白1 （MCP-1）在中枢神经系统中的早期存在为巨噬细胞的募集提供了一种机制，这些数据表明，在疾病过程的不同时期，T细胞、小胶质细胞和巨噬细胞连续不断地产生tnf - α。强调Th1细胞因子的重要性，很少有证据表明Th2细胞因子的作用。
Experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 (H-2(b)) mice is characterized by early (day 12) acute paralysis, followed by a sustained chronic clinical course that gradually stabilizes. Extensive inflammation and demyelination coincide with clinical signs of disease. To identify the mechanisms of these processes, individual proinflammatory and anti-inflammatory cytokines and chemokines were studied. Sensitive single-cell assays were utilized to determine the cellular origin and kinetics of cytokine production in the CNS, Immunization with MOG(35-55) peptide resulted in priming of both Th1 (lymphotoxin, IFN-gamma, and TNF-alpha) and Th2 (IL-4) cells in the spleen. However, only Th1 cells were apparent in the CNS, CD4 T cells that produced IFN-gamma or TNF-alpha were present in the CNS by day 7 after immunization with MOG(35-55), peaked at day 20, and then waned. TNF-alpha was also produced in the CNS by Mac-1(+) cells. On days 7 and 10 after immunization, the TNF-alpha-producing Mac1(+) cells were predominantly microglia, By day 14, a switch occurred in that the Mac1(+) TNF-alpha-producing cells had the phenotype of infiltrating macrophages, RANTES, IFN-inducible protein 10 (IP-10), and monocyte chemotactic protein 1 chemokine mRNA were detected in the CNS by day 8 after immunization. The early presence of monocyte chemotactic protein 1 (MCP-1) in the CNS provides a mechanism for the recruitment of macrophages, These data implicate TNF-alpha production by a continuum of T cells, microglia, and macrophages at various times during the course of disease. The importance of Th1 cytokines is highlighted, with little evidence for a role of Th2 cytokines.