CCR5+ and CXCR3+ T cells are increased in multiple sclerosis and their ligands MIP-1α and IP-10 are expressed in demyelinating brain lesions
CCR5+ and CXCR3+ T cells are increased in multiple sclerosis and their ligands MIP-1α and IP-10 are expressed in demyelinating brain lesions
复制标题
DOI：
10.1073/pnas.96.12.6873
复制
发表时间：
1999-06-08
影响因子：
11.1
通讯作者：
Hancock, WW
中科院分区：
文献类型：
--
作者：
Balashov, KE;Rottman, JB;Hancock, WW
多发性硬化（MS）是一种T细胞依赖性慢性炎症性中枢神经系统疾病，趋化因子在MS及其不同阶段的作用尚不清楚。最近的数据表明，Th 1细胞与Th 2细胞相比，趋化因子受体的表达存在偏倚;人Th 1克隆表达CXCR 3和CCR 5，Th 2克隆表达CCR 3和CCR 4。由Th 1细胞表达的趋化因子受体在MS中可能是重要的，因为在临床发作之前增加的干扰素-γ（IFN-γ），并且IFN-γ注射诱导疾病恶化。我们发现复发缓解型MS患者血液中CXCR 3（+）T细胞增加，进展型MS患者血液中CCR 5（+）和CXCR 3（+）T细胞均增加。此外，外周血CCR 5（+）T细胞分泌高水平的IFN-γ。在脑中，CCR 5配体MIP-1 α与小胶质细胞/巨噬细胞密切相关，CXCR 3配体IP-10由MS病变中的星形胶质细胞表达，但对照或MS受试者的白色物质不受影响。斑块形成区域被CCR 5表达细胞浸润，CXCR 3表达细胞浸润程度较低;白细胞介素（IL）-18和IFN-γ在脱髓鞘病变中表达，未观察到CCR 3、CCR 4或其他6种趋化因子或抗炎细胞因子IL-5、IL-10、IL-13和转化生长因子β的白细胞表达。因此，趋化因子受体表达可用于MS的免疫分期，并可能用于其他慢性自身免疫/炎症过程，如类风湿性关节炎，自身免疫性糖尿病或慢性移植排斥。此外，这些结果为使用阻断CCR 5和/或CXCR 3的药物作为治疗MS的治疗方法提供了理论基础。
Multiple sclerosis (MS) is a T cell-dependent chronic inflammatory disease of the central nervous system, The role of chemokines in MS and its different stages is uncertain. Recent data suggest a bias in expression of chemokine receptors by Th1 vs. Th2 cells; human Th1 clones express CXCR3 and CCR5 and Th2 clones express CCR3 and CCR4. Chemokine receptors expressed by Th1 cells may be important in MS, as increased interferon-gamma (IFN-gamma) precedes clinical attacks, and IFN-gamma injection induces disease exacerbations. We found CXCR3(+) T cells increased in blood of relapsing-remitting MS, and both CCR5(+) and CXCR3(+) T cells increased in progressive MS compared with controls. Furthermore, peripheral blood CCR5(+) T cells secreted high levels of IFN-gamma, In the brain, the CCR5 ligand, MIP-1 alpha, was strongly associated with microglia/macrophages, and the CXCR3 ligand, IP-10, was expressed by astrocytes in MS lesions but not unaffected white matter of control or MS subjects. Areas of plaque formation were infiltrated by CCR5-expressing and, to a lesser extent, CXCR3-expressing cells; Interleukin (IL)-18 and IFN-gamma were expressed in demyelinating lesions, No leukocyte expression of CCR3, CCR4, or six other chemokines, or anti-inflammatory cytokines IL-5, IL-10, IL-13, and transforming growth factor-beta was observed. Thus, chemokine receptor expression may be used for immunologic staging of MS and potentially for other chronic autoimmune/inflammatory processes such as rheumatoid arthritis, autoimmune diabetes, or chronic transplant rejection. Furthermore, these results provide a rationale for the use of agents that block CCR5 and/or CXCR3 as a therapeutic approach in the treatment of MS.