Ruth J H, Rottman J B, Katschke K J, Qin S, Wu L, LaRosa G, Ponath P, Pope R M, Koch A E
Northwestern University Medical School, Department of Medicine, Section of Rheumatology, Chicago, IL 60611, USA.
Arthritis Rheum. 2001 Dec;44(12):2750-60. doi: 10.1002/1529-0131(200112)44:12<2750::aid-art462>3.0.co;2-c.
In patients with rheumatoid arthritis (RA), chemokines and their receptors are important for lymphocyte trafficking into the inflamed joint. This study was undertaken to characterize the expression of chemokine receptors CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CXCR3, and CX3CR1 in normal (NL) peripheral blood (PB), RA PB, and RA synovial fluid (SF).
Using flow cytometry, immunohistochemistry, and 2-color immunofluorescence, we defined the expression of chemokine receptors on CD3+ T lymphocytes in RA synovial tissue (ST), RA SF, RA PB, and NL PB.
The percentage of CD3+ lymphocytes expressing CCR2, CCR4, CCR5, and CX3CR1 was significantly elevated in RA PB compared with that in NL PB, while the percentage of CD3+ lymphocytes expressing CCR5 was significantly enhanced in RA SF compared with that in NL and RA PB. In contrast, similar percentages of CD3+ lymphocytes in NL PB, RA PB, and RA SF expressed CCR6 and CXCR3. Immunohistochemistry of RA ST showed lymphocyte expression of CCR4, and 2-color immunofluorescence staining revealed RA ST CD3+ lymphocytes intensely immunoreactive for CXCR3, suggesting that these 2 receptors may be particularly important for CD3+ lymphocyte trafficking to the inflamed joint. In comparisons of chemokine receptor expression on naive (CD45RA+) and memory (CD45RO+) CD3+ lymphocytes, there were greater percentages of memory CD3+/CD4+ lymphocytes expressing CCR4, CCR5, and CXCR3 than naive CD3+/CD4+ lymphocytes in RA PB and RA SF, and greater percentages of memory CD3+/CD8+ lymphocytes expressing CCR4, CCR5, and CXCR3 than naive CD3+/CD8+ lymphocytes in RA SF, suggesting receptor up-regulation upon lymphocyte activation. In contrast, percentages of CD3+/CD8+ memory lymphocytes expressing CX3CR1 were significantly less than percentages of naive CD3+/CD8+ lymphocytes in RA PB, suggesting that this receptor may be down-regulated upon lymphocyte activation. A major difference between the RA PB and NL PB groups was significantly more CCR4+ memory leukocytes and memory CCR5+/ CD3+/CD8+ lymphocytes in RA PB than NL PB, further suggesting that these receptors may be particularly important for lymphocyte homing to the RA joint.
These results identify CCR4, CCR5, CXCR3, and CX3CR1 as critical chemokine receptors in RA.
在类风湿关节炎（RA）患者中，趋化因子及其受体对于淋巴细胞向炎症关节的迁移十分重要。本研究旨在描述趋化因子受体CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CXCR3和CX3CR1在正常（NL）外周血（PB）、RA外周血及RA滑液（SF）中的表达特征。
运用流式细胞术、免疫组织化学及双色免疫荧光法，我们确定了趋化因子受体在RA滑膜组织（ST）、RA滑液、RA外周血及NL外周血中CD3⁺T淋巴细胞上的表达情况。
与NL外周血相比，RA外周血中表达CCR2、CCR4、CCR5和CX3CR1的CD3⁺淋巴细胞百分比显著升高，而与NL及RA外周血相比，RA滑液中表达CCR5的CD3⁺淋巴细胞百分比显著增加。相反，NL外周血、RA外周血及RA滑液中表达CCR6和CXCR3的CD3⁺淋巴细胞百分比相近。RA滑膜组织的免疫组织化学显示CCR4在淋巴细胞中有表达，双色免疫荧光染色显示RA滑膜组织中的CD3⁺淋巴细胞对CXCR3呈强免疫反应性，这表明这两种受体对于CD3⁺淋巴细胞向炎症关节的迁移可能尤为重要。在比较初始（CD45RA⁺）和记忆（CD45RO⁺）CD3⁺淋巴细胞上趋化因子受体的表达时，RA外周血和RA滑液中表达CCR4、CCR5和CXCR3的记忆CD3⁺/CD4⁺淋巴细胞百分比高于初始CD3⁺/CD4⁺淋巴细胞，RA滑液中表达CCR4、CCR5和CXCR3的记忆CD3⁺/CD8⁺淋巴细胞百分比高于初始CD3⁺/CD8⁺淋巴细胞，这表明淋巴细胞激活后受体上调。相反，RA外周血中表达CX3CR1的CD3⁺/CD8⁺记忆淋巴细胞百分比显著低于初始CD3⁺/CD8⁺淋巴细胞，这表明该受体在淋巴细胞激活后可能下调。RA外周血与NL外周血组之间的一个主要差异是，RA外周血中CCR4⁺记忆白细胞及记忆CCR5⁺/CD3⁺/CD8⁺淋巴细胞显著多于NL外周血，这进一步表明这些受体对于淋巴细胞归巢至RA关节可能尤为重要。
这些结果确定CCR4、CCR5、CXCR3和CX3CRl为RA中关键的趋化因子受体。
