Feng Ningguo, Jaimes María C, Lazarus Nicole H, Monak Denise, Zhang Caiqui, Butcher Eugene C, Greenberg Harry B
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
J Immunol. 2006 May 15;176(10):5749-59. doi: 10.4049/jimmunol.176.10.5749.
Rotaviruses (RV) are the most important cause of severe childhood diarrheal disease. In suckling mice, infection with RV results in an increase in total and virus-specific IgA(+) plasmablasts in the small intestinal lamina propria (LP) soon after infection, providing a unique opportunity to study the mechanism of IgA(+) cell recruitment into the small intestine. In this study, we show that the increase in total and RV-specific IgA(+) plasmablasts in the LP after RV infection can be blocked by the combined administration of Abs against chemokines CCL25 and CCL28, but not by the administration of either Ab alone. RV infection in CCR9 knockout mice still induced a significant accumulation of IgA(+) plasmablasts in the LP, which was blocked by the addition of anti-CCL28 Ab, confirming the synergistic role of CCL25 and CCL28. The absence of IgA(+) plasmablast accumulation in LP following combined anti-chemokine treatment was not due to changes in proliferation or apoptosis in these cells. We also found that coadministration of anti-CCL25 and anti-CCL28 Abs with the addition of anti-alpha(4) Ab did not further inhibit IgA(+) cell accumulation in the LP and that the CCL25 receptor, CCR9, was coexpressed with the intestinal homing receptor alpha(4)beta(7) on IgA(+) plasmablasts. Finally, we showed that RV infection was associated with an increase in both CCL25 and CCL28 in the small intestine. Hence, our findings indicate that alpha(4)beta(7) along with either CCR9 or CCR10 are sufficient for mediating the intestinal migration of IgA(+) plasmablasts during RV infection.
轮状病毒（RV）是导致儿童严重腹泻病的最重要病因。在乳鼠中，感染RV后不久，小肠固有层（LP）中总的及病毒特异性IgA(+)浆母细胞数量会增加，这为研究IgA(+)细胞募集至小肠的机制提供了独特的机会。在本研究中，我们发现，联合给予抗趋化因子CCL25和CCL28的抗体可阻断RV感染后LP中总的及RV特异性IgA(+)浆母细胞数量的增加，但单独给予任一抗体则无此作用。CCR9基因敲除小鼠感染RV后，LP中仍会诱导IgA(+)浆母细胞显著积聚，添加抗CCL28抗体可阻断这种积聚，证实了CCL25和CCL28的协同作用。联合抗趋化因子治疗后LP中缺乏IgA(+)浆母细胞积聚并非由于这些细胞增殖或凋亡的改变。我们还发现，联合给予抗CCL25和抗CCL28抗体并添加抗α(4)抗体并不会进一步抑制LP中IgA(+)细胞的积聚，且CCL25受体CCR9与IgA(+)浆母细胞上的肠道归巢受体α(4)β(7)共表达。最后，我们表明RV感染与小肠中CCL25和CCL28均增加有关。因此，我们的研究结果表明，α(4)β(7)与CCR9或CCR10之一足以介导RV感染期间IgA(+)浆母细胞的肠道迁移。
