Oliviero B, Mantovani S, Ludovisi S, Varchetta S, Mele D, Paolucci S, Baldanti F, Mondelli M U
Research Laboratories, Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
J Viral Hepat. 2015 Apr;22(4):391-8. doi: 10.1111/jvh.12336. Epub 2014 Sep 25.
Chronic hepatitis C virus (HCV) infection is characterized by persistent B-cell activation, with enhanced differentiation and reduced proliferative ability. To assess the possible role of HCV in altering B-cell subset distribution, we examined ex vivo frequencies and B-cell inhibitory receptor expression in 37 chronic HCV-infected patients and 25 healthy donors (HD). In addition, we determined whether short-term exposure to culture-derived HCV (HCVcc) resulted in B-cell subset skewing and/or activation. There was a statistically significant increase in the frequencies of immature transitional, activated memory and tissue-like memory (TLM) B cells in HCV-infected patients compared with HD. We also found that the frequency of memory B cells correlated with serum HCV RNA levels. The proportion of B cells expressing the marker of exhaustion Fc receptor-like 4 (FcRL4) was generally low even though significantly higher in the patients' memory B-cell compartment compared with HD, and a positive correlation was found between the frequencies of the patients' TLM FcRL4+ B cells and serum alanine aminotransferase and histological activity index at liver biopsy. Exposure to cell-free HCVcc in vitro did not result in B-cell skewing but induced significant activation of naïve, TLM and resting memory B cells in HCV-infected patients but not in HD, in whom cell-associated virus was an absolute requirement for activation of memory B cells. These findings provide corroborative evidence in favour of significant B-cell subset skewing in chronic HCV infection and in addition show that expression of exhaustion markers in selected B-cell subsets does not impair virus-induced B-cell activation.
慢性丙型肝炎病毒（HCV）感染的特征是B细胞持续活化，分化增强但增殖能力降低。为了评估HCV在改变B细胞亚群分布中的可能作用，我们检测了37例慢性HCV感染患者和25名健康供者（HD）的体外B细胞频率和B细胞抑制性受体表达。此外，我们还确定了短期暴露于培养来源的HCV（HCVcc）是否会导致B细胞亚群偏移和/或活化。与HD相比，HCV感染患者中未成熟过渡性、活化记忆性和组织样记忆（TLM）B细胞的频率有统计学意义的增加。我们还发现记忆B细胞的频率与血清HCV RNA水平相关。尽管与HD相比，患者记忆B细胞区室中表达耗竭标志物Fc受体样4（FcRL4）的B细胞比例显著更高，但总体较低，并且在患者的TLM FcRL4 + B细胞频率与肝活检时的血清丙氨酸转氨酶和组织学活性指数之间发现了正相关。体外暴露于无细胞HCVcc不会导致B细胞偏移，但会诱导HCV感染患者中幼稚、TLM和静息记忆B细胞的显著活化，而在HD中则不会，在HD中细胞相关病毒是记忆B细胞活化的绝对必要条件。这些发现为慢性HCV感染中显著的B细胞亚群偏移提供了确凿证据，此外还表明在选定的B细胞亚群中耗竭标志物的表达不会损害病毒诱导的B细胞活化。
