Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, 110 070, New Delhi, India.
J Clin Immunol. 2011 Jun;31(3):498-508. doi: 10.1007/s10875-010-9506-2. Epub 2011 Feb 3.
Approximately 50% of acute viral hepatitis in young adults and in pregnant women is due to hepatitis E virus (HEV) infection in developing countries. T cell-mediated immune injury probably plays a key role in the pathogenesis of acute hepatitis illness. However, there is a paucity of data on the global gene expression programs activated on T cells, which are subsequently responsible for T cell recruitment to the liver and triggering of immune injury.
We performed a flow cytometric analysis of T cells in individuals with acute hepatitis E (AVH-E; n=10), resolving phase of HEV (n=9), and ten healthy controls (HC). Further transcriptional profiling analysis was performed using Affymetrix GeneChip DNA microarrays to identify the genes that were differentially expressed in AVH-E and HC.
Patients with AVH-E showed higher frequencies of CD8+ (27 ± 4%; P=0.02) and activated CD38+ CD69+ T cells (25% ± 3%; P=0.04) than in resolving phase patients (20 ± 2% and 9.1 ± 4%, respectively), who in turn exhibited higher CCR9 expression than cells from patients in active phase. The naïve T cell population (CD3+ CD45RA+) was decreased upon HEV infection (29 ± 4% in AVH-E vs. 53.1 ± 3.2% in HC; P=0.05); however, the CD11a high subpopulation within CD4+ CD45RA+ cells was increased in both AVH-E (6.1%) and resolving phase (7.7%) patients. Gene ontology analysis suggested that during AVH-E infection, there is in CD4+ T cells an activation of genes involved in pro-inflammatory responses. Additional RT-PCR analysis confirmed that in cells from AVH-E patients, there is an increased expression of CCR5, CCR9, CXCR3, CXCR4, STAT1, IRF-9, IFN-α, and TNF-α, together with a down-regulation of IL-2, SOCS3, and IL-10, with respect to cells from resolving phase patients.
Our findings suggest the involvement of a circulating CD45RA+ CD11a high population with CCR5 expression in the pathogenesis processes of AVH-E. The obtained results help to understand the underlying inflammatory process occurring in HEV infection, which can lead to either resolution or immunopathology.
在发展中国家，约有 50%的青年人和孕妇急性病毒性肝炎是由戊型肝炎病毒（HEV）感染引起的。细胞介导的免疫损伤可能在急性肝炎发病机制中起关键作用。然而，关于 T 细胞激活的全球基因表达谱的数据很少，这些基因表达谱随后负责 T 细胞向肝脏的募集和免疫损伤的触发。
我们对 10 例急性戊型肝炎（AVH-E）患者、9 例 HEV 缓解期患者和 10 例健康对照者（HC）进行 T 细胞流式细胞术分析。进一步采用 Affymetrix GeneChip DNA 微阵列进行转录谱分析，以鉴定 AVH-E 和 HC 中差异表达的基因。
AVH-E 患者的 CD8+（27±4%；P=0.02）和激活的 CD38+CD69+T 细胞（25%±3%；P=0.04）频率高于缓解期患者（分别为 20±2%和 9.1±4%），而后者的 CCR9 表达高于急性期患者。HEV 感染后，幼稚 T 细胞群（CD3+CD45RA+）减少（AVH-E 中为 29±4%，HC 中为 53.1±3.2%；P=0.05）；然而，AVH-E（6.1%）和缓解期（7.7%）患者的 CD4+CD45RA+细胞内的 CD11a 高亚群增加。基因本体分析表明，在 AVH-E 感染期间，CD4+T 细胞中参与促炎反应的基因被激活。另外的 RT-PCR 分析证实，与缓解期患者的细胞相比，AVH-E 患者的细胞中 CCR5、CCR9、CXCR3、CXCR4、STAT1、IRF-9、IFN-α和 TNF-α的表达增加，而 IL-2、SOCS3 和 IL-10 的表达减少。
我们的发现表明，循环 CD45RA+CD11a 高表达 CCR5 的群体参与了 AVH-E 的发病机制过程。获得的结果有助于了解 HEV 感染中发生的炎症过程，这可能导致疾病的缓解或免疫病理学。
