Indeterminate pediatric acute liver failure is uniquely characterized by a CD103+CD8+ T-cell infiltrate
Indeterminate pediatric acute liver failure is uniquely characterized by a CD103+CD8+ T-cell infiltrate
复制标题
DOI：
10.1002/hep.29901
复制
发表时间：
2018-09-01
期刊：
影响因子：
13.5
通讯作者：
Alonso, Estella M.
中科院分区：
文献类型：
--
作者：
Chapin, Catherine A.;Burn, Thomas;Alonso, Estella M.
在高达40%的病例中，小儿急性肝衰竭（PALF）的原因不明。有证据表明，异常的免疫系统激活可能发挥了作用。我们假设不确定的PALF病例将表现出独特的肝脏炎症模式。这是一项回顾性和前瞻性研究，针对病因不确定（iPALF）、自身免疫性肝炎或已知诊断（dPALF）的PALF病例。用细胞毒性T细胞（分化簇8 [CD 8]）、穿孔素和组织驻留记忆T细胞（CD 103）的免疫组织化学标记物对肝组织切片进行染色，并评分为极轻微、中度或致密。从肝组织中分离淋巴细胞用于T细胞受体β测序和流式细胞术研究。包括33例iPALF、9例自身免疫性肝炎和14例dPALF病例。iPALF组27例（82%），dPALF组1例（7%），CD 8（+）T细胞浸润明显（P < 0.0001）。26例iPALF病例中有19例（73%）的穿孔蛋白染色为致密或中度，而所有7例dPALF病例中为极轻微（P = 0.004）; 26例iPALF病例中有16例（62%）具有致密CD 103染色，而6例dPALF病例中无一例（P = 0.001）。与dPALF和对照病例相比，iPALF病例的T细胞受体β测序显示出增加的克隆性。流式细胞术和免疫组化显示iPALF肝内白细胞主要是组织驻留记忆性CD 8（+）T细胞。结论：不确定性PALF的特征是致密的CD 8（+）T细胞肝浸润，与组织驻留记忆T细胞表型的扩增一致; CD 8（+）T细胞是iPALF中免疫失调的生物标志物，可用于更好地识别和定义该组。（Hepatology 2018）。
The cause of pediatric acute liver failure (PALF) is unknown in up to 40% of cases. Evidence suggests that aberrant immune system activation may play a role. We hypothesized that indeterminate PALF cases would exhibit a unique pattern of hepatic inflammation. This was a retrospective and prospective study of PALF cases due to indeterminate (iPALF), autoimmune hepatitis, or known diagnosis (dPALF) etiology. Liver tissue sections were stained with immunohistochemical markers for cytotoxic T-cells (cluster of differentiation 8 [CD8]), perforin, and tissue resident memory T-cells (CD103) and scored as minimal, moderate, or dense. Lymphocytes were isolated from liver tissue for T-cell receptor beta sequencing and flow-cytometric studies. Thirty-three iPALF, 9 autoimmune hepatitis, and 14 dPALF cases were included. Dense hepatic infiltrates of CD8(+) T-cells were found in 27 (82%) iPALF cases compared to 1 (7%) dPALF case (P < 0.0001). Perforin staining was dense or moderate in 19 (73%) of 26 iPALF cases compared to minimal in all 7 dPALF cases (P = 0.004); 16 (62%) of 26 iPALF cases had dense CD103 staining compared to none of the 6 dPALF cases (P = 0.001). T-cell receptor beta sequencing of iPALF cases demonstrated increased clonality compared to dPALF and control cases. Flow cytometry and immunohistochemistry revealed that iPALF intrahepatic leukocytes were predominantly tissue resident memory CD8(+) T-cells. Conclusion: Indeterminate PALF is characterized by a dense CD8(+) T-cell hepatic infiltrate consistent with expansion of a tissue resident memory T-cell phenotype; CD8(+) T-cells are a biomarker of immune dysregulation in iPALF and may be used to better identify and define this group. (Hepatology 2018).