Morphologic and molecular analysis of liver injury after SARS-CoV-2 vaccination reveals distinct characteristics.
Morphologic and molecular analysis of liver injury after SARS-CoV-2 vaccination reveals distinct characteristics.
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DOI：
10.1016/j.jhep.2023.05.020
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发表时间：
2023-09
影响因子：
25.7
通讯作者：
Matter, Matthias S.
中科院分区：
文献类型：
--
作者：
Uzun, Sarp;Zinner, Carl P.;Beenen, Amke C.;Alborelli, Ilaria;Bartoszek, Ewelina M.;Yeung, Jason;Calgua, Byron;Reinscheid, Matthias;Bronsert, Peter;Stalder, Anna K.;Haslbauer, Jasmin D.;Vosbeck, Juerg;Mazzucchelli, Luca;Hoffmann, Tobias;Terracciano, Luigi M.;Hutter, Gregor;Manz, Michael;Panne, Isabelle;Boettler, Tobias;Hofmann, Maike;Bengsch, Bertram;Heim, Markus H.;Bernsmeier, Christine;Jiang, Sizun;Tzankov, Alexandar;Beretta-Piccoli, Benedetta Terziroli;Matter, Matthias S.
新冠肺炎疫苗接种后的肝损伤非常罕见，在临床和组织形态上与自身免疫性肝炎相似。新冠肺炎疫苗诱导的肝损伤(VILI)的病理生理机制及其与AIH的关系尚不清楚。因此，我们将VILI与AIH进行了比较。福尔马林固定和石蜡包埋的肝活检样本来自VILI患者(n=6)和初步诊断为AIH的患者(n=9)。通过组织形态评价、全转录组和空间转录组测序、多重免疫荧光和免疫谱系测序对两组进行比较。两组患者的组织形态相似，但VILI的小叶中心坏死更为明显。基因表达谱显示VILI中线粒体代谢和氧化应激相关途径较多，干扰素反应途径较少。多重分析显示，VILI的炎症反应以CD8+效应T细胞为主，类似于药物诱导的自身免疫性肝炎(DI-AILH)。相反，AIH以CD4+效应T细胞、CD79a+B细胞和浆细胞为主。T细胞受体(TCR)和B细胞受体(BCR)测序显示VILI中T细胞和B细胞克隆较AIH占优势。此外，在血液中也发现了许多在肝脏中检测到的T细胞克隆。有趣的是，对TCRβ链和Ig重链可变连接基因用法的分析进一步表明，TRBV6-1、TRBV5-1、TRBV7-6和IgHV1-24基因在VILI和AIH中的用法不同。我们的分析支持SARS-CoV-2疫苗诱导的肝损伤与AIH有关，但在组织形态、途径激活、细胞免疫浸润和TCR使用方面也与AIH有明显差异。VILI可能是一个独立的实体，与AIH不同，与DI-AILH关系更密切。新冠肺炎疫苗所致肝损伤的病理生理机制知之甚少。我们的分析表明，新冠肺炎疫苗诱导的肝损伤与自身免疫性肝炎有一些相似之处，但也有明显的区别，如代谢途径激活，CD8+T细胞浸润更明显，以及T和B细胞的寡克隆应答。我们的发现表明，疫苗诱导的肝损伤是一种独特的疾病实体。因此，许多新冠肺炎疫苗诱导的肝损伤患者很有可能完全康复，不会发展为长期的自身免疫性肝炎。
Liver injury after COVID-19 vaccination is very rare and shows clinical and histomorphological similarities with autoimmune hepatitis (AIH). Little is known about the pathophysiology of COVID-19 vaccine-induced liver injury (VILI) and its relationship to AIH. Therefore, we compared VILI with AIH. Formalin-fixed and paraffin-embedded liver biopsy samples from patients with VILI (n=6) and from patients with an initial diagnosis of AIH (n=9) were included. Both cohorts were compared by histomorphological evaluation, whole-transcriptome and spatial transcriptome sequencing, multiplex immunofluorescence and immune repertoire sequencing. Histomorphology was similar in both cohorts but showed more pronounced centrilobular necrosis in VILI. Gene expression profiling showed that mitochondrial metabolism and oxidative stress-related pathways were more and interferon response pathways less enriched in VILI. Multiplex analysis revealed that inflammation in VILI was dominated by CD8+ effector T cells, similar to drug-induced autoimmune like hepatitis (DI-AILH). In contrast, AIH showed a dominance of CD4+ effector T cells and CD79a+ B and plasma cells. T-cell receptor (TCR) and B-cell receptor (BCR) sequencing showed that T- and B-cell clones were more dominant in VILI than in AIH. In addition, many T-cell clones detected in the liver were also found in the blood. Interestingly, analysis of TCR beta chain and Ig heavy chain variable-joining gene usage further showed that TRBV6-1, TRBV5-1, TRBV7-6 and IgHV1-24 genes are used differently in VILI than in AIH. Our analyses support that SARS-CoV-2 vaccination-induced liver injury is related to AIH but also shows distinct differences from AIH in histomorphology, pathway activation, cellular immune infiltrates, and TCR usage. VILI may be a separate entity, which is distinct from AIH and more closely related to DI-AILH. Little is known about the pathophysiology of COVID-19 vaccine-induced liver injury. Our analysis shows that COVID-19 vaccine-induced liver injury shares some similarities with autoimmune hepatitis, but also has distinct differences such as increased activation of metabolic pathways, a more prominent CD8+ T cell infiltrate, and an oligoclonal T and B cell response. Our findings suggest that vaccine-induced liver injury is a distinct disease entity. Therefore, there is a good chance that many patients with COVID-19 vaccine-induced liver injury will recover completely and do not develop long-term autoimmune hepatitis.
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影响因子：
12.8
作者：
Avci E;Abasiyanik F
通讯作者：
Abasiyanik F
影响因子：
8.3
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通讯作者：
Beretta-Piccoli, Benedetta Terziroli
影响因子：
5.6
作者：
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影响因子：
12.8
作者：
Garrido I;Lopes S;Simões MS;Liberal R;Lopes J;Carneiro F;Macedo G
通讯作者：
Macedo G
影响因子：
39.3
作者：
Li M;Wang H;Tian L;Pang Z;Yang Q;Huang T;Fan J;Song L;Tong Y;Fan H
通讯作者：
Fan H