Discovery and characterization of cross-reactive intrahepatic antibodies in severe alcoholic hepatitis.
Discovery and characterization of cross-reactive intrahepatic antibodies in severe alcoholic hepatitis.
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作者：
Ahmadi AR;Song G;Gao T;Ma J;Han X;Hu MW;Cameron AM;Wesson RN;Philosophe B;Ottmann S;King E;Gurakar A;Qi L;Peiffer B;Burdick J;Anders R;Zhou Z;Lu H;Feng D;Chen CS;Qian J;Gao B;Zhu H;Sun Z
严重酒精性肝炎（SAH）抗体的发病机制尚不清楚。我们分析了接受肝移植的SAH患者（n=45）和相应的健康供者（n= 10）的移植肝脏中的免疫球蛋白（Ig），发现SAH肝脏中球状肝细胞中大量沉积与补体片段C3d和C4d染色相关的IgG和IgA同型抗体。从SAH肝脏中提取的Ig，而不是患者血清中显示出肝细胞杀伤作用。利用人和大肠杆菌K12蛋白质组阵列，我们分析了从外植的SAH、其他疾病肝脏和HD肝脏中提取的抗体。与从其他疾病和HD肝脏中提取的抗体相比，IgG和IgA同型抗体在SAH中高度积累，并识别出一组独特的人蛋白和大肠杆菌抗原。此外，从SAH肝脏中捕获的Ig和大肠杆菌捕获的Ig都能识别出共同的自身抗原，这些抗原在细胞质和细胞质（IgG和IgA）、细胞核、线粒体和局灶黏附（IgG）等细胞成分中富集。除了原发性胆管炎肝脏的IgM外，其他疾病肝脏的Ig和大肠杆菌捕获的Ig均不能识别共同的自身抗原。这些发现表明SAH肝脏中存在交叉反应的抗细菌IgG和IgA自身抗体。
The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissues from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy. Employing human and Escherichia coli K12 proteome arrays, we profiled the antibodies extracted from explanted SAH, livers with other diseases, and HD livers. Compared with their counterparts extracted from livers with other diseases and HD, antibodies of IgG and IgA isotypes were highly accumulated in SAH and recognized a unique set of human proteins and E. coli antigens. Further, both Ig- and E. coli-captured Ig from SAH livers recognized common autoantigens enriched in several cellular components including cytosol and cytoplasm (IgG and IgA), nucleus, mitochondrion, and focal adhesion (IgG). Except IgM from primary biliary cholangitis livers, no common autoantigen was recognized by Ig- and E. coli-captured Ig from livers with other diseases. These findings demonstrate the presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in SAH livers.