Apoptosis-associated antigens recognized by autoantibodies in patients with the autoimmune liver disease primary biliary cirrhosis
Apoptosis-associated antigens recognized by autoantibodies in patients with the autoimmune liver disease primary biliary cirrhosis
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DOI：
10.1007/s10495-007-0157-6
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发表时间：
2008-01-01
期刊：
影响因子：
7.2
通讯作者：
Lauber, Kirsten
中科院分区：
文献类型：
--
作者：
Berg, Christoph Peter;Stein, Gerburg Maria;Lauber, Kirsten
越来越多的证据表明，自身免疫性疾病的发生可能与对凋亡细胞的去除效率低下有关。由于消除凋亡细胞的缺陷会导致继发性坏死和随后细胞内成分的释放，这可能解释了产生针对细胞内抗原的自身抗体。因此，我们想要研究，来自自身免疫性肝病原发性胆汁性肝硬变(PBC)患者的抗体是否识别在细胞凋亡过程中产生和释放的自身蛋白。在Jurkat T白血病、HepG2肝癌和HT-29结肠癌细胞裂解产物中，用PBC患者的血清免疫球蛋白检测到细胞内抗原，而用正常人的血清免疫球蛋白检测不到细胞内抗原。有趣的是，PBC血清免疫球蛋白还能识别星形孢子素或TRAIL(肿瘤坏死因子相关的凋亡诱导配体)诱导的细胞凋亡中的caspase底物。除细胞内抗原外，PBC患者血清中还检测到凋亡(继发性坏死)细胞上清液中的caspase依赖抗原和凋亡Jurkat细胞表面的抗原。在PBC血清抗体识别的caspase底物中，我们可以鉴定出已知自身抗原PDC(丙酮酸脱氢酶复合体)的组分PDC-E2和-E1β。因此，caspase介导的细胞内蛋白的加工可能会产生从头开始的自身抗原，这些抗原一旦释放，就会导致自身抗体的产生和自身免疫性疾病，如PBC。
There is growing evidence that the onset of autoimmune disorders can be linked to the inefficient removal of apoptotic cells. Since defects in the elimination of apoptotic cells lead to secondary necrosis and subsequent release of intracellular components, this might explain the generation of autoantibodies against intracellular antigens. Accordingly, we wanted to investigate, whether antibodies from patients with the autoimmune liver disease primary biliary cirrhosis (PBC) recognize self-proteins generated and released during apoptosis. Using Western blot analyses we could detect intracellular antigens with serum IgG from PBC patients but not with serum IgG from healthy donors in lysates of Jurkat T-leukemia, HepG2 hepatoma, and HT-29 colon-carcinoma cells. Interestingly, PBC serum IgG also recognized caspase substrates in cells undergoing apoptosis induced by staurosporine or TRAIL (TNF-related apoptosis inducing ligand). In addition to intracellular antigens, serum IgG from PBC patients detected caspase-dependent antigens in the supernatants of apoptotic (secondary necrotic) cells and antigens on the surface of apoptotic Jurkat cells. Among the caspase substrates recognized by PBC serum IgG we could identify the components PDC-E2 and -E1 beta of the known autoantigen PDC (pyruvate dehydrogenase complex). Thus, caspase-mediated processing of intracellular proteins might generate de novo autoantigens that upon release contribute to the generation of autoantibodies and autoimmune diseases as PBC.