Spengler U, Leifeld L, Braunschweiger I, Dumoulin F L, Lechmann M, Sauerbruch T
Department of General Medicine, University of Bonn, Germany.
J Hepatol. 1997 Jan;26(1):31-6. doi: 10.1016/s0168-8278(97)80006-2.
T lymphocytes require two important signals for efficient activation: 1) recognition of antigens bound to self major histocompatibility complex antigens, and 2) simultaneous stimulation via so-called costimulatory molecules. Interaction of the costimulatory B7 molecules on antigen presenting cells with CD28 on T lymphocytes appears to be particularly important, as it modifies secretion of cytokines, especially interleukin 2. In primary biliary cirrhosis biliary epithelial cells aberrantly express major histocompatibility complex class II antigens and may function as antigen presenting cells.
We studied expression of HLA-DR, B7-1, B7-2 and CD28 on cryostat liver sections in 16 patients with primary biliary cirrhosis, three patients each with autoimmune hepatitis and primary sclerosing cholangitis and nine patients with chronic viral hepatitis (five hepatitis B, four hepatitis C) using mouse monoclonal antibodies in an indirect immunoperoxidase technique.
In advanced primary biliary cirrhosis, HLA-DR was found on 57% of bile ducts, B7-2 on 5% of bile ducts, and B7-1 could not be detected on any bile duct. Neither B7-1 nor B7-2 was seen on bile ducts in the four patients with early primary biliary cirrhosis. HLA-DR+ bile ducts also lacked expression of B7 molecules in autoimmune hepatitis. In contrast, HLA-DR, B7-1 and B7-2 were expressed simultaneously on professional antigen presenting cells such as macrophages in epitheloid granulomas.
HLA-DR+ biliary epithelial cells in primary biliary cirrhosis insufficiently co-express B7-1 or B7-2 molecules. Therefore, they must either use different costimulatory molecules, or otherwise are deficient in lymphocyte activation. Since recognition of antigen in the absence of B7-CD28 interaction may lead to anergy of lymphocytes, this might contribute to the impaired cytokine secretion found in primary biliary cirrhosis.
T淋巴细胞有效激活需要两个重要信号：1）识别与自身主要组织相容性复合体抗原结合的抗原，以及2）通过所谓的共刺激分子同时刺激。抗原呈递细胞上的共刺激B7分子与T淋巴细胞上的CD28相互作用似乎尤为重要，因为它会改变细胞因子的分泌，尤其是白细胞介素2。在原发性胆汁性肝硬化中，胆管上皮细胞异常表达主要组织相容性复合体II类抗原，并可能作为抗原呈递细胞发挥作用。
我们采用间接免疫过氧化物酶技术，使用小鼠单克隆抗体，研究了16例原发性胆汁性肝硬化患者、3例自身免疫性肝炎和原发性硬化性胆管炎患者以及9例慢性病毒性肝炎患者（5例乙型肝炎、4例丙型肝炎）的低温肝脏切片上HLA-DR、B7-1、B7-2和CD28的表达情况。
在晚期原发性胆汁性肝硬化中，57%的胆管上发现有HLA-DR，5%的胆管上有B7-2，而在任何胆管上均未检测到B7-1。4例早期原发性胆汁性肝硬化患者的胆管上均未见到B7-1和B7-2。自身免疫性肝炎中，HLA-DR+胆管也缺乏B7分子的表达。相比之下，在诸如上皮样肉芽肿中的巨噬细胞等专职抗原呈递细胞上，HLA-DR、B7-1和B7-2同时表达。
原发性胆汁性肝硬化中HLA-DR+胆管上皮细胞不能充分共表达B7-1或B7-2分子。因此，它们要么使用不同的共刺激分子，要么在淋巴细胞激活方面存在缺陷。由于在缺乏B7-CD28相互作用的情况下识别抗原可能导致淋巴细胞无反应性，这可能是原发性胆汁性肝硬化中细胞因子分泌受损的原因之一。
