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Primary Biliary Cirrhosis (cont.)

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What causes destruction of the bile ducts in PBC?

AMA are tremendously important as a diagnostic marker in patients with PBC. Despite that, no evidence exists that the AMA itself causes the destruction of the biliary epithelial cells lining the small bile ducts. Neither the presence nor the amount (titer) of AMA in the blood appears to be related to the inflammatory destruction of the bile ducts. Indeed, immunization of animals with PDC-E2 antigen results in production of AMA without any liver or bile duct damage (pathology).

What, then, causes the destruction of the bile ducts in PBC? Inspection of liver biopsies from patients with PBC indicates that T-lymphocytes surround and invade the small bile ducts. Thus, T-lymphocytes appear to be responsible for the death of the biliary epithelial cells lining the ducts and the destruction of the bile ducts. T-lymphocytes capable of directly killing target-cells (for example, biliary epithelial cells) are called cytotoxic T-lymphocytes, meaning that these T-cells are toxic to the target cells. And, in fact, cytotoxic T-lymphocytes have been observed in liver biopsies to invade the bile ducts and to be present in areas where biliary epithelial cells are dying.

Other T-lymphocytes that surround the bile ducts are known to produce chemicals that can also cause biliary epithelial cells to die. Some of these chemicals actually stimulate the biliary epithelial cells themselves to secrete small proteins that attract more T-lymphocytes. Paradoxically, then, this response by the biliary epithelial cells might result in even greater injury to the bile ducts, in sort of a vicious cycle.

Recent studies of T-lymphocytes isolated from the inflamed livers of patients with PBC have shown that these T-lymphocytes can, in fact, kill biliary epithelial cells. Moreover, many of the T-lymphocytes recognized the digested fragments of PDC-E2. These observations suggest the possibility (hypothesis) that the T-lymphocytes might attack the biliary epithelial cells because these cells display PDC-E2 antigens in their HLA (Human Lymphocyte Antigen) molecules to which the T lymphocytes react. No direct evidence, however, supports this hypothesis. The fact is that the actual antigens on biliary epithelial cells that are recognized by invading, destructive T-lymphocytes remain to be determined. However, the biliary epithelial cells do contain molecules, such as intercellular adhesion molecule-1, that are required for activated T lymphocytes to adhere to the cells that they kill.



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