The immune response to alkaline phosphatase and other immunogens in patients with primary biliary cirrhosis

Background/Aims: Primary biliary cirrhosis is a potentially lethal hepatobi liary disorder in which 90% of the patients are women. Histologically, the disease is characterized by a progressive destruction of intrahepatic bile ducts by autoreactive T lymphocytes. Although the underlying etiology remai ns unknown, potential hypotheses must take into account; a) the predilectio n of the disease for women of childbearing age, b) the frequent coexistence of bone and intestinal involvement, and c) the high prevalence of autoanti bodies directed towards intracellular enzymes. With these considerations in mind, we hypothesized that exposure to P-ALP (placental alkaline phosphata se) during pregnancy results in autoreactivity directed towards all human t issues harboring the ALP enzyme (liver, bone and intestine) in genetically predisposed individuals. Methodology: To test this hypothesis, we stimulated peripheral blood mononu clear cells of primary biliary cirrhosis patients (n=17) cholestatic liver disease controls (n=6) and healthy controls (n=14) with P-ALP, polyclonal a ctivators (phytohemagglutinin [PHA], anti-CDS) and recall antigens (tetanus toroid, streptokinase). We then determined their proliferative and cytokin e responses by H-3-thymidine incorporation and ELISA assays for IL-10, IL-6 , tumor necrosis factor-or and interferon-gamma, respectively. Results: The results of the study revealed that the proliferative response to P-ALP was similar in peripheral blood mononuclear cells from primary bil iary cirrhosis patients, cholestatic and healthy controls. Although the pro liferative responses to PHA (P<0.001) and anti-CD3 (P<0.001) were decreased in peripheral blood mononuclear cells from primary biliary cirrhosis patie nts when compared to both control groups, responses to the recall antigens; tetanus toroid and streptokinase were similar in the three groups. Cytokin e production following exposure to PALP, polyclonal activators or recall an tigens in peripheral blood mononuclear cells from primary biliary cirrhosis patients was similar to that of cholestatic and healthy controls. Conclusions: The results of the above experiments suggest that P-ALP is unl ikely to be the target autoantigen in primary biliary cirrhosis. The result s also support the findings of other investigators that primary biliary cir rhosis patients have suppressed proliferative responses to polyclonal stimu lation.