The immune response to alkaline phosphatase and other immunogens in patients with primary biliary cirrhosis.
OBJECTIVE
Primary biliary cirrhosis is a potentially lethal hepatobiliary 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 remains unknown, potential hypotheses must take into account; a) the predilection of the disease for women of childbearing age, b) the frequent coexistence of bone and intestinal involvement, and c) the high prevalence of autoantibodies directed towards intracellular enzymes. With these considerations in mind, we hypothesized that exposure to P-ALP (placental alkaline phosphatase) during pregnancy results in autoreactivity directed towards all human tissues harboring the ALP enzyme (liver, bone and intestine) in genetically predisposed individuals.


METHODS
To test this hypothesis, we stimulated peripheral blood mononuclear cells of primary biliary cirrhosis patients (n = 17) cholestatic liver disease controls (n = 6) and healthy controls (n = 14) with P-ALP, polyclonal activators (phytohemagglutinin [PHA], anti-CD3) and recall antigens (tetanus toxoid, streptokinase). We then determined their proliferative and cytokine responses by 3H-thymidine incorporation and ELISA assays for Il-10, IL-6, tumor necrosis factor-alpha 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 biliary cirrhosis patients, cholestatic and healthy controls. Although the proliferative responses to PHA (P < 0.001) and anti-CD3 (P < 0.001) were decreased in peripheral blood mononuclear cells from primary biliary cirrhosis patients when compared to both control groups, responses to the recall antigens; tetanus toxoid and streptokinase were similar in the three groups. Cytokine production following exposure to P-ALP, polyclonal activators or recall antigens 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 unlikely to be the target autoantigen in primary biliary cirrhosis. The results also support the findings of other investigators that primary biliary cirrhosis patients have suppressed proliferative responses to polyclonal stimulation.
Liver Diseases Unit, Department of Medicine, University of Manitoba, Health Sciences Centre, Winnipeg, Manitoba, Canada.
G
G
Harding
R
R
McKenna
G
G
Minuk
D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000276:immunology*; D000941:Antigens / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002455:Cell Division; D002779:Cholestasis / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010835:Phytohemagglutinins / Q000276:immunology; D010920:Placenta / Q000201:enzymology; D013300:Streptokinase / Q000276:immunology; D013745:Tetanus Toxoid / Q000276:immunology; D013936:Thymidine / Q000378:metabolism
D000941:Antigens; D001324:Autoantigens; D017252:CD3 Complex; D016207:Cytokines; D007527:Isoenzymes; D010835:Phytohemagglutinins; D013745:Tetanus Toxoid; D000469:Alkaline Phosphatase; D013300:Streptokinase; D013936:Thymidine