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Complement system is not activated in primary biliary cirrhosis
M Gardinali1, L Conciato, C Cafaro
1Institute of Internal Medicine, IRCCS Ospedale Policlinico, Milan, Italy.
Insights
Complement system activation is not implicated in primary biliary cirrhosis (PBC). Elevated C3 levels in PBC patients are linked to cholestasis, not liver inflammation or complement activation.
Area of Science:
- Immunology
- Hepatology
- Complement System Biology
Background:
- Controversial evidence suggests chronic complement system activation in primary biliary cirrhosis (PBC), potentially contributing to bile duct injury.
- Previous studies lacked sensitive methods to accurately assess complement activation in PBC.
Purpose of the Study:
- To reevaluate complement system activation in primary biliary cirrhosis (PBC) using sensitive assays.
- To investigate the relationship between complement activation by-products and disease progression in PBC.
Main Methods:
- Measured plasma by-products of complement activation (C4a, C3a, Bb, SC5b-9) in 44 PBC patients.
- Included age-matched healthy women and patients with chronic hepatitis as controls.
- Utilized sensitive methods to detect complement activation, including C3a/C3 ratio and C-reactive protein levels.
Main Results:
- PBC patients showed normal C4a and Bb levels, refuting classical and alternative pathway activation.
- Minor C3a increases were observed in some PBC patients, but the C3a/C3 ratio remained similar across groups.
- Elevated C3 concentrations were found in early-stage PBC and chronic cholestatic syndromes, correlating with bilirubin levels and cholestasis, not inflammation.
Conclusions:
- The complement system is not chronically activated in primary biliary cirrhosis (PBC).
- Increased serum C3 levels in PBC are associated with cholestasis, independent of liver inflammation or complement activation.
- Findings suggest cholestasis, not complement activation, is linked to altered C3 levels in PBC.
Abstract:
There is controversial evidence suggesting that the classical pathway of complement system is chronically activated in primary biliary cirrhosis (PBC) and that complement activation may be important in development of bile duct injury. We have reevaluated this issue by measuring by-products of complement activation such as C4a, C3a, Bb, and terminal complement complexes (SC5b-9) in plasma of 44 PBC patients with sensitive methods not previously used to detect complement activation in this disease. Age-matched healthy women and patients with chronic hepatitis of different etiology were studied as controls. We found that PBC patients have normal C4a concentrations. This finding argues strongly against chronic classical pathway activation. Although a minor increase of C3a levels was observed in a minority of PBC patients, the C3a/C3 ratio, an index used to evaluate the extent of native protein conversion, was remarkably similar in all groups. Potentially lytic terminal complement complexes were not increased. PBC patients had normal Bb plasma levels, indicating that the alternative pathway is also not activated. C3 concentration was higher in PBC patients than in healthy subjects and in chronic hepatitis patients, particularly in the early stages of the disease. C3 and C4 concentrations became lower in PBC and chronic hepatitis with the progression of the disease. The increase of C3 concentration in PBC does not reflect liver inflammation, since serum levels of C-reactive protein are normal. We found high serum C3 levels in patients with rare chronic cholestatic syndromes without superimposed infections and observed that serum C3 levels paralleled those of bilirubin in a patient with benign recurrent intrahepatic cholestasis. In conclusion, our data indicate that complement is not activated in PBC and that the increase of serum C3 levels is related to cholestasis.