No abstract

SUMMARYThe autoimmune nature of primary biliary cirrhosis (PBC) is well established. We tested the hypothesis that fetal microchimerism indicated by the persistence of circulating fetal cells in women years after pregnancy might contribute to the aetiopathogenesis of PBC through a graft-versus-host-like response. We extracted DNA from the peripheral blood cells of 36 women carefully selected from 173 consecutive PBC patients, who were matched with 36 healthy women by age, age of last son, and number of children. Both patients and controls had to have male offspring, and no history of miscarriages or blood transfusions; they could not be twins. We tested all of the samples for the presence of two specific Ychromosome sequences (SY154 and SRY) by amplifying DNA in a nested polymerase chain reaction. Y-chromosome-specific DNA was detected in the peripheral blood cell DNA of 13 (36%) of the 36 women with PBC and in 11 (31%) of the 36 healthy controls. The two groups of PBC patients with and without male DNA sequences were similar in terms of their clinical, biochemical, and serological features. Y-chromosome sequences were found in three of the four PBC women with associated systemic sclerosis. All of the 24 Y-positive samples contained SY154 sequences, but only three PBC patients and six controls showed the presence of both SY154 and SRY sequences. This discrepancy may suggest that not only fetal cells but also fragments of fetal DNA are present in maternal circulation. Overall, our data do not support the hypothesis that fetal microchimerism plays a significant role in the onset or progression of PBC.

Antibody to carbonic anhydrase II, an enzyme abundantly present in biliary epithelium, has been proposed as a diagnostic marker for antimitochondrial antibody-negative PBC. In this study we determine its prevalence and clinical significance in a large series of patients with antimitochondrial antibody-positive and -negative PBC. Reactivity to carbonic anhydrase II was sought by Western immunoblotting in sera from 215 consecutive patients with PBC (26 antimitochondrial antibody-negative), 13 with autoimmune hepatitis, 25 with primary Sjögren's syndrome (pSS), 12 with systemic sclerosis, 19 with systemic lupus erythematosus and 73 healthy subjects. The prevalence of antibody to carbonic anhydrase II (titre 1:100) in PBC was 8%. No specific reactivity to carbonic anhydrase II was found in antimitochondrial antibody-negative PBC (7% versus 8% in antimitochondrial antibody-positive PBC). Ascites (P = 0.006) and Sjögren's syndrome (SS) (P = 0.022) in PBC were significantly associated with presence of the antibody. In patients with SS associated with PBC, the prevalence (19%) was similar to that observed in pSS (16%). At a serum dilution of 1:40, the prevalence of positive sera in PBC rose to 27% but disease specificity was reduced. Our findings in a large population of PBC patients rule out a relation between presence of antibody to carbonic anhydrase II and lack of antimitochondrial antibody. The higher prevalence of ascites found in positive patients warrants further evaluation.

The provided evidence confirms the importance of Notch pathway in human malignancies indicating that a strong rationale exists for the development of a Notch-tailored therapy.