Increased sensitivity of peripheral CD27+ memory B cells to Fas-induced apoptosis contributes to their disappearance in cirrhosis (HUM1P.309)

Abstract

Abstract Liver cirrhosis is associated with a 70% decrease of peripheral CD27+ memory B cells. The mechanism for CD27+ B-cell loss in cirrhosis remains unknown. We hypothesize that increased sensitivity to fas-mediated apoptosis leads to reduced peripheral CD27+ B-cells survival. Methods: Ex vivo B-cell fas-receptor (CD95) expression and in vitro measurement of spontaneous and fas-induced apoptosis (annexin V/PI) in 11 cirrhotic (CIR) and 11 healthy donors (HD). We found that expression of CD95 was significantly higher in CD27+ B cells than in CD27- B-cells in both CIR and HD (CIR, 50.2% versus 3.8%, p< 0.0001). The ex vivo percentage and gMFI of CD95 on CD27+ B-cells was significantly higher in CIR than HD (CIR 50.2% versus HD 34.6%; CIR 624 versus HD 337, p<0.02). Surprisingly, ex vivo CD27+ B cells were resistant to fas-mediated apoptosis in both CIR and HD. Anti-CD40 activation of sort-purified CD27+ and CD27- B cells resulted in upregulation of CD95 (1.05-1.17-log-fold) to similar degrees in CIR and HD. Addition of agonist anti-fas resulted in significantly greater apoptosis in cirrhotic CD27+ B cells relative to HD (CIR 33.3% versus HD 18.5%, p=0.05). Conclusion: These data suggest that peripheral CD27+ memory B-cell in cirrhosis exhibit increased sensitivity to fas-induced apoptosis in an activation-dependent manner. This sensitivity may be associated with their reduced frequency in cirrhosis and possibly with resultant derangements of humoral immunity seen in cirrhosis.