Reply
Authors: Mathieu Sertorio, Rodrigo F. Carmo, Sandrine Cabantous, Luydson Vasconcelos, Leila Beltrao Pereira, Patricia Moura, Alain Dessein
Journal: Hepatology (2015)

Potential conflict of interest: Dr. Dessein consults for, owns stock in, and holds intellectual property rights in GenePred. We are concerned that Wu et al. do not seem to have fully understood that the genetic analyses we report demonstrate a causal link between interleukin (IL)22RA2 alleles and severe fibrosis in hepatitis C virus (HCV) and schistosome infections. In this study,1 we have excluded the possibility that the causal mutations lie outside IL22RA2. We also show that the alleles associated with a higher risk of severe fibrosis result in lower levels of IL22RA2 transcription. Increasing production of the inhibitor (IL‐22BP), which strongly competes with IL‐22 for binding to its receptor, therefore aggravates disease. This result was obtained in a cohort of schistosome‐infected individuals from China and was confirmed in two other cohorts from Sudan and Brazil. Finally, it was also extended to two separate cohorts of HCV‐infected subjects. The data provide strong evidence that IL‐22BP aggravates severe fibrosis and cirrhosis, whereas IL‐22 protects against these conditions. The data we presented on correlations between IL‐22 levels and protection against hepatic fibrosis were to illustrate our conclusions further and introduce the value of a strong genetic analysis. The possibility that IL‐22 might protect against hepatic fibrosis in HCV‐induced fibrosis, but aggravate HBV‐induced fibrosis, is an intriguing question. There is no definitive demonstration that IL‐22 aggravates disease in HBV‐infected subjects; Zhao et al.2 showed that IL‐22 is correlated with disease aggravation in human hepatitis B virus (HBV) infections. The data obtained in HBV transgenic mice stimulated with anti‐CD137 antibodies2 are interesting, but it remains unclear whether this acute model of disease accurately reflects human disease, which develops after many years and is unlikely to involve such strong chronic polyclonal stimulation of T cells. Zhao et al.2 also reported that the IL‐22 pathway is a major pathway in severe fibrosis, based on a comparison of the transcriptomes of three normal noninfected livers and four fibrotic livers infected with HBV. In contrast, our comparisons of the transcriptomes of 15 F0‐F1 and 13 F3‐F4 human livers infected with HCV showed no evidence that the IL‐22 pathway was among the major pathways recruited in the F3‐F4 livers in HCV‐infected subjects (Ambard S, Moura P, Beltrao L, Dessein A, unpublished results). Furthermore, Zhang et al. have suggested that IL‐22 increases HBV‐induced fibrosis by aggravating the effects of IL‐17,2 a conclusion supported by their demonstration that IL‐22 is, at least partly, produced by T helper (Th)17 cells2 in HBV‐infected patients. In our study,1 we showed that very little IL‐17A was produced by blood cells from schistosome‐infected subjects. These cells produce IL‐22 in abundance, and IL‐22 was not produced by Th17 cells. Altogether, these observations suggest that IL‐22 may have different effects in HBV and HCV or schistosome infections, but further studies are required to provide support for this hypothesis. Along these lines, a genetic analysis of IL‐22RA2 in HBV‐infected subjects similar to the study we reported on in this journal would be valuable, to obtain a convincing answer to this question.