Phenotypic alterations of regulatory T cells in autoimmune hepatitis: Causal or associated with treatment and remission?
Authors: Marcial Sebode, Moritz Peiseler, Christina Weiler‐Normann, Christoph Schramm, Ansgar W. Lohse, Johannes Herkel
Journal: Hepatology (2014)

This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 841). Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. To the Editor: We read with great interest the article by Grant et al.,1 as well as the accompanying editorial2 emphasizing that reduced frequencies of CD25+CD39+ T‐regulatory cells (Tregs) seem to predispose for autoimmune hepatitis (AIH). However, as is noted in the Patients and Methods section by Grant et al., only 3 of the studied 41 AIH patients were analyzed before immunosuppressive treatment was given. Therefore, it is not entirely clear whether the reported reduction in CD25+CD39+ Treg frequency is a disease characteristic of AIH or whether it might rather be a consequence of the received immunosuppressive treatment. We have previously observed that the Treg frequency in adult AIH patients receiving immunosuppressive treatment was significantly reduced, as compared to both untreated AIH patients and healthy subjects.3 Moreover, we have found that the expression levels of CD25 seemed to be associated with disease activity.3 Thus, both disease activity and treatment status of AIH patients might have an effect on the phenotype of T cells, including CD25+CD39+ Tregs. To address this possibility, we now reanalyzed our patient data according to the gating used by Grant et al. for the percentage of CD25+CD39+ Tregs among the CD4+ T cells and found that CD25+CD39+ Tregs were significantly reduced in immunosuppressed AIH patients (n = 6), but not in untreated AIH patients (n = 7) or healthy subjects (n = 23; Fig. 1; P < 0.05). Of the 6 immunosuppressed patients treated with azathioprine (1.0‐1.5 mg/kg daily; n = 6), 4 also received prednisolone (5‐10 mg per day; n = 4). Although the patient groups are too small to really clarify this issue, this finding seems to indicate that low expression of CD25 and CD39 seems to be a phenotypic Treg alteration caused by immunosuppression. Further studies should address this issue with more patients. However, loss of CD25 expression by Tregs has also been observed in lupus patients in correlation with the daily cortisone dose.4 Nonetheless, these CD25− Tregs still seemed to be functional suppressors.4Figure 1: Reduced frequencies of CD39+CD25+ Tregs in AIH are associated with immunosuppressive treatment. Frequencies of CD39+CD25+ Tregs were determined in peripheral blood of untreated (n = 7) or immunosuppressed (n = 6) AIH patients or healthy subjects (n = 23). *P < 0.05; **P < 0.001; assessed by one‐way analysis of variance and Tukey's post‐test.In conclusion, immunosuppressive treatment seems to be associated with phenotypical changes in Tregs; the functional relevance of these changes needs further investigation. Nonetheless, one should consider the possibility that these phenotypic alterations might indeed not reflect a disease‐causing Treg defect, but rather the complexity of the patient's response to immunosuppressive treatment.