Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study

Abstract

Alcoholic hepatitis (AH) develops only in small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty-eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls (HC) were enrolled and followed up to 12 months. At the baseline, HDC and HC had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (TNF-α, IL-6, IL-8, IP10, IL-4, IL-9, IL-10, FGF-2, IL-7, IL-15, and TGF-α), but lower levels of the anti-inflammatory macrophage-derived chemokine (MDC). AH patients also had more activated, yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of CD38 and CD69, but low levels of HLA-DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less IFN-γ in response to T cell stimulation. Upregulated IL-6, IL-8, CD38, and CD69 and downregulated MDC, HLA-DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL-6, IL-8, CD38, and CD69 were reduced, whereas levels of MDC, HLA-DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of TNF-α, IL-8, IL-10, FGF-2, and IL-7 remained higher. Conclusion: AH patients were in a highly immune-dysregulated state, whereas HDC showed little evidence of immune activation. Alcohol abstinence reversed most, but not all, of the immunological abnormalities.

Immune Checkpoint Axes Are Dysregulated in Patients With Alcoholic Hepatitis

“…Alcohol abstinence significantly improves disease outcome and survival but does not lead to complete recovery in most patients with AH . Consistent with this, we have recently reported that plasma levels of IL‐8 and TNF‐α are not normalized in abstinent patients with AH . Here, we identified four additional sICPs (sCD27, sCD40, sHVEM, and sTIM3) that were not fully reversed in abstinent patients with AH.…”

“…In this study, we systematically profiled 18 sICPs in the plasma samples from a large cohort of patients with AH, HDCs, and HCs. In line with profound immune dysregulation in patients with AH, (3,19) we found that 17 out of 18 sICPs examined here were dysregulated (six up-regulated and 11 down-regulated). A previous study found that the TIM-3 ligand galectin-9 was elevated in patients with AH.…”

“…(30) Consistent with this, we have recently reported that plasma levels of IL-8 and TNF-α are not normalized in abstinent patients with AH. (19) Here, we identified four additional sICPs (sCD27, sCD40, sHVEM, and sTIM3) that were not fully reversed in abstinent patients with AH. Our results suggest that these sICPs could serve as sensitive markers for persistent immune activation in abstinent patients with AH.…”

“…Baseline LPS, LBP, sCD14, and sCD163 levels were all elevated in patients with AH in comparison to HDCs and HCs. At follow‐up, levels of those markers greatly decreased from the baseline values in patients with AH while remaining unchanged in HDCs, but sCD163 level remained higher in patients with AH, suggesting that other persistent inflammatory factors, such as TNF‐α, might play a role in driving sCD163 abnormalities at follow‐up . We next determined their correlations with the nine sICPs that were associated with liver‐disease severity.…”

“…It is possible that other sheddases also contributed to the cleavage of these molecules. MMP expression and activities are often enhanced by inflammatory cytokines, including IL‐8, which is one of the most highly up‐regulated inflammatory cytokines in patients with AH and is associated with disease severity . Plasma levels of IL‐8 and MMP7/MMP2 correlated with levels of sCD27, sCD40, sHVEM, sTIM‐3, and sTLR‐2, suggesting that IL‐8 might contribute to production of these sICPs through up‐regulation of MMPs.…”