Prognostic Significance of the Systemic Inflammatory and Immune Balance in Alcoholic Liver Disease with a Focus on Gender-Related Differences - PubMed (original) (raw)

Beata Kasztelan-Szczerbińska et al. PLoS One. 2015.

Abstract

Objectives: Mechanisms of immune regulation in alcoholic liver disease (ALD) are still unclear. The aim of our study was to determine an impact of Th17 / regulatory T (Treg) cells balance and its corresponding cytokine profile on the ALD outcome. Possible gender-related differences in the alcohol-induced inflammatory response were also assessed.

Materials and methods: 147 patients with ALD were prospectively recruited, assigned to subgroups based on their gender, severity of liver dysfunction and presence of ALD complications at admission, and followed for 90 days. Peripheral blood frequencies of Th17 and Treg cells together with IL-1beta, IL-6, IL-17A, IL-23, and TGF-beta1 levels were investigated. Flow cytometry was used to identify T cell phenotype and immunoenzymatic ELISAs for the corresponding cytokine concentrations assessment. Multivariable logistic regression was applied in order to select independent predictors of advanced liver dysfunction and the disease complications.

Results: IL-17A, IL-1beta, IL-6 levels were significantly increased, while TGF-beta1 decreased in ALD patients. The imbalance with significantly higher Th17 and lower Treg frequencies was observed in non-survivors. IL-6 and TGF-beta1 levels differed in relation to patient gender in ALD group. Concentrations of IL-6 were associated with the severity of liver dysfunction, development of ALD complications, and turned out to be the only independent immune predictor of 90-day survival in the study cohort.

Conclusions: We conclude that IL-6 revealed the highest diagnostic and prognostic potential among studied biomarkers and was related to the fatal ALD course. Gender-related differences in immune regulation might influence the susceptibility to alcohol-associated liver injury.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1

Fig 1. Evaluation of CD4/CD3+/IL-17A+ (Th17) cells frequency in ALD patients by flow cytometry.

A. The lymphocyte subpopulation was gated (R1) based on linear forward vs. side scatter (FSC/SSC) characteristics. B. The R1 cells were further evaluated for CD3 PE-Cy5 and CD4 FITC staining with subsequent CD4+/CD3+ cell identification (region R2). C. Dot plots of CD4FITC versus mouse IgG1 PE were established (controls). D. Dot plots of CD4FITC versus IL-17A PE were established by combined gating of R1 and R2 events. The R3 region represents the percentage of CD4+/CD3+/IL-17A+ (Th17) cells among all CD4+CD3+ lymphocytes.

Fig 2

Fig 2. Evaluation of CD4+CD25highFoxP3+ (Treg) cells frequency in ALD patients by flow cytometry.

A. The lymphocyte subpopulation was gated (R1) based on linear forward vs. side scatter (FSC/SSC) characteristics. B. Dot plots of CD4 PE-Cy5 versus mouse IgG1 Alexa Fluor 488 were established (controls). C. Dot plots of CD4 PE-Cy5 versus the intracellular expression of FoxP3 Alexa Fluor 488 in CD4+ T cells were established. The R2 region represents the percentage of CD4+CD25highFoxP3+ (Treg) cells among all CD4+CD25+ lymphocytes. D. 99.8% of cells gated as CD4+FoxP3+ (R2) were CD25 high.

Fig 3

Fig 3. Gender- related differences in serum cytokine concentrations in ALD group.

IL-6 pg/mL; TGF-beta1 ng/mL. ALD- alcoholic liver disease, 95% CI- Confidence Interval, IL- interleukin, TGF- Transforming Growth Factor, p- level of significance.

Fig 4

Fig 4. IL-6 concentrations (pg/mL) in ALD patients assigned according to the CTP class.

ALD- alcoholic liver disease, 95% CI- Confidence Interval, CTP class- Child-Turcotte-Pugh class, IL- interleukin, p- level of significance.

Fig 5

Fig 5. Peripheral blood frequencies (%) of Th17 and Treg cells in ALD survivors and non-survivors.

ALD- alcoholic liver disease, 95% CI- Confidence Interval, p- level of significance, Th- T helper cells, Treg- regulatory T cells.

References

    1. World Health Organisation. Global Status Raport on Alcohol and Health 2011. Geneva, Switzerland: World Health Organisation, 2011.
    1. Paula H, Asrani SK, Boetticher NC, Pedersen R, Shah VH, Kim WR. Alcoholic liver disease-related mortality in the United States: 1980–2003 Am J Gastroenterol. 2010,105(8):1782–7. 10.1038/ajg.2010.46 - DOI - PMC - PubMed
    1. Curtis BJ, Hlavin S, Brubaker AL, Kovacs EJ, Radek KA. Episodic binge ethanol exposure impairs murine macrophage infiltration and delays wound closure by promoting defects in early innate immune responses. Alcohol Clin Exp Res. 2014;38(5):1347–55. 10.1111/acer.12369 - DOI - PMC - PubMed
    1. Ward RJ, Lallemand F, de Witte P. Influence of adolescent heavy session drinking on the systemic and brain innate immune system. Alcohol Alcohol 2014;49(2):193–7. 10.1093/alcalc/agu002 - DOI - PubMed
    1. Szabo G, Mandrekar P, Petrasek J, Catalano D. The unfolding web of innate immune dysregulation in alcoholic liver injury. Alcohol Clin Exp Res. 2011;35(5):782–6. 10.1111/j.1530-0277.2010.01398.x - DOI - PMC - PubMed

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