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Background Although decreased counts of peripheral blood ( PB) B cells-associated with an apparently contradictory polyclonal hypergammaglobulinemia-have been reported in chronic alcoholism, no information exists about the specific subsets of circulating B cells altered and their relationship with antibody production. Here, we analyzed for the first time the distribution of multiple maturation-associated subpopulations of PB B cells in alcoholism and its potential relationship with the onset of liver disease. Methods PB samples from 35 male patients-20 had alcoholic hepatitis ( AH) and 15 chronic alcoholism without liver disease ( AWLD)-were studied, in parallel to 19 male healthy donors (controls). The distribution of PB B-cell subsets (immature/regulatory, naïve, CD27− and CD27+ memory B lymphocytes, and circulating plasmablasts of distinct immunoglobulin-Ig-isotypes) was analyzed by flow cytometry. Results Patients with AH showed significantly decreased numbers of total PB B lymphocytes (vs. controls and AWLD), at the expense of immature, memory, and, to a lesser extent, also naïve B cells. AWLD showed reduced numbers of immature and naïve B cells (vs. controls), but higher PB counts of plasmablasts (vs. the other 2 groups). Although PB memory B cells were reduced among the patients, the percentage of surface (s) IgA+ cells (particularly CD27−/ sIgA+ cells) was increased in AH, whereas both sIgG+ and sIgA+ memory B cells were significantly overrepresented in AWLD versus healthy donors. Regarding circulating plasmablasts, patients with AH only showed significantly reduced counts of sIgG+ cells versus controls. In contrast, the proportion of both sIgA+ and sIgG+ plasmablasts-from all plasmablasts-was reduced in AH and increased in AWLD (vs. the other 2 groups). Conclusions AH and AWLD patients display a significantly reduced PB B-cell count, at the expense of decreased numbers of recently produced immature/regulatory B cells and naïve B cells, together with an increase in Ig-switched memory B lymphocytes and plasmablasts, particularly of IgA+ cells. [ABSTRACT FROM AUTHOR]

Background Development of alcoholic hepatitis ( AH) may be favored by the activation of the innate immune response. Recently, decreased numbers of circulating regulatory T cells ( Tregs) have been reported in diseases associated with an immune activation status, but no studies have focused so far, in investigating the distribution of Tregs in chronic alcoholism and its potential association with liver disease. Here, we analyzed for the first time the frequency of peripheral blood ( PB) Tregs and Treg subsets in AH and its relationship with the production of inflammatory cytokines by PB monocytes and dendritic cells ( DCs). Methods PB samples from 25 male patients with AH were studied; in parallel, 15 male chronic alcoholic patients without liver disease ( AWLD) and 17 male healthy donors were also studied, as controls. The distribution of CD4+ CD25hi CD127−/lo Tregs and their maturation subsets (naïve, central memory, and peripheral memory Tregs) was analyzed by flow cytometry. Spontaneous and in vitro-stimulated production of inflammatory cytokines by PB monocytes and DCs was analyzed by flow cytometry at the cytoplasmic level. Results Patients with AH showed decreased ( p < 0.05) numbers of PB CD4+ CD25hi CD127−/lo Tregs at the expense of all maturation-associated subsets, while AWLD and healthy subjects showed a similar ( p > 0.05) distribution of PB CD4+ CD25hi CD127−/lo Tregs. Interestingly, significantly increased amounts of spontaneously produced inflammatory cytokines were found among circulating monocyte-derived DCs and monocytes from AH (and AWLD) patients in comparison with healthy donors. Conversely, the ability of these cell subsets to produce cytokines after in vitro stimulation was lower ( p < 0.05) in AH versus the 2 control groups. Conclusions PB CD4+ CD25hi CD127−/lo Tregs are significantly decreased in patients with AH when compared to both healthy and AWLD; this may contribute to explain the more pronounced activation of the innate immune response observed in AH, as reflected by an increased secretion of inflammatory cytokines by PB DCs and monocytes, and could facilitate the development of liver disease. [ABSTRACT FROM AUTHOR]

Introduction and Aims: Alcoholic hepatitis is the most severe manifestation of alcoholic liver disease. Unfortunately, there are still some unresolved issues in the diagnosis and management of this disease, such as the need of histological diagnosis, an accurate prognostic stratification, and the development of novel targeted therapies. The present study aimed at addressing these issues by means of metabolomics, a novel high-throughput approach useful in other liver diseases., Material and Methods: 64 patients with biopsy-proven alcoholic hepatitis were included and compared with 26 patients with decompensated alcoholic cirrhosis without superimposed alcoholic hepatitis, which was ruled out by liver biopsy., Results: The comparison of the metabolic profiles of patients with alcoholic hepatitis and decompensated cirrhosis showed marked differences between both groups. Importantly, metabolic differences were found among alcoholic hepatitis patients when subjects were stratified according to 90-day survival. Based on these findings, two non-invasive signatures were developed. The first one allowed an accurate non-invasive diagnosis of alcoholic hepatitis (AUROC 0.932; 95% CI 0.901-0.963). The second signature showed a good performance in the prognostic stratification of patients with alcoholic hepatitis (AUROC 0.963; 95% CI 0.895-1.000)., Conclusions: Signatures based on metabolomics allowed an accurate non-invasive diagnosis and prognostic stratification of alcoholic hepatitis. The differences observed in the metabolic profile of the patients according to the presence and severity of alcoholic hepatitis are related with different mechanisms involved in the pathophysiology of alcoholic hepatitis such as peroxisomal activity, synthesis of inflammatory mediators or oxidation. This information could be useful for the development of novel targeted therapies., (Copyright © 2019 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)