Immune cell kinetics and antibody response in COVID-19 patients with low-count monoclonal B-cell lymphocytosis.

Low-count monoclonal B-cell lymphocytosis (MBLlo ) has been associated with an underlying immunodeficiency and has recently emerged as a new risk factor for severe COVID-19. Here, we investigated the kinetics of immune cell and antibody responses in blood during COVID-19 of MBLlo versus non-MBL patients. For this study, we analyzed the kinetics of immune cells in blood of 336 COVID-19 patients (74 MBLlo and 262 non-MBL), who had not been vaccinated against SARS-CoV-2, over a period of 43 weeks since the onset of infection, using high-sensitivity flow cytometry. Plasma levels of anti-SARS-CoV-2 antibodies were measured in parallel by ELISA. Overall, early after the onset of symptoms, MBLlo COVID-19 patients showed increased neutrophil, monocyte, and particularly, plasma cell (PC) counts, whereas eosinophil, dendritic cell, basophil, and lymphocyte counts were markedly decreased in blood of a variable percentage of samples, and with a tendency toward normal levels from week +5 of infection onward. Compared with non-MBL patients, MBLlo COVID-19 patients presented higher neutrophil counts, together with decreased pre-GC B-cell, dendritic cell, and innate-like T-cell counts. Higher PC levels, together with a delayed PC peak and greater plasma levels of anti-SARS-CoV-2-specific antibodies (at week +2 to week +4) were also observed in MBLlo patients. In summary, MBLlo COVID-19 patients share immune profiles previously described for patients with severe SARS-CoV-2 infection, associated with a delayed but more pronounced PC and antibody humoral response once compared with non-MBL patients.

Circulating MicroRNAs in Extracellular Vesicles as Potential Biomarkers of Alcohol-Induced Neuroinflammation in Adolescence: Gender Differences.

Current studies evidence the role of miRNAs in extracellular vesicles (EVs) as key regulators of pathological processes, including neuroinflammation and neurodegeneration. As EVs can cross the blood-brain barrier, and EV miRNAs are very stable in peripheral circulation, we evaluated the potential gender differences in inflammatory-regulated miRNAs levels in human and murine plasma EVs derived from alcohol-intoxicated female and male adolescents, and whether these miRNAs could be used as biomarkers of neuroinflammation. We demonstrated that while alcohol intoxication lowers anti-inflammatory miRNA (mir-146a-5p, mir-21-5p, mir-182-5p) levels in plasma EVs from human and mice female adolescents, these EV miRNAs increased in males. In mice brain cortices, ethanol treatment lowers mir-146a-5p and mir-21-5p levels, while triggering a higher expression of inflammatory target genes (Traf6, Stat3, and Camk2a) in adolescent female mice. These results indicate, for the first time, that female and male adolescents differ as regards the ethanol effects associated with the inflammatory-related plasma miRNAs EVs profile, and suggest that female adolescents are more vulnerable than males to the inflammatory effects of binge alcohol drinking. These findings also support the view that circulating miRNAs in EVs could be useful biomarkers for screening ethanol-induced neuroinflammation and brain damage in adolescence.

Gender differences in the inflammatory cytokine and chemokine profiles induced by binge ethanol drinking in adolescence.

Heavy binge drinking in adolescence can cause long-term cognitive and behavioral dysfunctions. Recent experimental evidence indicates the participation of immune system activation in the effects of ethanol in the adolescent brain and suggests gender differences. The present study aims to assess plasma cytokine and chemokine levels in male and female adolescents and young adults during acute alcohol intoxication and to correlate these results with the toll-like receptor 4 (TLR4) response. The potential role of the TLR4 signaling response was also assessed in plasma and prefrontal cortex (PFC) of adolescent wild-type and TLR4-knockout male and female mice with binge ethanol treatment. The results showed that alcohol intoxication increased the plasma levels of several cytokine and chemokine [interferon-γ, interleukin (IL)-10, IL-17A, IL-1ß, IL-2, IL-4, IL-6, IL-8, fractalkine, monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1α (MIP-1α)] and the upregulation of TLR4 mRNA levels occurred in intoxicated females, while elevation of colony-stimulating factor was only observed in the plasma of males. In wild-type female adolescent mice, intermittent ethanol treatment increased the levels of several cytokines (IL-17A and IL-1ß) and chemokines (MCP-1, MIP-1α and fractalkine) in PFC and in serum (IL-17A, MCP-1 and MIP-1α), but significant differences in the fractalkine levels in PFC were observed only in male mice. No changes in serum or prefrontal cortex cytokine and chemokine levels were noted in ethanol-treated male or female TLR4-knockout mice. Our findings revealed that females are more vulnerable than males to inflammatory effects of binge ethanol drinking and suggested that TLR4 is an important target of ethanol-induced inflammation and neuroinflammation in adolescence.

Histone Deacetylase Gene Expression Following Binge Alcohol Consumption in Rats and Humans.

BACKGROUND: Alcohol binge drinking is one of the most common patterns of excessive alcohol use and recent data would suggest that histone deacetylases (HDACs) gene expression profiling could be useful as a biomarker for psychiatric disorders. METHODS: This study aimed to characterize the gene expression patterns of Hdac 1-11 in samples of rat peripheral blood, liver, heart, prefrontal cortex, and amygdala following repeated binge alcohol consumption and to determine the parallelism of Hdac gene expression between rats and humans in peripheral blood. To accomplish this goal, we examined Hdac gene expression following 1, 4, or 8 alcohol binges (3 g/kg, orally) in the rat, in patients who were admitted to the hospital emergency department for acute alcohol intoxication, and in rats trained in daily operant alcohol self-administration. RESULTS: We primarily found that acute alcohol binging reduced gene expression (Hdac1-10) in the peripheral blood of alcohol-naïve rats and that this effect was attenuated following repeated alcohol binges. There was also a reduction of Hdac gene expression in the liver (Hdac2,4,5), whereas there was increased expression in the heart (Hdac1,7,8) and amygdala (Hdac1,2,5). Additionally, increased blood alcohol concentrations were measured in rat blood at 1 to 4 hours following repeated alcohol binging, and the only group that developed hepatic steotosis (fatty liver) were those animals exposed to 8 alcohol binge events. Finally, both binge consumption of alcohol in humans and daily operant alcohol self-administration in rats increased Hdac gene expression in peripheral blood. CONCLUSIONS: Our results suggest that increases in HDAC gene expression within the peripheral blood are associated with chronic alcohol consumption, whereas HDAC gene expression is reduced following initial exposure to alcohol.