Innate lymphocyte cells (ILCs), a novel family of innate immune cells are considered to function as key orchestrators of immune defences at mucosal surfaces and to be crucial for maintaining an intact intestinal barrier. Accordingly, first data suggest depletion of ILCs to be involved in human immunodeficiency virus (HIV)-associated damage of the intestinal mucosa and subsequent microbial translocation. However, although ILCs are preferentially localized at mucosal surfaces, only little is known regarding distribution and function of ILCs in the human gastrointestinal tract. Here, we show that in HIV(-) individuals composition and functional capacity of intestinal ILCs is compartment-specific with group 1 ILCs representing the major fraction in the upper gastrointestinal (GI) tract, whereas ILC3 are the predominant population in ileum and colon, respectively. In addition, we present first data indicating that local cytokine concentrations, especially that of IL-7, might modulate composition of gut ILCs. Distribution of intestinal ILCs was significantly altered in HIV patients, who displayed decreased frequency of total ILCs in ileum and colon owing to reduced numbers of both CD127(+)ILC1 and ILC3. Of note, frequency of colonic ILC3 was inversely correlated with serum levels of I-FABP and sCD14, surrogate markers for loss of gut barrier integrity and microbial translocation, respectively. Both expression of the IL-7 receptor CD127 on ILCs as well as mucosal IL-7 mRNA levels were decreased in HIV(+) patients, especially in those parts of the GI tract with reduced ILC frequencies, suggesting that impaired IL-7 responses of ILCs might contribute to incomplete reconstitution of ILCs under effective anti-retroviral therapy. This is the first report comparing distribution and function of ILCs along the intestinal mucosa of the entire human gastrointestinal tract in HIV(+) and HIV(-) individuals. Current treatment regimens are very effective in blocking replication of the human immunodeficiency virus (HIV). However, due to ongoing activation of the immune system this often does not fully restore human health. The mechanisms underlying such activation of the immune system are only incompletely understood but are likely to include HIV-induced injury of the gut epithelial barrier and subsequent intrusion of gut flora components into the systemic circulation (microbial translocation). This study looks at the distribution and function of innate lymphoid cells (ILCs) in the gut mucosa of HIV(-) and HIV(+) patients as these cells are important for maintaining an intact gut epithelium. We found that composition of the intestinal ILC pool differs between the specific segments of the digestive tract and is significantly altered in HIV(+) patients. Furthermore, our data suggest a link between dys-regulated intestinal ILCs and loss of intestinal barrier function in HIV infection, thereby allowing for microbial translocation and systemic immune activation. This finding is new and highlights the important role played by the gut immune system in HIV-induced illness.

Background: Lynch syndrome (LS), an autosomal dominant disorder caused by pathogenic germline variants in DNA mismatch repair (MMR) genes, represents the most common hereditary colorectal cancer (CRC) syndrome. Lynch syndrome patients are at high risk of CRC despite regular endoscopic surveillance.Objective: Our aim was to investigate the diagnostic performance of artificial intelligence (AI)‐assisted colonoscopy in comparison to High‐Definition white‐light endoscopy (HD‐WLE) for the first time.Methods: Patients ≥18 years with LS, with a pathogenic germline variant (MLH1, MHS2, MSH6), and at least one previous colonoscopy (interval 10–36 months) were eligible. Patients were stratified by previous CRC and affected MMR gene with a 1:1 allocation ratio (AI‐assisted vs. HD white‐light endoscopy) in this exploratory pilot trial.Results: Between Dec‐2021 and Dec‐2022, 101 LS patients were randomised and 96 patients were finally analyzed after exclusion of 5 patients due to insufficient bowel preparation. In the HD‐WLE arm, adenomas were detected in 12/46 patients compared to 18/50 in the AI arm (26.1% [95% CI 14.3–41.1] vs. 36.0% [22.9–50.8]; p = 0.379). The use of AI‐assisted colonoscopy especially increased detection of flat adenomas (Paris classification 0‐IIb) (examinations with detected flat adenomas: 3/46 [6.5%] vs. 10/50 [20%]; p = 0.07; numbers of detected flat adenomas: 4/20 vs. 17/30, p = 0.018). The median withdrawal time did not differ significantly between HD‐WLE and AI (14 vs. 15 min; p = 0.170).Conclusion: We here present first data suggesting that real‐time AI‐assisted colonoscopy is a promising approach to optimize endoscopic surveillance in LS patients, in particular to improve the detection of flat adenomas.

Group 1 innate lymphoid cells (ILCs) comprise a heterogeneous family of cytotoxic natural killer (NK) cells and ILC1s. We identify a population of "liver-type" ILC1s with transcriptional, phenotypic, and functional features distinct from those of conventional and liver-resident NK cells as well as from other previously described human ILC1 subsets. LT-ILC1s are CD49a⁺CD94⁺CD200R1⁺, express the transcription factor T-BET, and do not express the activating receptor NKp80 or the transcription factor EOMES. Similar to NK cells, liver-type ILC1s produce IFN-γ, TNF-α, and GM-CSF; however, liver-type ILC1s also produce IL-2 and lack perforin and granzyme-B. Liver-type ILC1s are expanded in cirrhotic liver tissues, and they can be produced from blood-derived ILC precursors in vitro in the presence of TGF-β1 and liver sinusoidal endothelial cells. Cells with similar signature and function can also be found in tonsil and intestinal tissues. Collectively, our study identifies and classifies a population of human cross-tissue ILC1s.

Hepatitis C virus (HCV) coinfection is an increasing health problem in human immunodeficiency virus-positive (HIV⁺) individuals. However, a considerable proportion of HIV⁺ patients manage to overcome acute hepatitis C (AHC) spontaneously. In the present study, we analyzed the role of natural killer (NK) cells in modulating the course of AHC in HIV⁺ patients. Twenty-seven HIV⁺ patients with AHC (self-limited course: n = 10; chronic course: n = 17), 12 HIV⁺ patients with chronic hepatitis C (CHC), 8 HIV monoinfected individuals, and 12 healthy controls were studied. NK cells were phenotypically analyzed by flow cytometry. Interferon-gamma (IFN-γ) secretion, degranulation (CD107a), and anti-HCV (= inhibition of HCV replication) activity of NK subpopulations were analyzed using the HuH7_A2HCV_replicon cell system. NK cell frequency did not differ significantly between HIV⁺ patients with chronic and self-limited course of AHC. However, we found NK cells from patients with self-limiting infection to be significantly more effective in inhibiting HCV replication in vitro than NK cells from patients developing CHC. Of note, antiviral NK cell activity showed no significant correlation with NK cell degranulation, but was positively correlated with IFN-γ secretion, and blocking experiments confirmed an important role for IFN-γ in NK cell-mediated inhibition of HCV replication. Accordingly, NK cells from patients that spontaneously cleared the virus displayed a stronger IFN-γ secretion than those developing chronic infection. Finally, we observed high expression of NKG2D and NKp46, respectively, to be associated with self-limiting course of aHCV. Accordingly, we found that blocking of these NK cell receptors significantly impaired antiviral NK cell activity. Conclusion: Our data suggest a strong IFN-γ-mediated antiviral NK cell response to be associated with a self-limited course of AHC in HIV⁺ patients. (HEPATOLOGY 2014;59:814–827)

Background: Perioperative myocardial ischemia poses a vital threat to surgical patients. Means to protect postischemic myocardium are clinically not available. Lidocaine has been demonstrated to exert antiinflammatory pleiotropic effects. The authors set out to test if lidocaine protects ischemic myocardium from reperfusion injury. Method: A mouse model of transient coronary artery ligation (30 min) and reperfusion (24 h) was used with animal care committee approval. Infarct size and area-at-risk were determined. Leukocyte recruitment was quantified on immunohistochemical stainings. Apoptosis was assessed using enzyme-linked immunosorbent assay to detect histone modifications and terminal deoxynucleotidyl transferase dUTP nick end labeling assays. Lidocaine effects on leukocyte-endothelial interactions were assessed in vitro by using a parallel-plate flow chamber or static adhesion assays. Results: Infarct size per area-at-risk was reduced by 27% in mice treated with a lidocaine bolus (1 mg/kg) before a continuous infusion (0.6 mg . kg(-1) . h(-1)) during ischemia (P < 0.005). Neutrophil density in the infarct and periinfarct zone was not reduced by lidocaine, although the size of the infiltrated area was. Terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cardiomyocytes and endothelial cells were significantly reduced in the periinfarct zone by lidocaine. In vitro, no effect on leukocyte rolling or firm adhesion to resting or activated endothelium was demonstrable. In vitro, lidocaine reduced cardiomyocyte apoptosis induced by hypoxia and reoxygenation (3h/1h) significantly. Infarct size and in vitro cardiomyocyte apoptosis were likewise reduced when lidocaine bolus and infusion were administered after the ischemic insult. Conclusion: Lidocaine exerts cardioprotective effects when administered before or after the ischemic insult. This effect is mediated through an antiapoptotic and not through an antiinflammatory pathway and may be therapeutically exploitable.