Publications by authors named "Jacob Nattermann"

121 Publications

N-protein presents early in blood, dried blood and saliva during asymptomatic and symptomatic SARS-CoV-2 infection.

Nat Commun 2021 03 26;12(1):1931. Epub 2021 Mar 26.

Quanterix Corporation, Billerica, MA, USA.

The COVID-19 pandemic continues to have an unprecedented impact on societies and economies worldwide. There remains an ongoing need for high-performance SARS-CoV-2 tests which may be broadly deployed for infection monitoring. Here we report a highly sensitive single molecule array (Simoa) immunoassay in development for detection of SARS-CoV-2 nucleocapsid protein (N-protein) in venous and capillary blood and saliva. In all matrices in the studies conducted to date we observe >98% negative percent agreement and >90% positive percent agreement with molecular testing for days 1-7 in symptomatic, asymptomatic, and pre-symptomatic PCR+ individuals. N-protein load decreases as anti-SARS-CoV-2 spike-IgG increases, and N-protein levels correlate with RT-PCR Ct-values in saliva, and between matched saliva and capillary blood samples. This Simoa SARS-CoV-2 N-protein assay effectively detects SARS-CoV-2 infection via measurement of antigen levels in blood or saliva, using non-invasive, swab-independent collection methods, offering potential for at home and point of care sample collection.
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http://dx.doi.org/10.1038/s41467-021-22072-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997897PMC
March 2021

Renal replacement therapy as bridging-to-recovery in refractory hepatorenal syndrome.

Z Gastroenterol 2021 Apr 25;59(4):331-335. Epub 2021 Feb 25.

Department of Internal Medicine I, University Hospital Bonn, Venusberg Campus 1, Bonn, Germany.

A 50-year-old female patient with cirrhosis due to alcoholic steatohepatitis was referred to our department because of recurrent hepatorenal syndrome (HRS) and hepatic hydrothorax. Clinically, severe anasarca was the leading problem. In contrast to previous episodes, HRS did not respond to standard treatment including terlipressin.Given the severe, refractory hyperhydration, we finally initiated renal replacement therapy (RRT). Subsequently, RRT was performed without severe side effects for more than 100 days. In the meantime, liver function remarkably improved, most probably due to the prolonged abstinence from alcohol. Finally, RRT could be stopped. Since then, our patient has remained in good clinical condition for more than 6 months, with well-compensated Child-Pugh stage A cirrhosis and only mild chronic kidney disease stage III.In conclusion, this case highlights that RRT may be considered in individual cases as bridging therapy in refractory HRS until the liver regenerates due to the absence of damaging mechanisms.
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http://dx.doi.org/10.1055/a-1369-9859DOI Listing
April 2021

SIV-induced terminally differentiated adaptive NK cells in lymph nodes associated with enhanced MHC-E restricted activity.

Nat Commun 2021 02 24;12(1):1282. Epub 2021 Feb 24.

Institut Pasteur, Unité HIV, Inflammation et Persistance, Paris, France.

Natural killer (NK) cells play a critical understudied role during HIV infection in tissues. In a natural host of SIV, the African green monkey (AGM), NK cells mediate a strong control of SIVagm infection in secondary lymphoid tissues. We demonstrate that SIVagm infection induces the expansion of terminally differentiated NKG2a NK cells in secondary lymphoid organs displaying an adaptive transcriptional profile and increased MHC-E-restricted cytotoxicity in response to SIV Env peptides while expressing little IFN-γ. Such NK cell differentiation was lacking in SIVmac-infected macaques. Adaptive NK cells displayed no increased NKG2C expression. This study reveals a previously unknown profile of NK cell adaptation to a viral infection, thus accelerating strategies toward NK-cell directed therapies and viral control in tissues.
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http://dx.doi.org/10.1038/s41467-021-21402-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904927PMC
February 2021

Solid organ transplantation is not a risk factor for COVID-19 disease outcome.

Transpl Int 2021 02 10;34(2):378-381. Epub 2021 Jan 10.

Department of Internal Medicine I, Department of Gastroenterology, Hepatology, Nephrology, Infectiology, Endocrinology and Diabetology, University Hospital Bonn, Bonn, Germany.

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http://dx.doi.org/10.1111/tri.13795DOI Listing
February 2021

Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients.

Genome Med 2021 01 13;13(1). Epub 2021 Jan 13.

Systems Medicine, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Background: The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system.

Methods: In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings.

Results: Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host.

Conclusions: Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity.
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http://dx.doi.org/10.1186/s13073-020-00823-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805430PMC
January 2021

Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status.

Cancers (Basel) 2020 Dec 11;12(12). Epub 2020 Dec 11.

Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany.

Hereditary diffuse gastric cancer (HDGC) is an inherited cancer susceptibility syndrome characterized by an elevated risk for diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Some patients fulfilling the clinical testing criteria harbor a pathogenic or germline variant. However, the underlying mechanism for around 80% of the patients with a family or personal history of DGC and LBC has so far not been elucidated. In this cohort study, patients meeting the 2015 HDGC clinical testing criteria were included, and subsequently, sequencing was performed. Of the 207 patients (161 families) in this study, we detected 21 pathogenic or likely pathogenic variants (PV) in 60 patients (28 families) and one PV in two patients from one family. Sixty-eight percent ( = 141) of patients were female. The overall PV detection rate was 18% (29/161 families). Criterion 1 and 3 of the 2015 HDGC testing criteria yielded the highest detection rate of PVs (21% and 28%). PV carriers and patients without proven PV were compared. Risk of gastric cancer (GC) (38/62 61% vs. 102/140 73%) and age at diagnosis (40 ± 13 years vs. 44 ± 12 years) were similar between the two groups. However, GC was more advanced in gastrectomy specimens of patients without PV (81% vs. 26%). LBC prevalence in female carriers of a PV was 20% ( = 8/40). Clinical phenotypes differed strongly between families with the same PV. Emphasis should be on detecting more causative genes predisposing for HDGC and improve the management of patients without a proven pathogenic germline variant.
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http://dx.doi.org/10.3390/cancers12123726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763201PMC
December 2020

Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19.

Immunity 2020 12 26;53(6):1296-1314.e9. Epub 2020 Nov 26.

Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, 24105 Kiel, Germany. Electronic address:

Temporal resolution of cellular features associated with a severe COVID-19 disease trajectory is needed for understanding skewed immune responses and defining predictors of outcome. Here, we performed a longitudinal multi-omics study using a two-center cohort of 14 patients. We analyzed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. Validation was performed in two independent cohorts of COVID-19 patients. Severe COVID-19 was characterized by an increase of proliferating, metabolically hyperactive plasmablasts. Coinciding with critical illness, we also identified an expansion of interferon-activated circulating megakaryocytes and increased erythropoiesis with features of hypoxic signaling. Megakaryocyte- and erythroid-cell-derived co-expression modules were predictive of fatal disease outcome. The study demonstrates broad cellular effects of SARS-CoV-2 infection beyond adaptive immune cells and provides an entry point toward developing biomarkers and targeted treatments of patients with COVID-19.
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http://dx.doi.org/10.1016/j.immuni.2020.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689306PMC
December 2020

Transpapillary tissue sampling of biliary strictures: balloon dilatation prior to forceps biopsy improves sensitivity and accuracy.

Sci Rep 2020 10 15;10(1):17423. Epub 2020 Oct 15.

Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

The early and definitive diagnosis of malignant bile duct stenoses is essential for a timely and adequate therapy. However, tissue sampling with transpapillary brush cytology (BC) or forceps biopsy (FB) remains challenging. With this study, we aimed to compare the effectiveness and safety of different tissue sampling modalities (BC, FB without/after previous balloon dilatation). Standardized database research identified all patients, who underwent endoscopic retrograde cholangiography with BC and/or FB for indeterminate bile duct stenosis between January 2010 and April 2018 and with a definitive diagnosis. 218 patients were enrolled (149 cases with malignant and 69 with benign disease). FB had a significant higher sensitivity than BC (43% vs. 16%, p < 0.01). Prior balloon dilatation of the stenosis improved the sensitivity of FB from 41 to 71% (p = 0.03), the NPV from 36 to 81% (p < 0.01) and the accuracy from 55 to 87% (p < 0.01). The complication rates did not differ significantly between the modalities. In our center FB turned out to be the diagnostically more effective procedure. Balloon dilatation of the stenosis before FB had a significant diagnostic benefit and was not associated with a higher complication rate.
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http://dx.doi.org/10.1038/s41598-020-74451-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566456PMC
October 2020

First results of the "Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS)".

Infection 2021 Feb 1;49(1):63-73. Epub 2020 Oct 1.

Department I for Internal Medicine, University Hospital of Cologne, University of Cologne, Cologne, Germany.

Purpose: Knowledge regarding patients' clinical condition at severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is sparse. Data in the international, multicenter Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort study may enhance the understanding of COVID-19.

Methods: Sociodemographic and clinical characteristics of SARS-CoV-2-infected patients, enrolled in the LEOSS cohort study between March 16, 2020, and May 14, 2020, were analyzed. Associations between baseline characteristics and clinical stages at diagnosis (uncomplicated vs. complicated) were assessed using logistic regression models.

Results: We included 2155 patients, 59.7% (1,287/2,155) were male; the most common age category was 66-85 years (39.6%; 500/2,155). The primary COVID-19 diagnosis was made in 35.0% (755/2,155) during complicated clinical stages. A significant univariate association between age; sex; body mass index; smoking; diabetes; cardiovascular, pulmonary, neurological, and kidney diseases; ACE inhibitor therapy; statin intake and an increased risk for complicated clinical stages of COVID-19 at diagnosis was found. Multivariable analysis revealed that advanced age [46-65 years: adjusted odds ratio (aOR): 1.73, 95% CI 1.25-2.42, p = 0.001; 66-85 years: aOR 1.93, 95% CI 1.36-2.74, p < 0.001; > 85 years: aOR 2.38, 95% CI 1.49-3.81, p < 0.001 vs. individuals aged 26-45 years], male sex (aOR 1.23, 95% CI 1.01-1.50, p = 0.040), cardiovascular disease (aOR 1.37, 95% CI 1.09-1.72, p = 0.007), and diabetes (aOR 1.33, 95% CI 1.04-1.69, p = 0.023) were associated with complicated stages of COVID-19 at diagnosis.

Conclusion: The LEOSS cohort identified age, cardiovascular disease, diabetes and male sex as risk factors for complicated disease stages at SARS-CoV-2 diagnosis, thus confirming previous data. Further data regarding outcomes of the natural course of COVID-19 and the influence of treatment are required.
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http://dx.doi.org/10.1007/s15010-020-01499-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527665PMC
February 2021

Value of upper gastrointestinal endoscopy for gastric cancer surveillance in patients with Lynch syndrome.

Int J Cancer 2021 Jan 13;148(1):106-114. Epub 2020 Oct 13.

Department of Hematology and Oncology, Klinikum Hochsauerland, Meschede, Germany.

In our study, we evaluated the effectiveness of upper gastrointestinal (GI) endoscopy as an instrument for early gastric cancer (GC) detection in Lynch syndrome (LS) patients by analyzing data from the registry of the German Consortium for Familial Intestinal Cancer. In a prospective, multicenter cohort study, 1128 out of 2009 registered individuals with confirmed LS underwent 5176 upper GI endoscopies. Compliance was good since 77.6% of upper GI endoscopies were completed within the recommended interval of 1 to 3 years. Forty-nine GC events were observed in 47 patients. MLH1 (n = 21) and MSH2 (n = 24) mutations were the most prevalent. GCs in patients undergoing regular surveillance were diagnosed significantly more often in an early-stage disease (UICC I) than GCs detected through symptoms (83% vs 25%; P = .0231). Thirty-two (68%) patients had a negative family history of GC. The median age at diagnosis was 51 years (range 28-66). Of all GC patients, 13 were diagnosed at an age younger than 45. Our study supports the recommendation of regular upper GI endoscopy surveillance for LS patients beginning no later than at the age of 30.
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http://dx.doi.org/10.1002/ijc.33294DOI Listing
January 2021

Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment.

Cell 2020 09 5;182(6):1419-1440.e23. Epub 2020 Aug 5.

Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany; German Center for Lung Research (DZL).

Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRCD11c inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DR monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.
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http://dx.doi.org/10.1016/j.cell.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405822PMC
September 2020

The "unnatural" history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance.

Int J Cancer 2021 Feb 3;148(4):800-811. Epub 2020 Aug 3.

Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy with polypectomy is recommended to reduce CRC risk in LS individuals. However, recent independent studies demonstrated that a substantial proportion of LS individuals develop CRC despite regular colonoscopy. The reasons for this surprising observation confirmed by large prospective studies are a matter of debate. In this review, we collect existing evidence from clinical, epidemiological and molecular studies and interpret them with regard to the origins and progression of LS-associated CRC. Alongside with hypotheses addressing colonoscopy quality and pace of progression from adenoma to cancer, we discuss the role of alternative precursors and immune system in LS-associated CRC. We also identify gaps in current knowledge and make suggestions for future studies aiming at improved CRC prevention for LS individuals.
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http://dx.doi.org/10.1002/ijc.33224DOI Listing
February 2021

Cancer risks in Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X: a prospective cohort study.

BMC Cancer 2020 May 24;20(1):460. Epub 2020 May 24.

Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.

Background: Individuals with pathogenic germline variants in DNA mismatch repair (MMR) genes are at increased risk of developing colorectal, endometrial and other cancers (Lynch syndrome, LS). While previous studies have extensively described cancer risks in LS, cancer risks in individuals from families without detectable MMR gene defects despite MMR deficiency (Lynch-like syndrome, LLS), and in individuals from families fulfilling the Amsterdam-II criteria without any signs of MMR deficiency (familial colorectal cancer type X, FCCX) are less well studied. The aim of this prospective study was to characterise the risk for different cancer types in LS, LLS, and FCCX, and to compare these with the cancer risks in the general population.

Methods: Data was taken from the registry of the German Consortium for Familial Intestinal Cancer, where individuals were followed up prospectively within the framework of an intensified surveillance programme at recommended annual examination intervals. A total of 1120 LS, 594 LLS, and 116 FCCX individuals were analysed. From this total sample, eight different cohorts were defined, in which age-dependent cumulative risks and standardised incidence ratios were calculated regarding the first incident occurrence of any, colorectal, stomach, small bowel, urothelial, female breast, ovarian, and endometrial cancer, separately for LS, LLS, and FCCX.

Results: The number of individuals at risk for first incident cancer ranged from 322 to 1102 in LS, 120 to 586 in LLS, and 40 to 116 in FCCX, depending on the cancer type of interest. For most cancer types, higher risks were observed in LS compared to LLS, FCCX, and the general population. Risks for any, colorectal, stomach, urothelial, and endometrial cancer were significantly higher in LLS compared to the general population. No significantly increased risks could be detected in FCCX compared to LLS patients, and the general population. Colorectal and endometrial cancer risks tended to be higher in LLS than in FCCX.

Conclusions: The characterisation of cancer risks in patients with LLS and FCCX is important to develop appropriate surveillance programmes for these specific intermediate risk groups. Larger prospective studies are needed to obtain more precise risk estimates.
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http://dx.doi.org/10.1186/s12885-020-06926-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245918PMC
May 2020

A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control.

J Hepatol 2020 05 15;72(5):960-975. Epub 2020 Jan 15.

Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Virology, Technical University of Munich and Helmholtz Zentrum München, Schneckenburgerstrasse 8, 81675 Munich, Germany; Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Ismaningerstraße 22, 81675 Munich, Germany. Electronic address:

Background & Aims: Hepatic innate immune control of viral infections has largely been attributed to Kupffer cells, the liver-resident macrophages. However, hepatocytes, the parenchymal cells of the liver, also possess potent immunological functions in addition to their known metabolic functions. Owing to their abundance in the liver and known immunological functions, we aimed to investigate the direct antiviral mechanisms employed by hepatocytes.

Methods: Using lymphocytic choriomeningitis virus (LCMV) as a model of liver infection, we first assessed the role of myeloid cells by depletion prior to infection. We investigated the role of hepatocyte-intrinsic innate immune signaling by infecting mice lacking canonical NF-κB signaling (Ikkβ) specifically in hepatocytes. In addition, mice lacking hepatocyte-specific interferon-α/β signaling-(Ifnar), or interferon-α/β signaling in myeloid cells-(Ifnar) were infected.

Results: Here, we demonstrate that LCMV activates NF-κB signaling in hepatocytes. LCMV-triggered NF-κB activation in hepatocytes did not depend on Kupffer cells or TNFR1 signaling but rather on Toll-like receptor signaling. LCMV-infected Ikkβ livers displayed strongly elevated viral titers due to LCMV accumulation within hepatocytes, reduced interferon-stimulated gene (ISG) expression, delayed intrahepatic immune cell influx and delayed intrahepatic LCMV-specific CD8 T cell responses. Notably, viral clearance and ISG expression were also reduced in LCMV-infected primary hepatocytes lacking IKKβ, demonstrating a hepatocyte-intrinsic effect. Similar to livers of Ikkβ mice, enhanced hepatocytic LCMV accumulation was observed in livers of Ifnar mice, whereas Ifnar mice were able to control LCMV infection. Hepatocytic NF-κB signaling was also required for efficient ISG induction in HDV-infected dHepaRG cells and interferon-α/β-mediated inhibition of HBV replication in vitro.

Conclusions: Together, these data show that hepatocyte-intrinsic NF-κB is a vital amplifier of interferon-α/β signaling, which is pivotal for strong early ISG responses, immune cell infiltration and hepatic viral clearance.

Lay Summary: Innate immune cells have been ascribed a primary role in controlling viral clearance upon hepatic infections. We identified a novel dual role for NF-κB signaling in infected hepatocytes which was crucial for maximizing interferon responses and initiating adaptive immunity, thereby efficiently controlling hepatic virus replication.
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http://dx.doi.org/10.1016/j.jhep.2019.12.019DOI Listing
May 2020

[Current recommendations for surveillance, risk reduction and therapy in Lynch syndrome patients].

Z Gastroenterol 2019 Nov 18;57(11):1309-1320. Epub 2019 Nov 18.

Medizinische Klinik und Poliklinik I, Universitätsklinikum Bonn.

Introduction:  Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome and accounts for ~3 % of all CRCs. This autosomal dominant disorder is caused by germline mutations in DNA mismatch repair genes (, and ). One in 300 individuals of the general population are considered to be mutation carriers (300 000 individuals/Germany). Mutation carriers are at a high CRC risk of 15-46 % till the age of 75 years. LS also includes a variety of extracolonic malignancies such as endometrial, small bowel, gastric, urothelial, and other cancers.

Methods:  The German Consortium for Familial Intestinal Cancer consists of 14 university centers in Germany. The aim of the consortium is to develop and evaluate surveillance programs and to further translate the results in clinical care. We have revisited and updated the clinical management guidelines for LS patients in Germany.

Results:  A surveillance colonoscopy should be performed every 12-24 months starting at the age of 25 years. At diagnosis of first colorectal cancer, an oncological resection is advised, an extended resection (colectomy with ileorectal anastomosis) has to be discussed with the patient. The lifetime risk for gastric cancer is 0.2-13 %. Gastric cancers detected during surveillance have a lower tumor stage compared to symptom-driven detection. The lifetime risk for small bowel cancer is 4-8 %. About half of small bowel cancer is located in the duodenum and occurs before the age of 35 years in 10 % of all cases. Accordingly, patients are advised to undergo an esophagogastroduodenoscopy every 12-36 months starting by the age of 25 years.

Conclusion:  LS colonic and extracolonic clinical management, surveillance and therapy are complex and several aspects remain unclear. In the future, surveillance and clinical management need to be more tailored to gene and gender. Future prospective trials are needed.
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http://dx.doi.org/10.1055/a-1008-9827DOI Listing
November 2019

Role of regulatory T cells and checkpoint inhibition in hepatocellular carcinoma.

Cancer Immunol Immunother 2019 Dec 13;68(12):2055-2066. Epub 2019 Nov 13.

Department I of Internal Medicine, University Hospital of Bonn (UKB), Venusberg-Campus-1, 53127, Bonn, Germany.

Immune checkpoint inhibition suggests promising progress for the treatment of advanced hepatocellular carcinoma (HCC). However, the underlying cellular mechanisms remain unclear because liver cancer cells apparently do not upregulate inhibitory checkpoint molecules. Here, we analysed whether regulatory T cells (Tregs) can alternatively trigger checkpoint inhibition pathways in HCC. Using flow cytometry we analysed expression of checkpoint molecules (PD-1, PD-L1, CTLA-4, GITR, Tim-3) on peripheral CD4CD25Foxp3 Tregs and their secretion of inhibitory mediators (IL-10, IL-35, TGF-beta, galectin-9) in 116 individuals (50 patients with HCC, 41 non-tumour bearing liver disease controls, 25 healthy controls). Functional activity of Tregs on T effector cells (IFN-gamma production, cytotoxicity) was characterized in vitro using a lectin-dependent cellular cytotoxicity (LDCC) assay against checkpoint inhibitor-negative P815 target cells. Unlike liver patients without malignancy and healthy controls, the frequency of checkpoint inhibitor-positive Tregs inversely correlated to age of patients with HCC (PD-L1, p = 0.0080; CTLA-4, p = 0.0029) and corresponded to enhanced numbers of Tregs producing IL-10 and IL-35 (p < 0.05 each). Tregs inhibited IFN-gamma secretion and cytotoxicity of CD8 T cells when added to LDCC against P815 cells. Treg-induced inhibition of IFN-gamma secretion could be partially blocked by neutralizing PD-1 and PD-L1 antibodies specifically in HCC patients. In HCC peripheral Tregs upregulate checkpoint inhibitors and contribute to systemic immune dysfunction and antitumoural activity by several inhibitory pathways, presumably facilitating tumour development at young age. Blocking PD-L1/PD-1 interactions in vitro selectively interfered with inhibitory Treg -T effector cell interactions in the patients with HCC and resulted in improved antitumoural activity also against checkpoint inhibitor-negative tumour cells.
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http://dx.doi.org/10.1007/s00262-019-02427-4DOI Listing
December 2019

The PNPLA3 I148M variant promotes lipid-induced hepatocyte secretion of CXC chemokines establishing a tumorigenic milieu.

J Mol Med (Berl) 2019 11 21;97(11):1589-1600. Epub 2019 Oct 21.

Department of Internal Medicine I, University Hospital, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

The I148M variant of the Patatin-like phospholipase domain-containing 3 (PNPLA3) protein is associated with an increased risk for liver inflammation and hepatocellular carcinoma (HCC), but the underlying mechanism is unknown. We hypothesized that enhanced CXC chemokine secretion mediates hepatic inflammation that accelerates development of HCC. Expandable primary human (upcyte®) hepatocytes and human PLC/PRF/5 hepatoma cells were lentivirally transduced with both PNPLA3 I148M variants and stimulated with lipids. Cytokine levels in culture supernatant and patient sera (n = 80) were analyzed by ELISA. Supernatants were assessed in transmigration experiments, tube formation, and proliferation assays. In vitro, lipid stimulation of transduced hepatocytes dose-dependently induced the production of interleukin-8 and CXCL1 in hepatocytes carrying the PNPLA3 148M variant. In line, sera from PNPLA3 148M-positive patients with alcoholic liver cirrhosis contained higher levels of interleukin-8 and CXCL1 than patients with wild-type PNPLA3. Supernatants from lipid-stimulated hepatocytes with the PNPLA3 148M variant induced enhanced migration of white blood cells, angiogenesis, and cell proliferation in comparison with supernatants from wild-type hepatocytes via CXC receptors 1 and 2. Increased production of interleukin-8 and CXCL1 by hepatocytes carrying the PNPLA3 148M variant contributes to a pro-inflammatory and tumorigenic milieu in patients with alcoholic liver disease. KEY MESSAGES: The PNPLA3 148M variant is associated with cirrhosis and hepatocellular carcinoma. Lipid stimulation of hepatocytes with this variant induces IL-8 and CXCL1. Supernatants from hepatocytes with this variant promote migration and angiogenesis. Sera from patients with this variant contained enhanced levels of IL-8 and CXCL1. The PNPLA3 148M variant contributes to a tumorigenic milieu via IL-8 and CXCL1.
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http://dx.doi.org/10.1007/s00109-019-01836-3DOI Listing
November 2019

NK Cells in Ascites From Liver Disease Patients Display a Particular Phenotype and Take Part in Antibacterial Immune Response.

Front Immunol 2019 7;10:1838. Epub 2019 Aug 7.

National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.

Ascites and spontaneous bacterial peritonitis (SBP) are frequent complications of liver cirrhosis. In spite of the clinical impact, knowledge about ascites as an immune cell compartment in liver disease is limited. Therefore, we analyzed NK cells in blood, ascites, and liver. Mononuclear cells from blood, ascites, and liver explants of patients with advanced liver disease were extracted by density gradient centrifugation. Phenotyping and analysis of functional responses were carried out using flow cytometry. Migratory potential was investigated with transwell chamber assays. NK cell metabolism was assessed by Seahorse technology. NK cell frequency was increased in uninfected ascites compared to blood, but not to liver. Ascites NK cells were predominantly CD16. CD56 ascites NK cells did not share the typical phenotype of their liver counterparts. In contrast to the inhibitory receptor NKG2A, expression of the activating receptor NKG2D was decreased on ascites and liver CD16 NK cells. Ascites NK cells expressed higher levels of CXCR3 than blood or liver NK cells, corresponding to increased ascites levels of CXCL10. Blood NK cells migrated toward ascites. Stimulation of mononuclear cells with led to downregulation of NKG2D expression and IL-12 and IL-18 mediated secretion of interferon-γ by ascites and liver, but not blood NK cells. , ascites NK cells expressed higher levels of the activation marker CD69 and lower levels of NKG2D during SBP compared to uninfected ascites. Ascites NK cells display a particular phenotype and are implicated in local immune defense against translocating bacteria.
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http://dx.doi.org/10.3389/fimmu.2019.01838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694841PMC
October 2020

A variant in the MICA gene is associated with liver fibrosis progression in chronic hepatitis C through TGF-β1 dependent mechanisms.

Sci Rep 2019 02 5;9(1):1439. Epub 2019 Feb 5.

Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia.

Hepatocarcinogenesis is tightly linked to liver fibrosis. Recently, two GWAS variants, MICA rs2596542 and DEPDC5 rs1012068 were identified as being associated with the development of HCV-induced hepatocellular carcinoma (HCC) in Japanese patients. The role of these variants on hepatic inflammation and fibrosis that are closely associated with HCC development is not known, nor are the biological mechanisms underlying their impact on the liver. Here, we demonstrate in 1689 patients with chronic hepatitis C (CHC) (1,501 with CHC and 188 with HCV-related HCC), that the MICA (T) allele, despite not being associated with HCC susceptibility, is associated with increased fibrosis stage (OR: 1.47, 95% CI: 1.05-2.06, p = 0.02) and fibrosis progression rate (hazards ratio: 1.41, 95% CI: 1.04-1.90, p = 0.02). The DEPDC5 variant was not associated with any of these phenotypes. MICA expression was down-regulated in advanced fibrosis stages. Further, (T) allele carriage was associated with lower MICA expression in liver and serum. Transforming growth factor-β1 (TGF-β1) expression suppresses MICA expression in hepatic stellate cells. Our findings suggest a novel mechanism linking susceptibility to advanced fibrosis and subsequently indirectly to HCC, to the level of MICA expression through TGF-β1-dependent mechanisms.
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http://dx.doi.org/10.1038/s41598-018-35736-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363805PMC
February 2019

Combined photodynamic therapy with systemic chemotherapy for unresectable cholangiocarcinoma.

Aliment Pharmacol Ther 2019 02 13;49(4):437-447. Epub 2019 Jan 13.

Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.

Background: Chemotherapy with gemcitabine and cisplatin is the current standard for patients with unresectable cholangiocarcinoma. Local photodynamic therapy has also demonstrated benefit in patients with extrahepatic cholangiocarcinoma.

Aim: To evaluate the benefit of photodynamic therapy in combination with systemic chemotherapy in advanced extrahepatic cholangiocarcinoma.

Methods: Three hundred and fifty-three patients diagnosed with cholangiocarcinoma between 2004 and 2016 were treated at the University Hospital of Bonn, Germany. Of these, 96 suffering from unresectable extrahepatic cholangiocarcinoma were included. Patients were stratified according to treatment: combination photodynamic therapy and chemotherapy (36 patients), photodynamic therapy alone (34 patients), and chemotherapy alone (26 patients).

Results: Combined photodynamic therapy with chemotherapy resulted in significantly longer overall survival than chemotherapy alone (P = 0.022). Median survival was 20 months in the combination group (95% CI: 16.38-23.62), 15 months in the photodynamic alone group (95% CI: 10.02-19.98) and 10 months in the chemotherapy alone group (95% CI: 8.45-11.55). In multivariate analysis, combination therapy and photodynamic therapy alone (HR: 0.41, 95% CI: 0.22-0.77, P = 0.006), metal stenting, and radiofrequency ablation were independent predictors of longer survival.

Conclusions: Combination photodynamic therapy and chemotherapy was well tolerated and resulted in significantly longer survival than chemotherapy alone. Application of photodynamic therapy significantly correlated with longer survival, demonstrating benefit in advanced cholangiocarcinoma. Thus, photodynamic therapy should be considered during therapeutic decision making in advanced cholangiocarcinoma.
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http://dx.doi.org/10.1111/apt.15050DOI Listing
February 2019

[Outcomes after Prophylactic Total Gastrectomy for Hereditary Diffuse Gastric Cancer].

Zentralbl Chir 2020 Feb 1;145(1):41-47. Epub 2018 Aug 1.

Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn.

Introduction: Prophylactic total gastrectomy is the treatment of choice in patients with germline mutation in the CDH1 gene and therefore high risk for hereditary diffuse gastric cancer (HDGC). Minimally invasive techniques have been established in recent years for treatment of gastric cancer.

Methods: We report findings with 12 patients with proven CDH1 mutation who underwent multidisciplinary treatment between 2013 and 3/2018 in our centre for hereditary tumour diseases, followed by prophylactic total gastrectomy in our department. Data were collected in a prospective hereditary tumour database.

Results: Open prophylactic total gastrectomy was performed in 5 patients (between 2013 and 2015) and minimally invasive prospective gastrectomy in 7 patients (between 2015 and 2018). The median age of all patients (7 women and 5 men) was 42 (range: 19 - 60) years. The mean operation time was 291 ± 72 minutes (open: 269 ± 70; minimally invasive: 307 ± 75). Perioperative 60-day mortality and anastomotic leakage rate were 0%. In 3 patients, postoperative complications occurred (according to the Clavien-Dindo classification: one each of grades II, IIIa and IVb, respectively), and therefore 25% morbidity. The average postoperative hospital stay was 14.5 ± 6.2 days (open: 16.2 ± 7.9; minimally invasive: 13.3 ± 5.0). In 10 of 12 patients (83%), foci of intramucosal signet ring cell carcinomas were found in the gastric specimen, in 9 patients with multifocal dissemination. There were no cases with advanced carcinomas (≥ pT1b) or lymph node metastases.

Conclusion: Patients with suspected high risk for hereditary diffuse gastric cancer should be cared for in a multidisciplinary centre for hereditary tumour diseases. Laparoscopic total gastrectomy is a safe and feasible risk-reducing procedure for patients with CDH1 germline mutation. Therefore, in the absence of contraindications and with available surgical expertise, the minimally invasive operation should be the standard procedure for these patients.
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http://dx.doi.org/10.1055/a-0646-4382DOI Listing
February 2020

Endoscopic Ultrasound-Guided Drainage and Treatment of Symptomatic Pancreatic Fluid Collection following Acute or Acute-on-Chronic Pancreatitis - A Single Center Case Series.

Zentralbl Chir 2018 Dec 11;143(6):577-585. Epub 2018 Jul 11.

Medizinische Klinik und Poliklinik I - Allgemeine Innere Medizin, Universitätsklinikum Bonn, Deutschland.

Introduction: Pancreatic fluid collection (PFC) is a common complication of acute pancreatitis. Endoscopic ultrasound (EUS)-guided drainage, which is often followed by direct endoscopic necrosectomy (DEN), has become the primary approach to treat PFC, including pancreatic pseudocysts (PP) and walled-off necrosis (WON). We aimed to determine retrospectively the short- and long-term results of patients treated in our endoscopy unit and to identify parameters that are associated with treatment efficacy and outcome.

Methods: The data of 41 consecutive patients with post-pancreatitic PFC, who underwent endoscopic transmural intervention between 2014 and 2016, were analyzed retrospectively. After an initial EUS-guided puncture, one or more plastic stents were placed and DEN was performed if necrotic tissue remained.

Results: The mean diameter of the PFC was 74.0 ± 4.8 mm. Of the PFCs, 29.3% were classified as PP and 70.7% as WON. Altogether, 196 transmural endoscopic procedures were performed, including 73 endoscopic necrosectomies in a subgroup of 21 patients (20 WON, 1 PP). Initial technical success was achieved in 97.6% of patients and the short-term clinical success rate was 90.2%. The long-term clinical success rate was 82.9%, since four patients died from septic shock and/or multiple organ failure and three patients developed recurrent PFC some months after the initial discharge from endoscopic treatment. Procedural complications were registered in 9 patients during 10 of 196 endoscopic procedures (5.1%): bleeding (6), cardiorespiratory insufficiency (2), perforation with pneumoperitoneum (1), aspiration with respiratory insufficiency (1), and non-perforating superficial damage of the gastric wall (1). Neither the size of the PFC nor the initial value of C-reactive protein (CRP) or other biochemical markers were correlated with efficacy or outcome of treatment. Only the cumulative number of days with CRP > 50 mg/L significantly correlated with the number of follow-up endoscopic sessions and DEN. Fungal colonization of PFC correlated significantly (p < 0.05) with the risk of mortality (44% vs. 0%), need for intensive care treatment (66.7% vs. 25%), and sepsis (55.6% vs. 12.5%).

Conclusions: We confirm that EUS-guided drainage followed by DEN in patients with solid necrotic material is an effective and relatively safe therapeutic approach. Prolonged elevation of CRP and fungal colonisation of the PFC are associated with a worse course of the disease.
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http://dx.doi.org/10.1055/a-0638-8505DOI Listing
December 2018

Exome sequencing characterizes the somatic mutation spectrum of early serrated lesions in a patient with serrated polyposis syndrome (SPS).

Hered Cancer Clin Pract 2017 29;15:22. Epub 2017 Nov 29.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

Background: Serrated or Hyperplastic Polyposis Syndrome (SPS, HPS) is a yet poorly defined colorectal cancer (CRC) predisposition characterised by the occurrence of multiple and/or large serrated polyps throughout the colon. A serrated polyp-CRC sequence (serrated pathway) of CRC formation has been postulated, however, to date only few molecular signatures of serrated neoplasia (, mutations, CpG Island Methylation, MSI) have been described in a subset of SPS patients and neither the etiology of the syndrome nor the distinct genetic alterations during tumorigenesis have been identified.

Methods: To identify somatic point mutations in potential novel candidate genes of SPS-associated lesions and the involved pathways we performed exome sequencing of eleven early serrated polyps obtained from a 41 year-old female patient with clinically confirmed SPS. For data filtering and analysis, standard pipelines were used. Somatic mutations were identified by comparison with leukocyte DNA and were validated by Sanger sequencing.

Results: The p.V600E or p.G12D mutation was identified in six polyps (~50%) and not found in polyps from the distal colon. In addition, we found seven unique rare somatic alterations of seven different genes in four serrated tumours, all of which are missense variants. The variant in and are predicted to be deleterious No established cancer gene or candidate genes related to serrated tumorigenesis were affected.

Conclusions: Somatic mutations seem to be rare events in early hyperplastic and serrated lesions of SPS patients. Neither frequently affected genes nor enrichment of specific pathways were observed. Thus, other alterations such as non-coding variants or epigenetic changes might be the major driving force of tumour progression in SPS.
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http://dx.doi.org/10.1186/s13053-017-0082-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707812PMC
November 2017

Misery acquaints a man with dangerous bedfellows: But how to get rid of them?

Liver Int 2017 10;37(10):1446-1448

Department of Internal Medicine I, University of Bonn, Bonn, Germany.

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http://dx.doi.org/10.1111/liv.13472DOI Listing
October 2017

Genomic and transcriptomic heterogeneity of colorectal tumours arising in Lynch syndrome.

J Pathol 2017 10 5;243(2):242-254. Epub 2017 Sep 5.

Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, Germany.

Colorectal cancer (CRC) arising in Lynch syndrome (LS) comprises tumours with constitutional mutations in DNA mismatch repair genes. There is still a lack of whole-genome and transcriptome studies of LS-CRC to address questions about similarities and differences in mutation and gene expression characteristics between LS-CRC and sporadic CRC, about the molecular heterogeneity of LS-CRC, and about specific mechanisms of LS-CRC genesis linked to dysfunctional mismatch repair in LS colonic mucosa and the possible role of immune editing. Here, we provide a first molecular characterization of LS tumours and of matched tumour-distant reference colonic mucosa based on whole-genome DNA-sequencing and RNA-sequencing analyses. Our data support two subgroups of LS-CRCs, G1 and G2, whereby G1 tumours show a higher number of somatic mutations, a higher amount of microsatellite slippage, and a different mutation spectrum. The gene expression phenotypes support this difference. Reference mucosa of G1 shows a strong immune response associated with the expression of HLA and immune checkpoint genes and the invasion of CD4+ T cells. Such an immune response is not observed in LS tumours, G2 reference and normal (non-Lynch) mucosa, and sporadic CRC. We hypothesize that G1 tumours are edited for escape from a highly immunogenic microenvironment via loss of HLA presentation and T-cell exhaustion. In contrast, G2 tumours seem to develop in a less immunogenic microenvironment where tumour-promoting inflammation parallels tumourigenesis. Larger studies on non-neoplastic mucosa tissue of mutation carriers are required to better understand the early phases of emerging tumours. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4948DOI Listing
October 2017

Relative Ascites Polymorphonuclear Cell Count Indicates Bacterascites and Risk of Spontaneous Bacterial Peritonitis.

Dig Dis Sci 2017 09 9;62(9):2558-2568. Epub 2017 Jun 9.

Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.

Background And Aims: Absolute polymorphonuclear (PMN) counts in ascites define spontaneous bacterial peritonitis (SBP), a severe form of bacterial infection in liver cirrhosis. Bacterascites, another form of ascites infection, can progress to SBP or may resolve spontaneously but is not reflected by absolute PMN counts. We investigated whether the relative ascites PMN count (the absolute PMN count divided by the absolute leukocyte count) provides additional information to detect bacterascites or predict SBP.

Methods: Hospitalized patients with liver cirrhosis requiring paracentesis were stratified with respect to a diagnosis of bacterascites and SBP with a prospective follow-up for 1 year. Diagnostic power of relative PMN counts in ascites was evaluated by receiver operating characteristics curves.

Results: At inclusion, we observed 28/269 (10%) and 43/269 (16%) episodes of BA and SBP, respectively. Unlike absolute PMN counts, relative PMN counts in ascites were significantly elevated in bacterascites (p = 0.001). During follow-up, 16 and 30 further episodes of BA and SBP were detected, respectively. Relative PMN counts increased significantly once patients developed BA (p = 0.001). At a threshold of 0.20 for the relative PMN count, sensitivity, specificity, positive and negative predictive values for bacterascites which required antibiotic treatment were 83, 75, 26 and 98%, respectively (p < 0.001). Furthermore, a relative PMN count in ascites ≥0.13 and MELD score >17 was independent factors associated with occurrence of SBP during follow-up.

Conclusion: The relative PMN count is a cheap immunological marker linked to bacterascites and future SBP, which may help to stratify patients according to their risk of infection.
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http://dx.doi.org/10.1007/s10620-017-4637-4DOI Listing
September 2017

Compartment-specific distribution of human intestinal innate lymphoid cells is altered in HIV patients under effective therapy.

PLoS Pathog 2017 May 15;13(5):e1006373. Epub 2017 May 15.

Department of Internal Medicine I, University of Bonn, Bonn, Germany.

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.
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http://dx.doi.org/10.1371/journal.ppat.1006373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444854PMC
May 2017