Research at the UKE?
DE
Liver Lab – Immune regulation
Liver inflammation is a physiological response to injury that is necessary for the healing and regeneration of the organ. However, a dysregulated inflammatory response can lead to liver disease. Our research projects aim to better understand the regulation of inflammation in the liver in order to therapeutically target mechanisms involved.
Particular focus is on autoimmune responses, which can be helpful to remove damaged or premalignant liver cells, but can also cause autoimmune liver diseases, when dysregulated.
"The physiological mechanisms of the liver can be harnessed to induce antigen-specific immune tolerance for the treatment of autoimmune diseases."
Dr. rer. nat. Antonella Carambia
"Identifying the mechanisms that lead to the accumulation of disease specific autoantibodies will gain novel insights in the pathogenesis of autoimmune liver diseases."
Dr. med. Johannes Hartl
“The liver is unique in many ways - one of them is its complex immunoregulatory role. Under physiological conditions the liver favours tolerance, but at the same time it can be the site of every immune-mediated diseases. To understand the rules that govern this spectrum need to be understood to develop more targeted immunotherapies, and to maintain health.”
Prof. Dr. med. Ansgar W. Lohse
"The microbiota is an important determinant of our health. We investigate how intestinal and biliary microbiota influence the regulation of immunity in the liver and thus will identify novel therapeutic targets."
Prof. Dr. med. Christoph Schramm
"Understanding how autoimmunity is regulated in the liver will pave the way towards new therapies for liver diseases."
Prof. Dr. rer. nat. Johannes Herkel
"Deciphering the functional role of cholangiocytes in shaping portal immune regulation will help identify novel treatment targets for autoimmune cholestatic liver diseases."
Dr. rer. nat. Dorothee Schwinge
Project details and goals
Immune cells continually survey the liver to check the organ’s state of health, and protect it from infections or malignancy. Aberrations from a healthy state can cause liver inflammation causing the removal of aberrant cells, followed by restoration of a healthy liver state. However, the regulation of liver inflammation and its resolution can go wrong, causing the development of chronic inflammation and autoimmune liver diseases.
There are three autoimmune liver diseases, autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cholangitis, causing life-long inflammation of the liver parenchyma or bile ducts. All three diseases have an unmet need for more specific, effective and tolerable treatments.
Yet in healthy state, the liver can also down-regulate inflammatory activities of immune cells, which can be harnessed for antigen-specific induction of immune tolerance and the treatment of autoimmune diseases affecting other organs.
Our research aims to elucidate the immune regulation in the liver, both in autoimmune liver diseases and in liver tolerance. We believe that understanding hepatic immune regulation is key to the development of novel therapies for autoimmune diseases of the liver and other organs. Indeed, our strategy has led to the development of two novel therapeutic approaches currently being tested in clinical trials.
Current projects
The role of androgens in autoimmune liver diseases
The autoimmune liver diseases (AILD) autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) exhibit some of the highest female predominance among all autoimmune diseases. Despite this notable sex imbalance, the underlying reasons for it remain unknown. There is mounting evidence that androgens play an important role in mediating sex differences in immunity. To investigate the effects of androgens on immune cells, we analysed cohorts of transgender people receiving gender-affirming hormone therapy (GAHT) and age- and sex-matched people with PBC, AIH and healthy controls. Our results show that testosterone has direct effects on T cell function and improves disease course in a patient with AILD. We believe that the elucidation of the role of androgens in the context of AILD will improve our understanding of autoimmune liver diseases.
Intestinal metabolites and their impact on thermogenic responses by brown and white adipose tissues
Microbial metabolites such as short chain fatty acids (SCFA) and secondary bile acids are assumed to play a major role in the regulation of energy metabolism of the host. Recently, we discovered a novel immunometabolic crosstalk between activated T cells in the liver and hepatocytes that decreased the expression of enzymes regulating bile acid metabolism. Here, transfer of antigen-specific T cells resulted in increased bile acids serum levels, which potentially could trigger energy expenditure. Within this project we hypothesize that hepatocellular handling of gut-derived metabolites and the immunometabolic interaction between hepatocytes and T cells in the liver control energy uptake and expenditure by thermogenic brown and beige adipocytes.
Composition and functional heterogeneity of T cells in primary sclerosing cholangitis (PSC)
Primary sclerosing cholangitis (PSC) is an enigmatic liver disease characterised by a chronic inflammation leading to scarring and obliteration of intra- and extrahepatic bile ducts. The pathogenesis is largely unknown but it is widely believed that PSC is an immune mediated disease with environmental and genetic factors contributing to immune dysregulation. We recently identified an intrahepatic naive-like population of CD4+ T cells in people with PSC that is prone to polarize towards a pro-inflammatory phenotype. Moreover, we found that a gene polymorphism in the BACH2 gene significantly impacts CD4+ T cell differentiation.
Immune cells and cholangiocytes: an interaction that determines biliary inflammation
Autoimmune cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are progressive disorders of bile ducts leading to cholestasis with fibrosis and subsequent biliary cirrhosis. A central pathogenetic mechanism is the immune response directed against cholangiocytes, the epithelial cells lining the bile ducts. Chronic inflammation in cholangiopathies leads to cholangiocyte damage, proliferation and neo-ductuli formation. Within this project we hypothesize that the bidirectional interaction between immune cells and cholangiocytes determines biliary inflammation. We expect these experiments to delineate the functional role of cholangiocytes in shaping the hepatic immune cell function and to identify novel treatment targets for autoimmune cholestatic liver diseases.
The role of intestinal and biliary microbiota in autoimmune liver diseases
Primary sclerosing cholangitis (PSC) is a disease characterised by immune dysregulation at mucosal surfaces and thus ideally suited to study the role of biliary mucosal barrier function for hepatic immune regulation. It has been shown that PSC is characterised by mucosal and (peri-)ductular inflammation of bile ducts that results in periductular fibrosis and ultimately biliary cirrhosis. Cholangiocytes are the lining cells of bile ducts that form the biliary mucosal barrier. They modify the composition of bile fluid, but also transport information from the biliary endoluminal environment to the portal tracts of the liver, including intrahepatic resident and migrating immune cell populations. Importantly, the biliary tree represents a large mucosal surface and clinical observations suggest that recurrent bacterial cholangitis and potentially also colonisation of the bile ducts with Candida sp. aggravates PSC disease course. Within this project we aim to understand how biliary microbiota affect cholangiocyte function and the interaction of cholangiocytes with immune cells. This understanding will enable novel therapeutic strategies aimed at restoring homeostasis at the mucosal biliary barrier.
In addition, we study the role of intestinal microbiota in autoimmune liver diseases and how they influence inflammatory activity and symptom burden of disease.
The role of TNF in autoimmune hepatitis
CD4+ T cells in the livers of autoimmune hepatitis (AIH) patients produce high levels of the cytokine TNF, and AIH can be treated with anti-TNF antibodies. What exactly TNF does in AIH livers is unclear, as TNF can have different effects in different contexts. Here we aim to elucidate the disease-causing mechanisms of TNF in AIH, and to identify additional treatment targets
Dysregulation of autoimmunity in autoimmune hepatitis: mechanisms and experimental therapies
Autoimmune hepatitis (AIH) is presumably caused by an immune response to liver antigens. In healthy people, such immunity to autoantigens is regulated by diverse mechanisms to prevent sustained organ damage. Here, we analyse the regulation of autoimmunity in AIH patients to identify dysregulated mechanisms that might be corrected therapeutically. To that end, we characterise the state of and interactions between liver cells, innate immune cells and lymphocytes. The aim is to find better therapies for AIH.
Immune tolerance induction in the hepatic sinusoids
The immune system attacks most antigens and substances that are deemed harmful to the body. The liver, however, has a remarkable ability to suppress inflammation and damaging immune activities directed to antigens in the liver. This so called hepatic tolerance can prevent inflammatory diseases, but also promote chronic infections or cancer. Here, we aim to elucidate the mechanisms of hepatic tolerance in the hepatic sinusoids, in order to develop new therapies by manipulating hepatic tolerance.
A nanoparticle-based therapy platform for antigen-specific tolerance induction in autoimmune diseases
Endothelial cells in the hepatic sinusoids (LSECs) are major inducers of hepatic tolerance. LSECs are scavenger cells that can take up blood-borne antigens with high capacity and present those to T cells, which then become tolerant to these antigens. We developed a nanoparticle-based therapy platform targeting LSECs for antigen-specific tolerance induction. This approach was successfully applied in various preclinical inflammation models and is currently tested in clinical trials. We will further study the applicability of this promising approach.
Publications 2025
Henze L*, Will N*, Lee D, Haas V, Casar C, Meyer J, Stein S, Mangler F, Steinmann S, Poch T, Krause J, Fuss J, Schröder J, Kulle AE, Holterhus PM, Bonn S, Altfeld M, Huber S, Lohse AW, Schwinge D, Schramm C. JCI Insight 2025 Apr 22;10(8):e184544.
Abstract
Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are autoimmune liver diseases with strong female predominance. They are caused by T cell–mediated injury of hepatic parenchymal cells, but the mechanisms underlying this sex bias are unknown. Here, we investigated whether testosterone contributes to T cell activation in women with PBC. Compared with sex- and age-matched healthy controls (n = 23), cisgender (cis) women with PBC (n = 24) demonstrated decreased testosterone serum levels and proinflammatory CD4+ T cell profile in peripheral blood. Testosterone suppressed the expression of TNF and IFN-γ by human CD4+ T cells in vitro. In trans men receiving gender-affirming hormone therapy (GAHT) (n = 25), testosterone affected CD4+ T cell function by inhibiting Th1 and Th17 differentiation and by supporting the differentiation into regulatory Treg. Mechanistically, we provide evidence for a direct effect of testosterone on T cells using mice with T cell–specific deletion of the cytosolic androgen receptor. Supporting a role for testosterone in autoimmune liver disease, we observed an improved disease course and profound changes in T cell states in a trans man with AIH/primary sclerosing cholangitis (PSC) variant syndrome receiving GAHT. We here report a direct effect of testosterone on CD4+ T cells that may contribute to future personalized treatment strategies.
Horst LJ, Kempski J, Walmsley M, Huber S, Schramm C. Hepatology 2025 Jan 22.
Abstract
Primary sclerosing cholangitis is one of the most challenging conditions in hepatology, and due to our limited understanding of its pathogenesis, no causal therapies are currently available. While it was long assumed that a minority of people with inflammatory bowel disease (IBD) also develop primary sclerosing cholangitis (PSC), which is sometimes labeled an extraintestinal manifestation of IBD, the clinical phenotype, genetic, and intestinal microbiota associations strongly argue for PSC-IBD being a distinct form of IBD, existing alongside ulcerative colitis and Crohn’s disease. In fact, the liver itself could contribute to intestinal pathology, clinically overt in 60%–80% of patients. Recent studies suggested that on a molecular level, almost all people with PSC have underlying colitis. The extent to which the liver and gut influence each other clinically and in terms of disease progression has not yet been conclusively revealed. However, while it seemed intuitive that the 2 diseases have a negative influence on each other, evidence suggests that sclerosing cholangitis can also be protective for the gut and that colitis can, in certain settings, ameliorate liver pathology. This underscores the complex pathophysiological relationships, where factors such as genetic predisposition, changes in the intestinal microbiota, altered bile acid metabolism, and immune cell migration are among the suspected contributors. PSC is an emerging disease with a significant impact on the health-related quality of life of affected people. With this review, we aim to summarize the current knowledge on the gut-liver axis in PSC-IBD, provide new perspectives on risk stratification and treatment, and identify gaps in our current knowledge. Our understanding of this complex relationship will therefore help to design clinical trials and shape the future therapy of PSC-IBD.
Publications 2024
Laschtowitz A, Lindberg EL, Liebhoff AM, Liebig LA, Casar C, Steinmann S, Guillot A, Xu J, Schwinge D, Trauner M, Lohse AW, Bonn S, Hübner N, Schramm C. JHEP Rep 2024 Nov 12;7(3):101267.
Abstract
Background & aims: Primary sclerosing cholangitis (PSC) is a chronic heterogenous cholangiopathy with unknown etiology where chronic inflammation of the bile ducts leads to multifocal biliary strictures and biliary fibrosis with consecutive cirrhosis development. We here aimed to identify a PSC-specific gene signature associated with biliary fibrosis development.
Methods: We performed RNA-sequencing of 47 liver biopsies from people with PSC (n = 16), primary biliary cholangitis (PBC, n = 15), and metabolic dysfunction-associated steatotic liver disease (MASLD, n = 16) with different fibrosis stages to identify a PSC-specific gene signature associated with biliary fibrosis progression. For validation, we compared an external transcriptome data set of liver biopsies from people with PSC (n = 73) with different fibrosis stages (baseline samples from NCT01672853).
Results: Differential gene expression analysis of the liver transcriptome from patients with PSC with advanced vs. early fibrosis revealed 431 genes associated with fibrosis development. Of those, 367 were identified as PSC-associated when compared with PBC or MASLD. Validation against an external data set of 73 liver biopsies from patients with PSC with different fibrosis stages led to a condensed set of 150 (out of 367) differentially expressed genes. Cell type specificity assignment of those genes by using published single-cell RNA-Seq data revealed genetic disease drivers expressed by cholangiocytes (e.g. CXCL1, SPP1), fibroblasts, innate, and adaptive immune cells while deconvolution along fibrosis progression of the PSC, PBC, and MASLD samples highlighted an early involvement of macrophage- and neutrophil-associated genes in PSC fibrosis.
Conclusions: We reveal a PSC-attributed gene signature associated with biliary fibrosis development that may enable the identification of potential new biomarkers and therapeutic targets in PSC-related fibrogenesis.
Impact and implications: Primary sclerosing cholangitis (PSC) is an inflammatory liver disease that is characterized by multifocal inflammation of bile ducts and subsequent biliary fibrosis. Herein, we identify a PSC-specific gene set of biliary fibrosis progression attributing to a uniquely complex milieu of different cell types, including innate and adaptive immune cells while neutrophils and macrophages showed an earlier involvement in fibrosis initiation in PSC in contrast to PBC and metabolic dysfunction-associated steatotic liver disease. Thus, our unbiased approach lays an important groundwork for further mechanistic studies for research into PSC-specific fibrosis.
Liwinski T*, Auer MK*, Schröder J, Pieknik I, Casar C, Schwinge D, Henze L, Stalla GK, Lang UE, von Klitzing A, Briken P, Hildebrandt T, Desbuleux JC, Biedermann SV, Holterhus P-M, Bang C, Schramm C*, Fuss J*. BMC Medicine 2024;22:346.
Abstract
Background: Limited data exists regarding gender-specific microbial alterations during gender-affirming hormonal therapy (GAHT) in transgender individuals. This study aimed to investigate the nuanced impact of sex steroids on gut microbiota taxonomy and function, addressing this gap. We prospectively analyzed gut metagenome changes associated with 12 weeks of GAHT in trans women and trans men, examining both taxonomic and functional shifts.
Methods: Thirty-six transgender individuals (17 trans women, 19 trans men) provided pre- and post-GAHT stool samples. Shotgun metagenomic sequencing was used to assess the changes in gut microbiota structure and potential function following GAHT.
Results: While alpha and beta diversity remained unchanged during transition, specific species, including Parabacteroides goldsteinii and Escherichia coli, exhibited significant abundance shifts aligned with affirmed gender. Overall functional metagenome analysis showed a statistically significant effect of gender and transition (R2 = 4.1%, P = 0.0115), emphasizing transitions aligned with affirmed gender, particularly in fatty acid-related metabolism.
Conclusions: This study provides compelling evidence of distinct taxonomic and functional profiles in the gut microbiota between trans men and women. GAHT induces androgenization in trans men and feminization in trans women, potentially impacting physiological and health-related outcomes.
Hartl J, Buck L, Löwe B, Toussaint A, Schramm C. J Hepatol 2025;82:e44-e45.
Abstract
Although fatigue has been identified as a major determinant of health-related quality of life (HRQL) in chronic liver disease (CLD), it has received only little attention from scientists or physicians in the past. Therefore, we are pleased that fatigue has been given the spotlight in a recent review article by Younossi et al. in the Journal of Hepatology. As highlighted by the authors, while improvement or cure in certain CLDs may alleviate fatigue, currently licensed treatment options do not improve fatigue in primary biliary cholangitis (PBC), which represents the CLD in which fatigue has the greatest impact on HRQL, affecting 30 – 60% of patients. Therefore, investigating fatigue in PBC addresses a major unmet clinical need for patients. This should not narrow our clinical focus to PBC and distract from the fact that fatigue can also be relevant and severe in other autoimmune liver diseases such as primary sclerosing cholangitis (PSC). However, as pointed out in the current review, data on fatigue from large cohorts of patients with PSC are lacking so far.
Therefore, we prospectively explored the frequency and severity of fatigue, as well as potential contributing biomedical factors in a large, well-characterized cohort of patients with PSC (n = 228) compared to patients with PBC (n = 238), according to the previously published study protocol (SOMA.LIV; trial registration number ISRCTN14379650). Fatigue was assessed by PBC-40, a patient-derived, disease-specific quality of life measure with robust psychometric properties, including a fatigue domain that is also commonly used as patient-reported outcome measure in PSC.
In PBC, 29% of the patients had a mean PBC-40 fatigue domain score greater than 33, which is considered clinically significant fatigue. Fatigue severity correlated with younger age at diagnosis (r = -0.20, p = 0.004), but not with any biochemical markers, such as alkaline phosphatase, or stage of liver disease as assessed by liver stiffness. Of note, when we explored the sex impact, questionnaires revealed a significantly higher median fatigue score among women than in men (26 vs. 17 [median], p = 0.003;
Poch T*, Bahn J*, Casar C, Krause J, Evangelakos I, Gilladi H, Kunzmann LK, Laschtowitz A, Iuso N, Schäfer AM, Liebig LA, Steinmann S, Sebode M, Folseraas T, Engesæter LK, Karlsen TH, Franke A, Hubner N, Schlein C, Galun E, Huber S, Lohse AW, Gagliani N, Schwinge D*, Schramm C*. Cell Rep Med 2024 Jun 13:101620. doi: 10.1016/j.xcrm.2024.101620. Online ahead of print. PMID: 38901430
Abstract
Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease of unknown pathogenesis, with a high risk to develop cirrhosis and malignancies. Functional dysregulation of T cells and association with genetic polymorphisms in T cell-related genes were previously reported for PSC. Here, we genotyped a representative PSC cohort for several disease-associated risk loci and identified rs56258221 (BACH2/MIR4464) to correlate with not only the peripheral blood T cell immunophenotype but also the functional capacities of naive CD4+ T (CD4+ TN) cells in people with PSC. Mechanistically, rs56258221 leads to an increased expression of miR4464, in turn causing attenuated translation of BACH2, a major gatekeeper of T cell quiescence. Thereby, the fate of CD4+TN is skewed toward polarization into pro-inflammatory subsets. Clinically, people with PSC carrying rs56258221 show signs of accelerated disease progression. The data presented here highlight the importance of assigning functional outcomes to disease-associated genetic polymorphisms as potential drivers of diseases.
Weltzsch JP, Bartel CF, Waldmann M, Renné T, Schulze S, Terziroli Beretta-Piccoli B, Papp M, Ye O, Ronca V, Sebode M, Lohse AW, Schramm C, Hartl J. Hepatology 2024;80:1026-1040.
Abstract
Background and aims: In autoimmune hepatitis, achieving complete biochemical remission (CBR) with current weight-based thiopurine dosing is challenging. We investigated whether patients could be stratified regarding CBR according to a target range of thiopurine metabolites. Moreover, we explored the effects of azathioprine dosage increases and co-therapy of allopurinol with low-dose thiopurines on metabolite profiles and treatment response.
Approach and results: The relation between metabolites and treatment response was assessed in 337 individuals from 4 European centers. In a global, cross-sectional analysis, active metabolites 6-thioguanine nucleotides (6TGN) were similar in those with and without CBR. However, analyzing patients with sequential measurements over 4 years (N = 146) revealed higher average 6TGN levels in those with stable CBR (260 pmol/0.2 mL) compared to those failing to maintain CBR (181 pmol/0.2 mL; p = 0.0014) or never achieving CBR (153 pmol/0.2 mL; p < 0.0001), with an optimal 6TGN cutoff of ≥223 pmol/0.2 mL (sensitivity: 76% and specificity: 78%). Only 42% exhibited 6TGN ≥223 pmol/0.2 mL following weight-based dosing, as doses weakly correlated with 6TGN but with 6-methylmercaptopurine (6MMP), a metabolite associated with toxicity. Azathioprine dose increases led to preferential 6MMP formation (+127% vs. 6TGN +34%; p < 0.0001). Conversely, adding allopurinol to thiopurines in difficult-to-treat patients (N = 36) raised 6TGN (168→321 pmol/0.2 mL; p < 0.0001) and lowered 6MMP (2125→184 pmol/0.2 mL; p < 0.0001), resulting in improved transaminases in all patients and long-term CBR in 75%.
Conclusions: Maintaining CBR in autoimmune hepatitis was associated with 6TGN ≥223 pmol/0.2 mL. For patients who fail to achieve CBR and therapeutic 6TGN levels despite thiopurine dose increase due to preferential 6MMP formation, comedication of allopurinol alongside low-dose thiopurines represents an efficient alternative.
Zecher BF, Ellinghaus D, Schloer S, Niehrs A, Padoan B, Baumdick ME, Yuki Y, Martin MP, Glow D, Schröder-Schwarz J, Niersch J, Brias S, Müller LM, Habermann R, Kretschmer P, Früh T, Dänekas J, Wehmeyer MH, Poch T, Sebode M; International PSC Study Group (IPSCSG); Ellinghaus E, Degenhardt F, Körner C, Hoelzemer A, Fehse B, Oldhafer KJ, Schumacher U, Sauter G, Carrington M, Franke A, Bunders MJ, Schramm C*, Altfeld M*. Gut 2024 Jan 5;73(2):325-337.
Abstract
Objective: Primary sclerosing cholangitis (PSC) is characterised by bile duct strictures and progressive liver disease, eventually requiring liver transplantation. Although the pathogenesis of PSC remains incompletely understood, strong associations with HLA-class II haplotypes have been described. As specific HLA-DP molecules can bind the activating NK-cell receptor NKp44, we investigated the role of HLA-DP/NKp44-interactions in PSC.
Design: Liver tissue, intrahepatic and peripheral blood lymphocytes of individuals with PSC and control individuals were characterised using flow cytometry, immunohistochemical and immunofluorescence analyses. HLA-DPA1 and HLA-DPB1 imputation and association analyses were performed in 3408 individuals with PSC and 34 213 controls. NK cell activation on NKp44/HLA-DP interactions was assessed in vitro using plate-bound HLA-DP molecules and HLA-DPB wildtype versus knock-out human cholangiocyte organoids.
Results: NKp44+NK cells were enriched in livers, and intrahepatic bile ducts of individuals with PSC showed higher expression of HLA-DP. HLA-DP haplotype analysis revealed a highly elevated PSC risk for HLA-DPA1*02:01~B1*01:01 (OR 1.99, p=6.7×10−50). Primary NKp44+NK cells exhibited significantly higher degranulation in response to plate-bound HLA-DPA1*02:01-DPB1*01:01 compared with control HLA-DP molecules, which were inhibited by anti-NKp44-blocking. Human cholangiocyte organoids expressing HLA-DPA1*02:01-DPB1*01:01 after IFN-γ-exposure demonstrated significantly increased binding to NKp44-Fc constructs compared with unstimulated controls. Importantly, HLA-DPA1*02:01-DPB1*01:01-expressing organoids increased degranulation of NKp44+NK cells compared with HLA-DPB1-KO organoids.
Conclusion: Our studies identify a novel PSC risk haplotype HLA-DP A1*02:01~DPB1*01:01 and provide clinical and functional data implicating NKp44+NK cells that recognise HLA-DPA1*02:01-DPB1*01:01 expressed on cholangiocytes in PSC pathogenesis.
Publications 2023
Cell Mol Gastroenterol Hepatol. Krzikalla D, Laschtowitz A, Leypoldt L, Gottwick C, Averhoff P, Weidemann S, Lohse AW, Huber S, Schramm C, Schwinge D, Herkel J, Carambia A. IFNγ and CTLA-4 Drive 2024;17(1):79-91.
Abstract
Background & aims: The liver has a distinct capacity to induce immune tolerance to hepatic antigens. Although liver tolerance can be advantageous for preventing autoimmune and inflammatory diseases, it also can be detrimental by preventing immune surveillance of infected or malignant cells. Here, we investigated the immune mechanisms that establish hepatic tolerance.
Methods: Tolerance was investigated in C-reactive protein (CRP)-myelin basic protein (MBP) mice expressing the neuroantigen MBP in hepatocytes, providing profound resistance to MBP-induced neuroinflammation. Tolerance induction was studied after transfer of MBP-specific CD4 T cells into CRP-MBP mice, and tolerance mechanisms were tested using depleting or blocking antibodies.
Results: Although tolerant CRP-MBP mice display increased numbers of forkhead box P3+ regulatory T cells, we here found them not essential for the maintenance of hepatic tolerance. Instead, upon MBP recognition in the liver, MBP-specific T cells became activated to produce interferon (IFN)γ, which, in turn, induced local up-regulation of recruitment molecules, including Chemokine (C-X-C motif) ligand9 and its receptor C-X-C motif chemokine receptor3, facilitating endothelial translocation and redirection of MBP-specific T cells into the hepatic parenchyma. There, the translocated MBP-specific CD4 T cells partly converted into interleukin 10-producing type 1 regulatory T cells, and significantly up-regulated the expression of immune checkpoint molecules, notably cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Intriguingly, although liver tolerance was not affected by impairment of interleukin 10 signaling, concomitant blockade of IFNγ and CTLA-4 abrogated hepatic tolerance induction to MBP, resulting in neuroinflammatory autoimmune disease in these mice.
Conclusions: IFNγ-mediated redirection of autoreactive CD4 T cells into the liver and up-regulation of checkpoint molecules, including CTLA-4, were essential for tolerance induction in the liver, hence representing a potential treatment target for boosting or preventing liver tolerance.
Abstract
During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis. Mechanistically, IL-22 acted on endothelial cells, promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Multi-parameter flow cytometry and single-cell sequencing of immune cells isolated during cancer cell extravasation into the liver revealed iNKT17 cells as source of IL-22. iNKT-cell-deficient mice exhibited reduced metastases, which was reversed by injection of wild type, but not Il22-deficient, invariant natural killer T (iNKT) cells. IL-22-producing iNKT cells promoting metastasis were tissue resident, as demonstrated by parabiosis. Thus, IL-22 may present a therapeutic target for prevention of metastasis.
Previous publications
Müller AL, Casar C, Preti M, Krzikalla D, Gottwick C, Averhoff P, Rosenstiel P, Gelderblom M, Altfeld M, Lohse AW, Steinmann S, Sebode M, Krause J, Schwinge D, Schramm C, Carambia A, Herkel J. J Hepatol 2022 Jul 4:S0168-8278(22)02923-3. doi: 10.1016/j.jhep.2022.06.025.
Lay summary
Primary sclerosing cholangitis (PSC) is an inflammatory liver disease of the bile ducts for which there is no effective treatment. Herein, we show that the inflammatory immune response to bile duct injury is organised by a specific subtype of immune cell called conventional type 2 dendritic cells. Our findings suggest that this cell subtype and the inflammatory molecules it produces are potential therapeutic targets for PSC.
Poch T#, Krause J#, Casar C, Liwinski T, Glau L, Kaufmann M, Ahrenstorf AE, Hess LU, Ziegler AE, Martrus G, Lunemann S, Sebode M, Li J, Schwinge D, Krebs CF, Franke A, Friese MA, Oldhafer KJ, Fischer L, Altfeld M, Lohse AW, Huber S, Tolosa E#, Gagliani N #, Schramm C #. J Hepatol 2021;75:414-423.
Lay summary
The composition of intrahepatic immune cells in primary sclerosing cholangitis (PSC) and their contribution to disease pathogenesis is widely unknown. We analysed intrahepatic T cells and identified a previously uncharacterized population of liver-resident CD4+ T cells which are expanded in the livers of patients with PSC compared to healthy liver tissue and other liver diseases. These cells are likely to contribute to the pathogenesis of PSC and could be targeted in novel therapeutic approaches.
Stein S, Henze L, Poch T, Carambia A, Krech T, Preti M, Schuran FA, Reich M, Keitel V, Fiorotto R, Strazzabosco M, Fischer L, Li J, Müller LM, Wagner J, Gagliani N, Herkel J, Schwinge D, Schramm C. J Hepatol 2021;74:919-930. doi: 10.1016/j.jhep.2020.10.035. Epub 2020 Nov 13.
Lay summary
IL-17 is assumed to be a driver of inflammation in several autoimmune diseases, such as psoriasis. IL-17 is also present in inflammatory diseases of the bile duct, but its role in these conditions is not clear, as the effects of IL-17 depend on the context of its expression. Herein, we investigated the role of IL-17 in an experimental autoimmune cholangitis mouse model, and we identified an important protective effect of IL-17 on cholangiocytes, enabling them to downregulate bile duct inflammation via checkpoint inhibitor PD-L1.
Liwinski T*, Zenouzi R*, John C, Ehlken H, Rühlemann MC, Bang C, Groth S, Lieb W, Kantowski M, Andersen N, Schachschal G, Karlsen TH, Hov JR, Rösch T, Lohse AW, Heeren J, Franke A, Schramm C. Gut 2020;69:665-672. doi: 10.1136/gutjnl-2019-318416. Epub 2019 Jun 26.
Abstract
Background: Patients with primary sclerosing cholangitis (PSC) display an altered colonic microbiome compared with healthy controls. However, little is known on the bile duct microbiome and its interplay with bile acid metabolism in PSC.
Methods: Patients with PSC (n=43) and controls without sclerosing cholangitis (n=22) requiring endoscopic retrograde cholangiography were included prospectively. Leading indications in controls were sporadic choledocholithiasis and papillary adenoma. A total of 260 biospecimens were collected from the oral cavity, duodenal fluid and mucosa and ductal bile. Microbiomes of the upper alimentary tract and ductal bile were profiled by sequencing the 16S-rRNA-encoding gene (V1–V2). Bile fluid bile acid composition was measured by high-performance liquid chromatography mass spectrometry and validated in an external cohort (n=20).
Results: The bile fluid harboured a diverse microbiome that was distinct from the oral cavity, the duodenal fluid and duodenal mucosa communities. The upper alimentary tract microbiome differed between PSC patients and controls. However, the strongest differences between PSC patients and controls were observed in the ductal bile fluid, including reduced biodiversity (Shannon entropy, p=0.0127) and increase of pathogen Enterococcus faecalis (FDR=4.18×10−5) in PSC. Enterococcus abundance in ductal bile was strongly correlated with concentration of the noxious secondary bile acid taurolithocholic acid (r=0.60, p=0.0021).
Conclusion: PSC is characterised by an altered microbiome of the upper alimentary tract and bile ducts. Biliary dysbiosis is linked with increased concentrations of the proinflammatory and potentially cancerogenic agent taurolithocholic acid.
Team
Prof. Dr. med. Ansgar Lohse
Principal Investigator
E-mail address:
Prof. Dr. med. Christoph Schramm
Principal Investigator
E-mail address:
Prof. Dr. rer. nat. Johannes Herkel
Principal Investigator
E-mail address:
