Research at the UKE?
DE
Publications
Publications 2025
Arck Lab
Urbschat C, Arck PC. Semin Immunopathol. 2025 Aug 6;47(1):33.
Abstract
Microchimerism refers to the presence of a small number of foreign, mostly conspecific, cells within an individual. Decades ago, the pioneering researcher in this field faced significant skepticism because the prevailing view was that foreign cells could not survive for long periods inside the host. Today, the existence of microchimerism is widely accepted. Nonetheless, the field still lacks a clear quantitative definition, especially in mammals. There is no universally agreed threshold or precise boundary that qualifies as microchimerism. Additionally, distinguishing microchimerism from other types, such as ‘macrochimerism’ or ‘multichimerism,’ remains difficult. Although its functional role is largely an unresolved mystery, recent studies show that chimerism plays an essential role during immune and neurocognitive development. Here, we compile a comprehensive collection of articles highlighting recent advances across different areas of chimerism research and summarize the known types of chimerism and their modes of acquisition.
Thiele K, Urbschat C, Riquelme JIA, Ahrendt LS, Wöhrle R, Schepanski S, Eckert JJ, Becht E, Qi M, Alawi M, Becker M, Gagliani N, Mittrücker HW, Diemert A, Arck PC. Nat Commun. 2025 Jul 15;16(1):6522.
Abstract
Subsequent pregnancies are generally less prone to obstetric complications. A successful pregnancy outcome requires pivotal immunological adaptation to ensure immune tolerance towards the foetus. Thus, the lower risk for pregnancy complication during subsequent pregnancies may be attributable to immune memory mounted during first pregnancies. Here we identify higher frequencies of fetal-antigen-specific CD4+ regulatory T (Treg) cells both postpartum and in subsequent pregnancies in mice which are partly originating from trans-differentiated Th17 cells. Our functional experiments demonstrate that these CD4+ Treg cells have memory functions (CD4+ mTreg) and account for an improved fetal development and pregnancy outcome, also during adverse conditions, such as gestational sound stress. Using a high-throughput single-cell quantification method, we identify candidate markers for the detection of CD4+ mTreg cells, which include CXCR4 and CD274. Our findings thus contribute to the improved understanding of pregnancy-induced immune memory and foster the identification of immune targets aiming to reduce the risk for immune-mediated pregnancy complications.
Wiemers P, Graf I, Addo MM, Arck PC, Diemert A. Semin Immunopathol. 2025 Apr 24;47(1):25.
Abstract
Infectious diseases have threatened individuals and societies since the dawn of humanity. Certain population groups, including pregnant women, young children and the elderly, are particularly vulnerable to severe infections. Over the past few centuries, advances in medical standards and the availability of vaccines have reduced infection-related mortality and morbidity rates in industrialized countries. However, the global rise in temperatures and increased precipitation present a new challenge, facilitating the broader distribution of disease vectors, such as mosquitoes, bugs and ticks, to higher altitudes and latitudes. Consequently, epidemic and pandemic outbreaks associated with these vectors, such as Zika, West Nile, dengue, yellow fever, chikungunya and malaria, are increasingly impacting diverse populations. This review comprehensively examines how infections associated with climate change disproportionately affect the health and well-being of pregnant women and their unborn children. There has been a noticeable emergence of vector-borne diseases in Europe. Consequently, we stress the importance of implementing measures that effectively protect pregnant women from these increasing infections globally and regionally. We advocate for initiatives to safeguard pregnant women from these emerging threats, beginning with enhanced education to raise awareness about the evolving risks this particularly vulnerable population faces.
Padula AM, Salihovic S, Zazara DE, Diemert A, Arck PC. Environ Res. 2025 Apr 1;270:120976.
Abstract
Background: Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous chemicals posing environmental and health risks. Impact on the human immune system is of particular concern, especially during fetal immune development. Alterations to fetal immune development can impact immunity later in life, e.g., the response to vaccines and pathogens.
Objectives: This study investigated the association between PFAS concentrations in healthy pregnant women from Hamburg, Germany, and antibody levels to routine vaccines in childhood and occurrence of childhood infections.
Methods: Mid-pregnancy serum samples from 152 mothers-child pairs were analyzed for 18 PFAS compounds, and antibody levels to measles, mumps, rubella, diphtheria, and tetanus were assessed at age 5. Maternal questionnaires provided data on childhood infections each year at age 1–5. Linear and Poisson regression models were adjusted for maternal age, education, parity, and breastfeeding duration. Weighted quantile sum (WQS) regression was used to assess the PFAS mixture.
Results: Higher PFAS concentrations were associated with lower antibody titers at age 5 years, particularly for mumps, tetanus, diphtheria, and rubella. Several PFAS were also linked to increased childhood infections, especially respiratory infections, during ages 3 and 4 years. WQS regression revealed a negative association between combined PFAS and tetanus titers.
Conclusions: Maternal PFAS concentrations during pregnancy are inversely associated with antibody levels in children and positively associated with increased childhood infections, notably respiratory infections. These findings underscore the importance of understanding environmental exposures' impact on immune responses and call for continued monitoring of PFAS in both the environment and human populations to mitigate health risks.
Systems Biology
Kuehl, M., Okabayashi, Y., Wong, M.N. et al. Nature 644, 516–526 (2025).
Abstract
The expression and location of proteins in tissues represent key determinants of health and disease. Although recent advances in multiplexed imaging have expanded the number of spatially accessible proteins, the integration of biological layers (that is, cell structure, subcellular domains and signalling activity) remains challenging. This is due to limitations in the compositions of antibody panels and image resolution, which together restrict the scope of image analysis. Here we present pathology-oriented multiplexing (PathoPlex), a scalable, quality-controlled and interpretable framework. It combines highly multiplexed imaging at subcellular resolution with a software package to extract and interpret protein co-expression patterns (clusters) across biological layers. PathoPlex was optimized to map more than 140 commercial antibodies at 80 nm per pixel across 95 iterative imaging cycles and provides pragmatic solutions to enable the simultaneous processing of at least 40 archival biopsy specimens. In a proof-of-concept experiment, we identified epithelial JUN activity as a key switch in immune-mediated kidney disease, thereby demonstrating that clusters can capture relevant pathological features. PathoPlex was then used to analyse human diabetic kidney disease. The framework linked patient-level clusters to organ disfunction and identified disease traits with therapeutic potential (that is, calcium-mediated tubular stress). Finally, PathoPlex was used to reveal renal stress-related clusters in individuals with type 2 diabetes without histological kidney disease. Moreover, tissue-based readouts were generated to assess responses to inhibitors of the glucose cotransporter SGLT2. In summary, PathoPlex paves the way towards democratizing multiplexed imaging and establishing integrative image analysis tools in complex tissues to support the development of next-generation pathology atlases.
Wang, H., Engesser, J., Khatri, R. et al. Nat Commun 16, 4686 (2025).
Abstract
In anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and systemic lupus erythematosus (SLE), glomerulonephritis is a severe kidney complication driven by immune cells, including T cells. However, the mechanisms underlying T cell activation in these contexts remain elusive. Here we report that in patients with AAV and SLE, type I interferon (IFN-I) induces T cell differentiation into interferon-stimulated genes-expressing T (ISG-T) cells, which are characterized by an elevated IFN-I signature, an immature phenotype, and cytotoxicity in inflamed tissue. Mechanistically, IFN-I stimulates the expression of interferon regulatory factor 7 (IRF7) in T cells, which in turn induces granzyme B production. In mice, blocking IFN-I signaling reduces IRF7 and granzyme B expression in T cells, thus ameliorating glomerulonephritis. In parallel, spatial transcriptomic analyses of kidney biopsies from patients with AAV or SLE reveal an elevated ISG signature and the presence of ISG-T cells in close proximity to plasmacytoid dendritic cells, the primary producers of IFN-I. Our results from both patients and animal models thus suggest that IFN-I production in inflamed tissue may drive ISG-T cell differentiation to expand the pool of cytotoxic T cells in autoimmune diseases.
Manuel Friese Group
Woo MS, Brand J, Bal LC, Moritz M, Walkenhorst M, Vieira V, Ipenberg I, Rothammer N, Wang M, Dogan B, Loreth D, Mayer C, Nagel D, Wagner I, Pfeffer LK, Landgraf P, van Ham M, Mattern KM, Winschel I, Frantz N, Sonner JK, Grosshans HK, Miguela A, Bauer S, Meurs N, Müller A, Binkle-Ladisch L, Salinas G, Jänsch L, Dieterich DC, Riedner M, Krüger E, Heppner FL, Glatzel M, Puelles VG, Engler JB, Nyengaard JR, Misgeld T, Kerschensteiner M, Merkler D, Meyer-Schwesinger C, Friese MA. Cell. 2025 Jun 13:S0092-8674(25)00616-6.
Abstract
Inflammation, aberrant proteostasis, and energy depletion are hallmarks of neurodegenerative diseases such as multiple sclerosis (MS). However, the interplay between inflammation, proteasomal dysfunction in neurons, and its consequences for neuronal integrity remains unclear. Using transcriptional, proteomic, and functional analyses of proteasomal subunits in inflamed neurons, we found that interferon-γ-mediated induction of the immunoproteasome subunit, proteasome 20S beta 8 (PSMB8) impairs the proteasomal balance, resulting in reduced proteasome activity. This reduction causes the accumulation of phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key metabolic regulator, leading to enhanced neuronal glycolysis, reduced pentose phosphate pathway activity, oxidative injury, and ferroptosis. Neuron-specific genetic and systemic pharmacological targeting of PSMB8 or PFKFB3 protected neurons in vitro and in a mouse model of MS. Our findings provide a unifying explanation for proteasomal dysfunction in MS and possibly other neurodegenerative diseases, linking inflammation to metabolic disruption, and presenting an opportunity for targeted neuroprotective therapies.
Liver Lab
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.
Kidney Immunology
Asada N, Ginsberg P, Paust HJ, Song N, Riedel JH, Turner JE, Peters A, Kaffke A, Engesser J, Wang H, Zhao Y, Khatri R, Gild P, Dahlem R, Diercks BP, Das S, Ignatova Z, Huber TB, Prinz I, Gagliani N, Mittrücker HW, Krebs CF, Panzer U. Nat Immunol. 2025 Apr;26(4):557-566.
Abstract
Tissue-resident memory T (TRM) cells are a specialized T cell population that reside in tissues and provide a rapid protective response upon activation. Here, we showed that human and mouse CD4+ TRM cells existed in a poised state and stored messenger RNAs encoding proinflammatory cytokines without protein production. At steady state, cytokine mRNA translation in TRM cells was suppressed by the integrated stress response (ISR) pathway. Upon activation, the central ISR regulator, eIF2α, was dephosphorylated and stored cytokine mRNA was translated for immediate cytokine production. Genetic or pharmacological activation of the ISR–eIF2α pathway reduced cytokine production and ameliorated autoimmune kidney disease in mice. Consistent with these results, the ISR pathway in CD4+ TRM cells was downregulated in patients with immune-mediated diseases of the kidney and the intestine compared to healthy controls. Our results indicated that stored cytokine mRNA and translational regulation in CD4+ TRM cells facilitate rapid cytokine production during local immune response.
Publications 2024
Systems Biology
Engesser, J., Khatri, R., Schaub, D.P. et al. Nat Commun 15, 8220 (2024).
Abstract
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a life-threatening autoimmune disease that often results in kidney failure caused by crescentic glomerulonephritis (GN). To date, treatment of most patients with ANCA-GN relies on non-specific immunosuppressive agents, which may have serious adverse effects and be only partially effective. Here, using spatial and single-cell transcriptome analysis, we characterize inflammatory niches in kidney samples from 34 patients with ANCA-GN and identify proinflammatory, cytokine-producing CD4+ and CD8+ T cells as a pathogenic signature. We then utilize these transcriptomic profiles for digital pharmacology and identify ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, as the strongest therapeutic drug to use. Moreover, four patients with relapsing ANCA-GN are treated with ustekinumab in combination with low-dose cyclophosphamide and steroids, with ustekinumab given subcutaneously (90 mg) at weeks 0, 4, 12, and 24. Patients are followed up for 26 weeks to find this treatment well-tolerated and inducing clinical responses, including improved kidney function and Birmingham Vasculitis Activity Score, in all ANCA-GN patients. Our findings thus suggest that targeting of pathogenic T cells in ANCA-GN patients with ustekinumab might represent a potential approach and warrants further investigation in clinical trials.
Manuel Friese Group
Binkle-Ladisch L, Pironet A, Zaliani A, Alcouffe C, Mensching D, Haferkamp U, Willing A, Woo MS, Erdmann A, Jessen T, Hess SD, Gribbon P, Pless O, Vennekens R, Friese MA. iScience. 2024 Nov 19;27(12):111425.
Abstract
Neurodegeneration in central nervous system disorders is linked to dysregulated neuronal calcium. Direct inhibition of glutamate-induced neuronal calcium influx, particularly via N-methyl-D-aspartate receptors (NMDAR), has led to adverse effects and clinical trial failures. A more feasible approach is to modulate NMDAR activity or calcium signaling indirectly. In this respect, the calcium-activated non-selective cation channel transient receptor potential melastatin 4 (TRPM4) has been identified as a promising target. However, high affinity and specific antagonists are lacking. Here, we conducted high-throughput screening of a compound library to identify high affinity TRPM4 antagonists. This yielded five lead compound series with nanomolar half-maximal inhibitory concentration values. Through medicinal chemistry optimization of two series, we established detailed structure-activity relationships and inhibition of excitotoxicity in neurons. Moreover, we identified their potential binding site supported by electrophysiological measurements. These potent TRPM4 antagonists are promising drugs for treating neurodegenerative disorders and TRPM4-related pathologies, potentially overcoming previous therapeutic challenges.
Walkenhorst M, Sonner JK, Meurs N, Engler JB, Bauer S, Winschel I, Woo MS, Raich L, Winkler I, Vieira V, Unger L, Salinas G, Lantz O, Friese MA, Willing A. Nat Commun. 2024 Oct 28;15(1):9287.
Abstract
Mucosal-associated invariant T (MAIT) cells express semi-invariant T cell receptors (TCR) for recognizing bacterial and yeast antigens derived from riboflavin metabolites presented on the non-polymorphic MHC class I-related protein 1 (MR1). Neuroinflammation in multiple sclerosis (MS) is likely initiated by autoreactive T cells and perpetuated by infiltration of additional immune cells, but the precise role of MAIT cells in MS pathogenesis remains unknown. Here, we use experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, and find an accumulation of MAIT cells in the inflamed central nervous system (CNS) enriched for MAIT17 (RORγt+) and MAIT1/17 (T-bet+RORγt+) subsets with inflammatory and protective features. Results from transcriptome profiling and Nur77GFP reporter mice show that these CNS MAIT cells are activated via cytokines and TCR. Blocking TCR activation with an anti-MR1 antibody exacerbates EAE, whereas enhancing TCR activation with the cognate antigen, 5-(2-oxopropylideneamino)−6-D-ribitylaminouracil, ameliorates EAE severity, potentially via the induction of amphiregulin (AREG). In summary, our findings suggest that TCR-mediated MAIT cell activation is protective in CNS inflammation, likely involving an induction of AREG.
Woo MS, Bal LC, Winschel I, Manca E, Walkenhorst M, Sevgili B, Sonner JK, Di Liberto G, Mayer C, Binkle-Ladisch L, Rothammer N, Unger L, Raich L, Hadjilaou A, Noli B, Manai AL, Vieira V, Meurs N, Wagner I, Pless O, Cocco C, Stephens SB, Glatzel M, Merkler D, Friese MA. J Clin Invest. 2024 Jun 18;134(16):e177692.
Abstract
A disturbed balance between excitation and inhibition (E/I balance) is increasingly recognized as a key driver of neurodegeneration in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. To understand how chronic hyperexcitability contributes to neuronal loss in MS, we transcriptionally profiled neurons from mice lacking inhibitory metabotropic glutamate signaling with shifted E/I balance and increased vulnerability to inflammation-induced neurodegeneration. This revealed a prominent induction of the nuclear receptor NR4A2 in neurons. Mechanistically, NR4A2 increased susceptibility to excitotoxicity by stimulating continuous VGF secretion leading to glycolysis-dependent neuronal cell death. Extending these findings to people with MS (pwMS), we observed increased VGF levels in serum and brain biopsies. Notably, neuron-specific deletion of Vgf in a mouse model of MS ameliorated neurodegeneration. These findings underscore the detrimental effect of a persistent metabolic shift driven by excitatory activity as a fundamental mechanism in inflammation-induced neurodegeneration.
Abstract
Inflammation-induced neurodegeneration is a defining feature of multiple sclerosis (MS), yet the underlying mechanisms remain unclear. By dissecting the neuronal inflammatory stress response, we discovered that neurons in MS and its mouse model induce the stimulator of interferon genes (STING). However, activation of neuronal STING requires its detachment from the stromal interaction molecule 1 (STIM1), a process triggered by glutamate excitotoxicity. This detachment initiates non-canonical STING signaling, which leads to autophagic degradation of glutathione peroxidase 4 (GPX4), essential for neuronal redox homeostasis and thereby inducing ferroptosis. Both genetic and pharmacological interventions that target STING in neurons protect against inflammation-induced neurodegeneration. Our findings position STING as a central regulator of the detrimental neuronal inflammatory stress response, integrating inflammation with glutamate signaling to cause neuronal cell death, and present it as a tractable target for treating neurodegeneration in MS.
Gagliani Lab
Liebold I, Al Jawazneh A, Casar C, Lanzloth C, Leyk S, Hamley M, Wong MN, Kylies D, Gräfe SK, Edenhofer I, Aranda-Pardos I, Kriwet M, Haas H, Krause J, Hadjilaou A, Schromm AB, Richardt U, Eggert P, Tappe D, Weidemann SA, Ghosh S, Krebs CF, A-Gonzalez N, Worthmann A, Lohse AW, Huber S, Rothlin CV, Puelles VG, Jacobs T, Gagliani N, Bosurgi L. Science. 2024 Apr 5;384(6691):eabo7027.
Abstract
Macrophages are functionally heterogeneous cells essential for apoptotic cell clearance. Apoptotic cells are defined by homogeneous characteristics, ignoring their original cell lineage identity. We found that in an interleukin-4 (IL-4)-enriched environment, the sensing of apoptotic neutrophils by macrophages triggered their tissue remodeling signature. Engulfment of apoptotic hepatocytes promoted a tolerogenic phenotype, whereas phagocytosis of T cells had little effect on IL-4-induced gene expression. In a mouse model of parasite-induced pathology, the transfer of macrophages conditioned with IL-4 and apoptotic neutrophils promoted parasitic egg clearance. Knockout of phagocytic receptors required for the uptake of apoptotic neutrophils and partially T cells, but not hepatocytes, exacerbated helminth infection. These findings suggest that the identity of apoptotic cells may contribute to the development of distinct IL-4-driven immune programs in macrophages.
Huber Lab
Abstract
Adeno-associated virus (AAV) is a promising in vivo gene delivery platform showing advantages in delivering therapeutic molecules to difficult or undruggable cells. However, natural AAV serotypes have insufficient transduction specificity and efficiency in kidney cells. Here, we developed an evolution-directed selection protocol for renal glomeruli and identified what we believe to be a new vector termed AAV2-GEC that specifically and efficiently targets the glomerular endothelial cells (GEC) after systemic administration and maintains robust GEC tropism in healthy and diseased rodents. AAV2-GEC-mediated delivery of IdeS, a bacterial antibody-cleaving proteinase, provided sustained clearance of kidney-bound antibodies and successfully treated antiglomerular basement membrane glomerulonephritis in mice. Taken together, this study showcases the potential of AAV as a gene delivery platform for challenging cell types. The development of AAV2-GEC and its successful application in the treatment of antibody-mediated kidney disease represents a significant step forward and opens up promising avenues for kidney medicine.
Abstract
Background: Minimal change disease and primary focal segmental glomerulosclerosis in adults, along with idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies that lead to nephrotic syndrome. Autoantibodies targeting nephrin have been found in patients with minimal change disease, but their clinical and pathophysiological roles are unclear.
Methods: We conducted a multicenter study to analyze antinephrin autoantibodies in adults with glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, antineutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis, as well as in children with idiopathic nephrotic syndrome and in controls. We also created an experimental mouse model through active immunization with recombinant murine nephrin.
Results: The study included 539 patients (357 adults and 182 children) and 117 controls. Among the adults, antinephrin autoantibodies were found in 46 of the 105 patients (44%) with minimal change disease, 7 of 74 (9%) with primary focal segmental glomerulosclerosis, and only in rare cases among the patients with other conditions. Of the 182 children with idiopathic nephrotic syndrome, 94 (52%) had detectable antinephrin autoantibodies. In the subgroup of patients with active minimal change disease or idiopathic nephrotic syndrome who were not receiving immunosuppressive treatment, the prevalence of antinephrin autoantibodies was as high as 69% and 90%, respectively. At study inclusion and during follow-up, antinephrin autoantibody levels were correlated with disease activity. Experimental immunization induced a nephrotic syndrome, a minimal change disease-like phenotype, IgG localization to the podocyte slit diaphragm, nephrin phosphorylation, and severe cytoskeletal changes in mice.
Conclusions: In this study, circulating antinephrin autoantibodies were common in patients with minimal change disease or idiopathic nephrotic syndrome and appeared to be markers of disease activity. Their binding at the slit diaphragm induced podocyte dysfunction and nephrotic syndrome, which highlights their pathophysiological significance. (Funded by Deutsche Forschungsgemeinschaft and others.).
Abstract
Objective: There is a strong clinical association between IBD and primary sclerosing cholangitis (PSC), a chronic disease of the liver characterised by biliary inflammation that leads to strictures and fibrosis. Approximately 60% – 80% of people with PSC will also develop IBD (PSC-IBD). One hypothesis explaining this association would be that PSC drives IBD. Therefore, our aim was to test this hypothesis and to decipher the underlying mechanism.
Design: Colitis severity was analysed in experimental mouse models of colitis and sclerosing cholangitis, and people with IBD and PSC-IBD. Foxp3+ Treg-cell infiltration was assessed by qPCR and flow cytometry. Microbiota profiling was carried out from faecal samples of people with IBD, PSC-IBD and mouse models recapitulating these diseases. Faecal microbiota samples collected from people with IBD and PSC-IBD were transplanted into germ-free mice followed by colitis induction.
Results: We show that sclerosing cholangitis attenuated IBD in mouse models. Mechanistically, sclerosing cholangitis causes an altered intestinal microbiota composition, which promotes Foxp3+ Treg-cell expansion, and thereby protects against IBD. Accordingly, sclerosing cholangitis promotes IBD in the absence of Foxp3+ Treg cells. Furthermore, people with PSC-IBD have an increased Foxp3+ expression in the colon and an overall milder IBD severity. Finally, by transplanting faecal microbiota into gnotobiotic mice, we showed that the intestinal microbiota of people with PSC protects against colitis.
Conclusion: This study shows that PSC attenuates IBD and provides a comprehensive insight into the mechanisms involved in this effect.
Abstract
Background & Aims: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo.
Methods: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10.
Results: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions.
Conclusions: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases.
Impact and implications: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.
Liver Lab
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;
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.
Kidney Immunology
Abstract
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a life-threatening autoimmune disease that often results in kidney failure caused by crescentic glomerulonephritis (GN). To date, treatment of most patients with ANCA-GN relies on non-specific immunosuppressive agents, which may have serious adverse effects and be only partially effective. Here, using spatial and single-cell transcriptome analysis, we characterize inflammatory niches in kidney samples from 34 patients with ANCA-GN and identify proinflammatory, cytokine-producing CD4+ and CD8+ T cells as a pathogenic signature. We then utilize these transcriptomic profiles for digital pharmacology and identify ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, as the strongest therapeutic drug to use. Moreover, four patients with relapsing ANCA-GN are treated with ustekinumab in combination with low-dose cyclophosphamide and steroids, with ustekinumab given subcutaneously (90 mg) at weeks 0, 4, 12, and 24. Patients are followed up for 26 weeks to find this treatment well-tolerated and inducing clinical responses, including improved kidney function and Birmingham Vasculitis Activity Score, in all ANCA-GN patients. Our findings thus suggest that targeting of pathogenic T cells in ANCA-GN patients with ustekinumab might represent a potential approach and warrants further investigation in clinical trials.
Abstract
Pro-inflammatory CD4+ T cells are major drivers of autoimmune diseases, yet therapies modulating T cell phenotypes to promote an anti-inflammatory state are lacking. Here, we identify T helper 17 (TH17) cell plasticity in the kidneys of patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis on the basis of single-cell (sc) T cell receptor analysis and scRNA velocity. To uncover molecules driving T cell polarization and plasticity, we established an in vivo pooled scCRISPR droplet sequencing (iCROP-seq) screen and applied it to mouse models of glomerulonephritis and colitis. CRISPR-based gene targeting in TH17 cells could be ranked according to the resulting transcriptional perturbations, and polarization biases into T helper 1 (TH1) and regulatory T cells could be quantified. Furthermore, we show that iCROP-seq can facilitate the identification of therapeutic targets by efficient functional stratification of genes and pathways in a disease- and tissue-specific manner. These findings uncover TH17 to TH1 cell plasticity in the human kidney in the context of renal autoimmunity.
Publications 2023
Gagliani Lab
Abstract
Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time, but the health consequences of this short-term consumption of energy-dense nutrients are unclear. Here, we show that short-term reiterative switching to 'feast diets', mimicking our social eating behavior, breaches the potential buffering effect of the intestinal microbiota and reorganizes the immunological architecture of mucosa-associated lymphoid tissues. The first dietary switch was sufficient to induce transient mucosal immune depression and suppress systemic immunity, leading to higher susceptibility to Salmonella enterica serovar Typhimurium and Listeria monocytogenes infections. The ability to respond to antigenic challenges with a model antigen was also impaired. These observations could be explained by a reduction of CD4+ T cell metabolic fitness and cytokine production due to impaired mTOR activity in response to reduced microbial provision of fiber metabolites. Reintroducing dietary fiber rewired T cell metabolism and restored mucosal and systemic CD4+ T cell functions and immunity. Finally, dietary intervention with human volunteers confirmed the effect of short-term dietary switches on human CD4+ T cell functionality. Therefore, short-term nutritional changes cause a transient depression of mucosal and systemic immunity, creating a window of opportunity for pathogenic infection.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second most deadly cancer by 2040, owing to the high incidence of metastatic disease and limited responses to treatment. Less than half of all patients respond to the primary treatment for PDAC, chemotherapy, and genetic alterations alone cannot explain this. Diet is an environmental factor that can influence the response to therapies, but its role in PDAC is unclear. Here, using shotgun metagenomic sequencing and metabolomic screening, we show that the microbiota-derived tryptophan metabolite indole-3-acetic acid (3-IAA) is enriched in patients who respond to treatment. Faecal microbiota transplantation, short-term dietary manipulation of tryptophan and oral 3-IAA administration increase the efficacy of chemotherapy in humanized gnotobiotic mouse models of PDAC. Using a combination of loss- and gain-of-function experiments, we show that the efficacy of 3-IAA and chemotherapy is licensed by neutrophil-derived myeloperoxidase. Myeloperoxidase oxidizes 3-IAA, which in combination with chemotherapy induces a downregulation of the reactive oxygen species (ROS)-degrading enzymes glutathione peroxidase 3 and glutathione peroxidase 7. All of this results in the accumulation of ROS and the downregulation of autophagy in cancer cells, which compromises their metabolic fitness and, ultimately, their proliferation. In humans, we observed a significant correlation between the levels of 3-IAA and the efficacy of therapy in two independent PDAC cohorts. In summary, we identify a microbiota-derived metabolite that has clinical implications in the treatment of PDAC, and provide a motivation for considering nutritional interventions during the treatment of patients with cancer.
Huber Lab
Abstract
Current therapies for Fabry disease are based on reversing intracellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement therapy (ERT) or chaperone-mediated stabilization of the defective enzyme, thereby alleviating lysosomal dysfunction. However, their effect in the reversal of end-organ damage, like kidney injury and chronic kidney disease, remains unclear. In this study, ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not reverse podocyte injury. Then, a CRISPR/Cas9-mediated α-galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptome-based connectivity mapping and SILAC-based quantitative proteomics identified α-synuclein (SNCA) accumulation as a key event mediating podocyte injury. Genetic and pharmacological inhibition of SNCA improved lysosomal structure and function in Fabry podocytes, exceeding the benefits of ERT. Together, this work reconceptualizes Fabry-associated cell injury beyond Gb3 accumulation, and introduces SNCA modulation as a potential intervention, especially for patients with Fabry nephropathy.
Abstract
Expansion microscopy physically enlarges biological specimens to achieve nanoscale resolution using diffraction-limited microscopy systems. However, optimal performance is usually reached using laser-based systems (for example, confocal microscopy), restricting its broad applicability in clinical pathology, as most centres have access only to light-emitting diode (LED)-based widefield systems. As a possible alternative, a computational method for image resolution enhancement, namely, super-resolution radial fluctuations (SRRF), has recently been developed. However, this method has not been explored in pathology specimens to date, because on its own, it does not achieve sufficient resolution for routine clinical use. Here, we report expansion-enhanced super-resolution radial fluctuations (ExSRRF), a simple, robust, scalable and accessible workflow that provides a resolution of up to 25 nm using LED-based widefield microscopy. ExSRRF enables molecular profiling of subcellular structures from archival formalin-fixed paraffin-embedded tissues in complex clinical and experimental specimens, including ischaemic, degenerative, neoplastic, genetic and immune-mediated disorders. Furthermore, as examples of its potential application to experimental and clinical pathology, we show that ExSRRF can be used to identify and quantify classical features of endoplasmic reticulum stress in the murine ischaemic kidney and diagnostic ultrastructural features in human kidney biopsies.
Abstract
Membranous nephropathy (MN) is an antibody-mediated autoimmune disease characterized by glomerular immune complexes containing complement components. However, both the initiation pathways and the pathogenic significance of complement activation in MN are poorly understood. Here, we show that components from all three complement pathways (alternative, classical and lectin) are found in renal biopsies from patients with MN. Proximity ligation assays to directly visualize complement assembly in the tissue reveal dominant activation via the classical pathway, with a close correlation to the degree of glomerular C1q-binding IgG subclasses. In an antigen-specific autoimmune mouse model of MN, glomerular damage and proteinuria are reduced in complement-deficient mice compared with wild-type littermates. Severe disease with progressive ascites, accompanied by extensive loss of the integral podocyte slit diaphragm proteins, nephrin and neph1, only occur in wild-type animals. Finally, targeted silencing of C3 using RNA interference after the onset of proteinuria significantly attenuates disease. Our study shows that, in MN, complement is primarily activated via the classical pathway and targeting complement components such as C3 may represent a promising therapeutic strategy.
Liver Lab
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.
Kidney Immunology
Abstract
Adaptation of immune cells to tissue-specific microenvironments is a crucial process in homeostasis and inflammation. Here, we show that murine effector type 2 innate lymphoid cells (ILC2s) from various organs are equally effective in repopulating ILC2 niches in other anatomical locations where they adapt tissue-specific phenotypes of target organs. Single-cell transcriptomics of ILC2 populations revealed upregulation of retinoic acid (RA) signaling in ILC2s during adaptation to the small intestinal microenvironment, and RA signaling mediated reprogramming of kidney effector ILC2s toward the small intestinal phenotype in vitro and in vivo. Inhibition of intestinal ILC2 adaptation by blocking RA signaling impaired worm expulsion during Strongyloides ratti infection, indicating functional importance of ILC2 tissue imprinting. In conclusion, this study highlights that effector ILC2s retain the ability to adapt to changing tissue-specific microenvironments, enabling them to exert tissue-specific functions, such as promoting control of intestinal helminth infections.
Abstract
GM-CSF in glomerulonephritisDespite glomerulonephritis being an immune-mediated disease, the contributions of individual immune cell types are not clear. To address this gap in knowledge, Paust et al. characterized pathological immune cells in samples from patients with glomerulonephritis and in samples from mice with the disease. The authors found that CD4+ T cells producing granulocyte-macrophage colony-stimulating factor (GM-CSF) licensed monocytes to promote disease by producing matrix metalloproteinase 12 and disrupting the glomerular basement membrane. Targeting GM-CSF to inhibit this axis reduced disease severity in mice, implicating this cytokine as a potential therapeutic target for patients with glomerulonephritis.
Abstract
γδ T cells are involved in the control of Staphylococcus aureus infection, but their importance in protection compared to other T cells is unclear. We used a mouse model of systemic S. aureusinfection associated with high bacterial load and persistence in the kidney. Infection caused fulminant accumulation of γδ T cells in the kidney. Renal γδ T cells acquired tissue residency and were maintained in high numbers during chronic infection. At day 7, up to 50% of renal γδ T cells produced IL-17A in situ and a large fraction of renal γδ T cells remained IL-17A+ during chronic infection. Controlled depletion revealed that γδ T cells restricted renal S. aureus replication in the acute infection and provided protection during chronic renal infection and upon reinfection. Our results demonstrate that kidney-resident γδ T cells are nonredundant in limiting local S. aureus growth during chronic infection and provide enhanced protection against reinfection.