Publications by authors named "Paust H"

Th17 cells play crucial roles in host defense and the pathogenesis of autoimmune diseases in the skin. While their differentiation mechanisms have been extensively studied, the origin of skin Th17 cells remains unclear. In this study, we analyzed single-cell RNA-sequencing data and identify the presence of Th17 cells in the human thymus.

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  • ANCA-associated vasculitis is a severe autoimmune disease that can lead to kidney failure due to crescentic glomerulonephritis, and current treatments using non-specific immunosuppressive drugs may be insufficient and carry risks.
  • Researchers analyzed kidney samples from 34 patients with ANCA-GN and identified specific inflammatory T cells that contribute to the disease, leading to the discovery of ustekinumab as a promising targeted treatment.
  • In a trial, four patients with recurring ANCA-GN treated with ustekinumab and low-dose cyclophosphamide showed significant improvement in kidney function and overall health, indicating potential for this approach to be further explored in clinical settings.
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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 (T17) 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.

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T regulatory type 1 (Tr1) cells, which are defined by their regulatory function, lack of Foxp3, and high expression of IL-10, CD49b, and LAG-3, are known to be able to suppress Th1 and Th17 in the intestine. Th1 and Th17 cells are also the main drivers of crescentic glomerulonephritis (GN), the most severe form of renal autoimmune disease. However, whether Tr1 cells emerge in renal inflammation and, moreover, whether they exhibit regulatory function during GN have not been thoroughly investigated yet.

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Introduction: The chemokine receptor CCR4 is expressed by diverse CD4+ T cell subsets including regulatory T cells (Tregs) but its functional importance for leukocyte recruitment and the relevance of its two corresponding chemokines CCL17 and CCL22 have not been studied in immune-mediated crescentic glomerulonephritis (cGN).

Methods: Utilizing the single-cell RNA sequencing (scRNAseq) data in analyzing leukocytes isolated from both human and murine nephritic kidneys, we identified CCL17 as a potential therapeutic target in immune-mediated renal disease. Using a mouse model of murine cGN, we then delineated the effects of targeting CCL17 by neutralizing antibodies and in Ccl17 gene-deficient mice.

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Ischemia-reperfusion injury (IRI) is one of the major causes of acute kidney injury (AKI), and experimental work has revealed detailed insight into the inflammatory response in the kidney. T cells and NFκB pathway play an important role in IRI. Therefore, we examined the regulatory role and mechanisms of IkappaB kinase 1 (IKK1) in CD4T lymphocytes in an experimental model of IRI.

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  • Scientists found a special group of immune cells called RORγt Tregs that help control the immune response in kidney diseases, particularly glomerulonephritis (GN).
  • When they studied mice without these cells, they discovered that kidney damage got worse, showing that RORγt Tregs are important for protecting the kidneys.
  • The research showed that RORγt Tregs are good at reducing inflammation and might be useful for new treatments for kidney diseases in humans.
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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 . characterized pathological immune cells in samples from patients with glomerulonephritis and in samples from mice with the disease.

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Significance Statement: T-cell infiltration is a hallmark of crescentic GN (cGN), often caused by ANCA-associated vasculitis. Pathogenic T-cell subsets, their clonality, and downstream effector mechanisms leading to kidney injury remain to be fully elucidated. Single-cell RNA sequencing and T-cell receptor sequencing revealed activated, clonally expanded cytotoxic CD4 + and CD8 + T cells in kidneys from patients with ANCA-associated cGN.

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Glucocorticoids remain a cornerstone of therapeutic regimes for autoimmune and chronic inflammatory diseases - for example, in different forms of crescentic glomerulonephritis - because of their rapid antiinflammatory effects, low cost, and wide availability. Despite their routine use for decades, the underlying cellular mechanisms by which steroids exert their therapeutic effects need to be fully elucidated. Here, we demonstrate that high-dose steroid treatment rapidly reduced the number of proinflammatory CXCR3+CD4+ T cells in the kidney by combining high-dimensional single-cell and morphological analyses of kidney biopsies from patients with antineutrophil cytoplasmic antibody-associated (ANCA-associated) crescentic glomerulonephritis.

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Staphylococcus aureus is frequently detected in patients with sepsis and thus represents a major health burden worldwide. CD4+ T helper cells are involved in the immune response to S. aureus by supporting antibody production and phagocytosis.

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Background: IL-17A-producing CD4 T helper (T17) cells play a critical role in autoimmune and chronic inflammatory diseases, such as crescentic GN. The proinflammatory effects of IL-17 are mediated by the activation of the IL-17RA/IL-17RC complex. Although the expression of these receptors on epithelial and endothelial cells is well characterized, the IL-17 receptor expression pattern and function on hematopoietic cells, , CD4 T cell subsets, remains to be elucidated.

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  • Hyperinflammation is a key factor in lung injury and high mortality rates in severe COVID-19 cases, leading to acute respiratory distress syndrome (ARDS).
  • Researchers studied immune cells from the lungs and blood of severe COVID-19 patients and found a specific type of T cell, called Trm17 cells, that persists even after the virus is cleared.
  • These Trm17 cells produce cytokines associated with inflammation and may interact with other immune cells, contributing to the severe symptoms and lung damage seen in COVID-19 patients.
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Although it is well established that microbial infections predispose to autoimmune diseases, the underlying mechanisms remain poorly understood. After infection, tissue-resident memory T (T) cells persist in peripheral organs and provide immune protection against reinfection. However, whether T cells participate in responses unrelated to the primary infection, such as autoimmune inflammation, is unknown.

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Immune-mediated glomerular diseases like crescentic glomerulonephritis (cGN) are driven by inappropriately regulated cellular and humoral immune responses subsequently leading to renal tissue injury. Recent studies demonstrated the crucial role for regulatory T cells (Tregs) in suppressing pathogenic T-cell responses during nephrotoxic nephritis (NTN), a murine model of cGN. However, mechanisms of immune regulation in cGN are less clear.

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Anti-glomerular basement membrane (anti-GBM) disease is characterized by antibodies and T cells directed against the Goodpasture antigen, the noncollagenous domain of the α3-chain of type IV collagen [α3(IV)NC1] of the GBM. Consequences are the deposition of autoantibodies along the GBM and the development of crescentic glomerulonephritis (GN) with rapid loss of renal function. Forkhead box protein P3 (Foxp3) regulatory T (Treg) cells are crucial for the maintenance of peripheral tolerance to self-antigens and the prevention of immunopathology.

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Immune-mediated glomerular diseases (glomerulonephritis) encompass a heterogeneous collection of diseases that cause inflammation within the glomerulus and other renal compartments with significant morbidity and mortality. In general, CD4 T cells orchestrate the immune response and play a unique role in autoimmune and chronic inflammatory diseases. In particular, the characterization of a distinct, IL-17 cytokines producing CD4 T cell subset named T17 cells has significantly advanced the current understanding of the pathogenic mechanisms of organ-specific immunity.

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Experimental nephrotoxic serum nephritis (NTN) is a model for T-cell-mediated human rapid progressive glomerulonephritis. T-cell receptor stimulation involves intracellular signaling events that ultimately lead to the activation of transcription factors, such as NF-κB. We explored the involvement of the NF-κB components IKK-2 and NEMO in NTN, by using cell-specific knockouts of IKK-2 and NEMO in CD4 T lymphocytes.

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The role of CXCR1, also known as fractalkine receptor, in hypertension is unknown. The present study determined the role of the fractalkine receptor CXCR1 in hypertensive renal and cardiac injury. Expression of CXCR1 was determined using CXCR1 mice that express a green fluorescent protein (GFP) reporter in CXCR1 cells.

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The IL-17 cytokine family and the cognate receptors thereof have a unique role in organ-specific autoimmunity. Most studies have focused on the founding member of the IL-17 family, IL-17A, as the central mediator of diseases. Indeed, although pathogenic functions have been ascribed to IL-17A and IL-17F in the context of immune-mediated glomerular diseases, the specific functions of the other IL-17 family members in immunity and inflammatory kidney diseases is largely unknown.

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Th17 cells are most abundant in the gut, where their presence depends on the intestinal microbiota. Here, we examined whether intestinal Th17 cells contribute to extra-intestinal Th17 responses in autoimmune kidney disease. We found high frequencies of Th17 cells in the kidneys of patients with antineutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis.

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Acute kidney injury (AKI) is associated with poor patient outcome and a global burden for end-stage renal disease. Ischemia-reperfusion injury (IRI) is one of the major causes of AKI, and experimental work has revealed many details of the inflammatory response in the kidney, such as activation of the NF-κB pathway. Here, we investigated whether deletion of the NF-κB kinases IKK2 or NEMO in lymphocytes or systemic inhibition of IKK2 would cause different kidney inflammatory responses after IRI induction.

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The ability of CD4(+) T cells to differentiate into pathogenic Th1 and Th17 or protective T regulatory cells plays a pivotal role in the pathogenesis of autoimmune diseases. Recent data suggest that CD4(+) T cell subsets display a considerable plasticity. This plasticity seems to be a critical factor for their pathogenicity, but also for the potential transition of pathogenic effector T cells toward a more tolerogenic phenotype.

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The T17 immune response has a central role in the pathogenesis of autoimmune diseases, implicating the T17 master cytokine, IL-17A, as the critical mediator of diseases such as human and experimental crescentic GN. However, the relative importance of additional T17 effector cytokines, including IL-17F, in immune-mediated tissue injury remains to be fully elucidated. Here, using a mouse model of acute crescentic GN (nephrotoxic nephritis), we identified CD4 T cells and γδ T cells as the major cellular source of IL-17F in the inflamed kidney.

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Article Synopsis
  • Tregs (regulatory T cells) play a crucial role in controlling immune responses during inflammation and autoimmune diseases, but how they migrate to affected areas is not fully understood.
  • In patients with an autoimmune kidney condition, Tregs that express the CXCR3 receptor are found to cluster with effector T cells in the kidneys.
  • Research using mice lacking CXCR3 in Tregs showed that this receptor is vital for Treg migration to the kidneys, helping to manage TH1 immune responses; without it, the inflammation worsens but can be treated with anti-IFNγ therapy.
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