Platelet and fibrin clots occlude blood vessels in hemostasis and thrombosis. Here we report a noncanonical mechanism for vascular occlusion based on neutrophil extracellular traps (NETs), DNA fibers ...released by neutrophils during inflammation. We investigated which host factors control NETs in vivo and found that two deoxyribonucleases (DNases), DNase1 and DNase1-like 3, degraded NETs in circulation during sterile neutrophilia and septicemia. In the absence of both DNases, intravascular NETs formed clots that obstructed blood vessels and caused organ damage. Vascular occlusions in patients with severe bacterial infections were associated with a defect to degrade NETs ex vivo and the formation of intravascular NET clots. DNase1 and DNase1-like 3 are independently expressed and thus provide dual host protection against deleterious effects of intravascular NETs.
Dendritic cells (DCs) are chief inducers of adaptive immunity and regulate local inflammatory responses across the body. Together with macrophages, the other main type of mononuclear phagocyte, DCs ...constitute the most abundant component of the intrarenal immune system. This network of functionally specialized immune cells constantly surveys its microenvironment for signs of injury or infection, which trigger the initiation of an immune response. In the healthy kidney, DCs coordinate effective immune responses, for example, by recruiting neutrophils for bacterial clearance in pyelonephritis. The pro-inflammatory actions of DCs can, however, also contribute to tissue damage in various types of acute kidney injury and chronic glomerulonephritis, as DCs recruit and activate effector T cells, which release toxic mediators and maintain tubulointerstitial immune infiltrates. These actions are counterbalanced by DC subsets that promote the activation and maintenance of regulatory T cells to support resolution of the immune response and allow kidney repair. Several studies have investigated the multiple roles for DCs in kidney homeostasis and disease, but it has become clear that current tools and subset markers are not sufficient to accurately distinguish DCs from macrophages. Multidimensional transcriptomic analysis studies promise to improve mononuclear phagocyte classification and provide a clearer view of DC ontogeny and subsets.
The cause of paraneoplastic membranous nephropathy is unclear. In the current case, new expression of THSD7A in a gallbladder carcinoma and the development of membranous nephropathy may indicate a ...potential mechanism for the association between cancer and this nephropathy.
To the Editor:
An association between membranous nephropathy and malignant tumors has been known for decades.
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It was hypothesized that circulating, preformed immune complexes containing tumor antigens deposit in the glomeruli and induce membranous nephropathy; however, this hypothesis no longer appears to explain how subepithelial immune deposition occurs.
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The in situ binding of antibodies to endogenous antigens, which is strongly supported by the characterization of phospholipase A
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receptor 1 and thrombospondin type-1 domain-containing 7A (THSD7A) as podocyte antigens in membranous nephropathy, constitutes the most probable established mechanism for the formation of subepithelial deposits of immune complexes.
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It is . . .
Therapeutic targeting of IL-17A and its receptor IL-17RA with antibodies has turned out to be a tremendous success in the treatment of several autoimmune conditions. As the IL-17 cytokine family ...consists of six members (IL-17A to F), it is intriguing to elucidate the biological function of these five other molecules to identify more potential targets. In the past decade, IL-17C has emerged as quite a unique member of this pro-inflammatory cytokine group. In contrast to the well-described IL-17A and IL-17F, IL-17C is upregulated at very early timepoints of several disease settings. Also, the cellular source of the homodimeric cytokine differs from the other members of the family: Epithelial rather than hematopoietic cells were identified as the producers of IL-17C, while its receptor IL-17RE is expressed on T
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17 cells as well as the epithelial cells themselves. Numerous investigations led to the current understanding that IL-17C (a) maintains an autocrine loop in the epithelium reinforcing innate immune barriers and (b) stimulates highly inflammatory T
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17 cells. Functionally, the IL-17C/RE axis has been described to be involved in the pathogenesis of several diseases ranging from infectious and autoimmune conditions to cancer development and progression. This body of evidence has paved the way for the first clinical trials attempting to neutralize IL-17C in patients. Here, we review the latest knowledge about identification, regulation, and function of the IL-17C/IL-17receptor E pathway in inflammation and immunity, with a focus on the mechanisms underlying tissue injury. We also discuss the rationale for the translation of these findings into new therapeutic approaches in patients with immune-mediated disease.
This open-label trial randomly assigned patients with IgA nephropathy to supportive care or supportive care plus immunosuppression. The added immunosuppression did not significantly improve outcomes; ...more adverse events occurred, with no change in the rate of decrease in eGFR.
IgA nephropathy is the most common form of glomerulonephritis.
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Several findings support the use of immunosuppressive therapy to target mesangial IgA deposits and circulating IgA autoantibodies.
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The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines regarding IgA nephropathy recommend treatment with a blocker of the renin–angiotensin system (i.e., an angiotensin-converting–enzyme inhibitor or an angiotensin II–receptor blocker) in patients who have proteinuria with urinary protein excretion of more than 1 g per day.
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The KDIGO guidelines also suggest the use of systemic glucocorticoids in patients who have a proteinuria level above 1 g of urinary protein excretion per day and a . . .
IL-9 fate reporter mice established type 2 innate lymphoid cells (ILC2s) as major producers of this cytokine in vivo. Here we focus on the role of IL-9 and ILC2s during the lung stage of infection ...with Nippostrongylus brasiliensis, which results in substantial tissue damage. IL-9 receptor (IL-9R)-deficient mice displayed reduced numbers of ILC2s in the lung after infection, resulting in impaired IL-5, IL-13, and amphiregulin levels, despite undiminished numbers of Th2 cells. As a consequence, the restoration of tissue integrity and lung function was strongly impaired in the absence of IL-9 signaling. ILC2s, in contrast to Th2 cells, expressed high levels of the IL-9R, and IL-9 signaling was crucial for the survival of activated ILC2s in vitro. Furthermore, ILC2s in the lungs of infected mice required the IL-9R to up-regulate the antiapoptotic protein BCL-3 in vivo. This highlights a unique role for IL-9 as an autocrine amplifier of ILC2 function, promoting tissue repair in the recovery phase after helminth-induced lung inflammation.
Single-cell biology is transforming the ability of researchers to understand cellular signaling and identity across medical and biological disciplines. Especially for immune-mediated diseases, a ...single-cell look at immune cell subtypes, signaling, and activity might yield fundamental insights into the disease etiology, mechanisms, and potential therapeutic interventions. In this review, we highlight recent advances in the field of single-cell RNA profiling and their application to understand renal function in health and disease. With a focus on the immune system, in particular on T cells, we propose some key directions of understanding renal inflammation using single-cell approaches. We detail the benefits and shortcomings of the various technological approaches outlined and give advice on potential pitfalls and challenges in experimental setup and computational analysis. Finally, we conclude with a brief outlook into a promising future for single-cell technologies to elucidate kidney function.
The discovery of tissue-resident memory T cells (T
cells) reinterpreted the potential of human tissue-specific immunity. Following T cell receptor (TCR) activation and clonal expansion, effector T ...cells migrate to peripheral tissues where they remain long-term and differentiate to T
cells after antigen clearance. This allows for prompt immunological responses upon antigen re-encounter. In addition to their protective properties in acute infections, recent studies have revealed that T
cells might lead to aggravation of autoimmune diseases, such as lupus nephritis (LN) and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). These diseases present as proliferative and crescentic glomerulonephritis (cGN), which is a life-threatening condition leading to end-stage renal disease (ESRD) if left untreated. A better understanding of renal T
cells might lead to identifying new therapeutic targets for relapsing autoimmune diseases of the kidney. In this review, we summarize the current knowledge of renal T
cells and discuss their potential pathophysiological roles in renal autoimmune diseases.
We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East ...Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.
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