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Immune Mechanisms in Glomerulonephritis
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Immune Mechanisms in Glomerulonephritis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (20 October 2022) | Viewed by 22881

Special Issue Editor

Dr. Kathrin Eller

E-Mail Website
Guest Editor
Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
Interests: inflammation; Immune system; renal failure; Glomerulonephritis

Special Issue Information

Dear Colleagues,

Components of the innate and adaptive immune system critically mediate, but also regulate inflammation in different forms of glomerulonephritis. We do need this information to develop new therapeutic strategies to fight disease since current immunosuppressive protocol are still associated with serious short and long-term side effects such as infection, cancer and diabetes which all together increase mortality in this patient population. Recent clinical trials have shown efficacy of B-cell depleting strategies and complement inhibition in ANCA vasculitis, which would not have been possible without a fundamental understanding of immune mechanisms in this disease entity. In contrast, various immunosuppressive strategies failed in IgA nephropathy, whereas encapsuled budesonide acting locally in the terminal ileum as well as SGLT-2 inhibition improved the outcome. Still, pathomechanisms responsible for these protective effects are largely unknown.

The primary focus of this of this topic will be reviews and research articles, which explore immune mechanisms in various glomerulonephritis entities and current as well as novel immune-modulating/inhibiting strategies in the treatment of glomerulonephritis.

Dr. Kathrin Eller
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • glomerulonephritis
  • complement
  • T cells
  • B cells
  • Innate immune cells
  • Chemokines

Published Papers (6 papers)

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Research

Jump to: Review

14 pages, 2080 KiB  
Article
Glomerular Galactose-Deficient IgA1(KM55) Positive May Predict Poorer Prognosis in Coexisting Primary Membranous Nephropathy and IgA Nephropathy Patients
by Wenrong Cheng, Guoqin Wang, Weiyi Guo, Lijun Sun, Xiaoyi Xu, Hongrui Dong, Suhua Ye, Yanqiu Geng and Hong Cheng
Cells 2023, 12(1), 116; https://doi.org/10.3390/cells12010116 - 28 Dec 2022
Viewed by 1886
Abstract
Primary membrane nephropathy (PMN) and IgA nephropathy (IgAN) are the most common glomerular diseases in China. Because of different pathogenesis, prognosis is significantly different. When the two diseases coexist (PMN/IgAN), the clinicopathological manifestations and prognosis remain unclear. In the present study, we analyzed [...] Read more.
Primary membrane nephropathy (PMN) and IgA nephropathy (IgAN) are the most common glomerular diseases in China. Because of different pathogenesis, prognosis is significantly different. When the two diseases coexist (PMN/IgAN), the clinicopathological manifestations and prognosis remain unclear. In the present study, we analyzed the clinicopathological characteristics of PMN/IgAN patients, with only IgA deposition (PMN/IgA deposition) patients as controls. Galactose-deficient IgA1(KM55) and M-type Phospholipase A2 Receptor(PLA2R), both in circulation and renal tissues, were detected. Furthermore, prognosis of PMN/IgAN was explored. We found that PMN/IgAN also had some clinical features of IgAN in addition to PMN, such as higher serum albumin, along with a similar heavy proteinuria and lower titers of serum anti-PLA2R antibody. The positive rate of glomerular KM55 in PMN/IgAN was 23.5% (20/85), and 0% (0/29) in PMN/IgA deposition. Among those glomerular KM55 positive patients, KM55 and IgA colocalized mainly along the glomerular mesangial and capillary areas. Unfortunately, there was no significant difference in serum level of Gd-IgA1 between KM55+ and KM55− subgroups in PMN/IgAN patients, similar to the PMN/IgA deposition group. Notably, glomerular KM55 positive may predict a poorer prognosis in PMN/IgAN patients. In conclusion, our study suggested that, when glomerular KM55 staining was positive, this special coexisting PMN/IgAN disorder was prone to have more characteristics of IgAN besides PMN, and may predict poorer prognosis, while the mechanism requires further investigation. Full article
(This article belongs to the Special Issue Immune Mechanisms in Glomerulonephritis)
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15 pages, 7082 KiB  
Article
Low-Dose rIL-15 Protects from Nephrotoxic Serum Nephritis via CD8+ T Cells
by Agnes A. Mooslechner, Max Schuller, Katharina Artinger, Alexander H. Kirsch, Corinna Schabhüttl, Philipp Eller, Alexander R. Rosenkranz and Kathrin Eller
Cells 2022, 11(22), 3656; https://doi.org/10.3390/cells11223656 - 18 Nov 2022
Cited by 3 | Viewed by 1779
Abstract
Rapid progressive glomerulonephritis (GN) often leads to end-stage kidney disease, driving the need for renal replacement therapy and posing a global health burden. Low-dose cytokine-based immunotherapies provide a new strategy to treat GN. IL-15 is a strong candidate for the therapy of immune-mediated [...] Read more.
Rapid progressive glomerulonephritis (GN) often leads to end-stage kidney disease, driving the need for renal replacement therapy and posing a global health burden. Low-dose cytokine-based immunotherapies provide a new strategy to treat GN. IL-15 is a strong candidate for the therapy of immune-mediated kidney disease since it has proven to be tubular-protective before. Therefore, we set out to test the potential of low-dose rIL-15 treatment in a mouse model of nephrotoxic serum nephritis (NTS), mimicking immune complex-driven GN in humans. A single low-dose treatment with rIL-15 ameliorated NTS, reflected by reduced albuminuria, less tissue scarring, fewer myeloid cells in the kidney, and improved tubular epithelial cell survival. In addition, CD8+ T cells, a primary target of IL-15, showed altered gene expression and function corresponding with less cytotoxicity mediated by rIL-15. With the use of transgenic knock-out mice, antibody depletion, and adoptive cell transfer studies, we here show that the beneficial effects of rIL-15 treatment in NTS depended on CD8+ T cells, suggesting a pivotal role for them in the underlying mechanism. Our findings add to existing evidence of the association of IL-15 with kidney health and imply a potential for low-dose rIL-15 immunotherapies in GN. Full article
(This article belongs to the Special Issue Immune Mechanisms in Glomerulonephritis)
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23 pages, 3373 KiB  
Article
Antigen Cross-Presentation by Murine Proximal Tubular Epithelial Cells Induces Cytotoxic and Inflammatory CD8+ T Cells
by Alexandra Linke, Hakan Cicek, Anne Müller, Catherine Meyer-Schwesinger, Simon Melderis, Thorsten Wiech, Claudia Wegscheid, Julius Ridder, Oliver M. Steinmetz, Linda Diehl, Gisa Tiegs and Katrin Neumann
Cells 2022, 11(9), 1510; https://doi.org/10.3390/cells11091510 - 30 Apr 2022
Cited by 5 | Viewed by 2895
Abstract
Immune-mediated glomerular diseases are characterized by infiltration of T cells, which accumulate in the periglomerular space and tubulointerstitium in close contact to proximal and distal tubuli. Recent studies described proximal tubular epithelial cells (PTECs) as renal non-professional antigen-presenting cells that stimulate CD4+ [...] Read more.
Immune-mediated glomerular diseases are characterized by infiltration of T cells, which accumulate in the periglomerular space and tubulointerstitium in close contact to proximal and distal tubuli. Recent studies described proximal tubular epithelial cells (PTECs) as renal non-professional antigen-presenting cells that stimulate CD4+ T-cell activation. Whether PTECs have the potential to induce activation of CD8+ T cells is less clear. In this study, we aimed to investigate the capacity of PTECs for antigen cross-presentation thereby modulating CD8+ T-cell responses. We showed that PTECs expressed proteins associated with cross-presentation, internalized soluble antigen via mannose receptor-mediated endocytosis, and generated antigenic peptides by proteasomal degradation. PTECs induced an antigen-dependent CD8+ T-cell activation in the presence of soluble antigen in vitro. PTEC-activated CD8+ T cells expressed granzyme B, and exerted a cytotoxic function by killing target cells. In murine lupus nephritis, CD8+ T cells localized in close contact to proximal tubuli. We determined enhanced apoptosis in tubular cells and particularly PTECs up-regulated expression of cleaved caspase-3. Interestingly, induction of apoptosis in the inflamed kidney was reduced in the absence of CD8+ T cells. Thus, PTECs have the capacity for antigen cross-presentation thereby inducing cytotoxic CD8+ T cells in vitro, which may contribute to the pathology of immune-mediated glomerulonephritis. Full article
(This article belongs to the Special Issue Immune Mechanisms in Glomerulonephritis)
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Review

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15 pages, 1129 KiB  
Review
Voclosporin: Unique Chemistry, Pharmacology and Toxicity Profile, and Possible Options for Implementation into the Management of Lupus Nephritis
by Ajinath Kale, Vishwadeep Shelke, Yutian Lei, Anil Bhanudas Gaikwad and Hans-Joachim Anders
Cells 2023, 12(20), 2440; https://doi.org/10.3390/cells12202440 - 11 Oct 2023
Cited by 1 | Viewed by 2062
Abstract
Calcineurin inhibitors (CNI) can suppress allo- and autoimmunity by suppressing T cell function but also have anti-proteinuric effects by stabilizing the cellular components of the kidney’s filtration barrier. Therefore, CNI are used in autoimmune kidney diseases with proteinuria. However, the traditional CNI, cyclosporine [...] Read more.
Calcineurin inhibitors (CNI) can suppress allo- and autoimmunity by suppressing T cell function but also have anti-proteinuric effects by stabilizing the cellular components of the kidney’s filtration barrier. Therefore, CNI are used in autoimmune kidney diseases with proteinuria. However, the traditional CNI, cyclosporine A and tacrolimus, have a narrow therapeutic range, need monitoring of drug levels, and their use is associated with nephrotoxicity and metabolic alterations. Voclosporin (VOC), a novel CNI, no longer requires drug level monitoring and seems to lack these adverse effects, although hypertension and drug–drug interactions still occur. VOC demonstrated efficacy superior to standard-of-care in controlling active lupus nephritis in the phase 2 AURA-LV and the phase 3 AURORA-1 trials and was approved for the treatment of active lupus nephritis. However, how to implement VOC into the current and changing treatment landscape of lupus nephritis is still debated. Here, we review the unique chemistry, pharmacology, and toxicity profile of VOC, summarize the efficacy and safety data from the AURA-LV and AURORA-1 trials, and discuss the following four possible options to implement VOC into the management of lupus nephritis, namely regarding B cell-targeting therapy with belimumab (BEL). These include: 1. patient stratification to either VOC or BEL, 2. VOC/BEL combination therapy, 3. VOC-BEL sequential therapy, or 4. alternative options for the rapid antiproteinuric effect of VOC. Full article
(This article belongs to the Special Issue Immune Mechanisms in Glomerulonephritis)
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29 pages, 1665 KiB  
Review
Pathogenic T-Cell Responses in Immune-Mediated Glomerulonephritis
by Alexandra Linke, Gisa Tiegs and Katrin Neumann
Cells 2022, 11(10), 1625; https://doi.org/10.3390/cells11101625 - 12 May 2022
Cited by 16 | Viewed by 6258
Abstract
Glomerulonephritis (GN) comprises a group of immune-mediated kidney diseases affecting glomeruli and the tubulointerstitium. Glomerular crescent formation is a histopathological characteristic of severe forms of GN, also referred to as crescentic GN (cGN). Based on histological findings, cGN includes anti-neutrophil cytoplasmic antibody (ANCA)-associated [...] Read more.
Glomerulonephritis (GN) comprises a group of immune-mediated kidney diseases affecting glomeruli and the tubulointerstitium. Glomerular crescent formation is a histopathological characteristic of severe forms of GN, also referred to as crescentic GN (cGN). Based on histological findings, cGN includes anti-neutrophil cytoplasmic antibody (ANCA)-associated GN, a severe form of ANCA-associated vasculitis, lupus nephritis associated with systemic lupus erythematosus, Goodpasture’s disease, and IgA nephropathy. The immunopathogenesis of cGN is associated with activation of CD4+ and CD8+ T cells, which particularly accumulate in the periglomerular and tubulointerstitial space but also infiltrate glomeruli. Clinical observations and functional studies in pre-clinical animal models provide evidence for a pathogenic role of Th1 and Th17 cell-mediated immune responses in cGN. Emerging evidence further argues that CD8+ T cells have a role in disease pathology and the mechanisms of activation and function of recently identified tissue-resident CD4+ and CD8+ T cells in cGN are currently under investigation. This review summarizes the mechanisms of pathogenic T-cell responses leading to glomerular damage and renal inflammation in cGN. Advanced knowledge of the underlying immune mechanisms involved with cGN will enable the identification of novel therapeutic targets for the replacement or reduction in standard immunosuppressive therapy or the treatment of refractory disease. Full article
(This article belongs to the Special Issue Immune Mechanisms in Glomerulonephritis)
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21 pages, 2304 KiB  
Review
Pediatric Atypical Hemolytic Uremic Syndrome Advances
by Rupesh Raina, Nina Vijayvargiya, Amrit Khooblall, Manasa Melachuri, Shweta Deshpande, Divya Sharma, Kashin Mathur, Manav Arora, Sidharth Kumar Sethi and Sonia Sandhu
Cells 2021, 10(12), 3580; https://doi.org/10.3390/cells10123580 - 18 Dec 2021
Cited by 21 | Viewed by 7085
Abstract
Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by dysregulation of the alternate pathway. The diagnosis of aHUS is one of exclusion, which complicates its early detection and corresponding intervention to mitigate its high rate of mortality and associated morbidity. Heterozygous [...] Read more.
Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by dysregulation of the alternate pathway. The diagnosis of aHUS is one of exclusion, which complicates its early detection and corresponding intervention to mitigate its high rate of mortality and associated morbidity. Heterozygous mutations in complement regulatory proteins linked to aHUS are not always phenotypically active, and may require a particular trigger for the disease to manifest. This list of triggers continues to expand as more data is aggregated, particularly centered around COVID-19 and pediatric vaccinations. Novel genetic mutations continue to be identified though advancements in technology as well as greater access to cohorts of interest, as in diacylglycerol kinase epsilon (DGKE). DGKE mutations associated with aHUS are the first non-complement regulatory proteins associated with the disease, drastically changing the established framework. Additional markers that are less understood, but continue to be acknowledged, include the unique autoantibodies to complement factor H and complement factor I which are pathogenic drivers in aHUS. Interventional therapeutics have undergone the most advancements, as pharmacokinetic and pharmacodynamic properties are modified as needed in addition to their as biosimilar counterparts. As data continues to be gathered in this field, future advancements will optimally decrease the mortality and morbidity of this disease in children. Full article
(This article belongs to the Special Issue Immune Mechanisms in Glomerulonephritis)
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