B cells have a central role in many autoimmune diseases, including in those with renal involvement, as well as in the immunological response to kidney transplantation. The majority of B cell studies have focused on their pathological role as antibody producers. However, these cells have broad functions in immune responses beyond immunoglobulin secretion, including antigen presentation to T cells and cytokine production. Importantly, not all B cell subsets enhance immune responses. Regulatory B (Breg) cells attenuate inflammation and contribute to the maintenance of immune tolerance. Breg cells are numerically deficient and/or dysfunctional in several autoimmune diseases that can affect the kidneys, including systemic lupus erythematosus and anti-neutrophil cytoplasmic antibody-associated vasculitis, as well as in some groups of renal transplant recipients with alloimmune graft damage. B cell-targeting biologics have been trialled with promising results in diverse immune-mediated renal conditions. These therapies can affect both pro-inflammatory B cells and Breg cells, potentially limiting their long-term efficacy. Future strategies might involve the modulation of pro-inflammatory B cells in combination with the stimulation of regulatory subsets. Additionally, the monitoring of individual B cell subsets in patients may lead to the discovery of novel biomarkers that could help to predict disease relapse or progression.

/pdf/effector-and-regulatory-b-cells-in-immune-mediated-kidney-2xo1y4ddho.pdf

Effector and regulatory B cells in immune-mediated kidney disease

Goodpasture's or anti-glomerular basement membrane (GBM) disease is classically characterized by the presence of circulating autoantibodies directed against the non-collagenous domain of the α3 chain of type IV collagen, targeting glomerular and alveolar basement membranes, and associated with rapidly progressive crescentic glomerulonephritis, with alveolar haemorrhage in over half the patients. However, there are increasing examples of variants or atypical presentations of this disease, and novel therapeutic options have been proposed, which nephrologists should be aware of. The pathophysiology of this condition has been understood through molecular analysis of the antibody-antigen interactions and the use of human leucocyte antigen-transgenic animals, while the association of anti-GBM antibodies with anti-neutrophil cytoplasm antibodies and their combined impact on disease phenotype is increasingly recognized, providing some insights into the basis of glomerular damage and autoimmunity.

/pdf/diagnostic-and-management-challenges-in-goodpasture-s-anti-5fyx93fswl.pdf

Diagnostic and management challenges in Goodpasture's (anti-glomerular basement membrane) disease.

Background There is a growing public concern about diabetic kidney disease (DKD), which poses a severe threat to human health and life. It is important to discover noninvasive and sensitive immune-associated biomarkers that can be used to predict DKD development. ScRNA-seq and transcriptome sequencing were performed here to identify cell types and key genes associated with DKD. Methods Here, this study conducted the analysis through five microarray datasets of DKD (GSE131882, GSE1009, GSE30528, GSE96804, and GSE104948) from gene expression omnibus (GEO). We performed single-cell RNA sequencing analysis (GSE131882) by using CellMarker and CellPhoneDB on public datasets to identify the specific cell types and cell-cell interaction networks related to DKD. DEGs were identified from four datasets (GSE1009, GSE30528, GSE96804, and GSE104948). The regulatory relationship between DKD-related characters and genes was evaluated by using WGCNA analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) datasets were applied to define the enrichment of each term. Subsequently, immune cell infiltration between DKD and the control group was identified by using the “pheatmap” package, and the connection Matrix between the core genes and immune cell or function was illuminated through the “corrplot” package. Furthermore, RcisTarget and GSEA were conducted on public datasets for the analysis of the regulation relationship of key genes and it revealed the correlation between 3 key genes and top the 20 genetic factors involved in DKD. Finally, the expression of key genes between patients with 35 DKD and 35 healthy controls were examined by ELISA, and the relationship between the development of DKD rate and hub gene plasma levels was assessed in a cohort of 35 DKD patients. In addition, we carried out immunohistochemistry and western blot to verify the expression of three key genes in the kidney tissue samples we obtained. Results There were 8 cell types between DKD and the control group, and the number of connections between macrophages and other cells was higher than that of the other seven cell groups. We identified 356 different expression genes (DEGs) from the RNA-seq, which are enriched in urogenital system development, kidney development, platelet alpha granule, and glycosaminoglycan binding pathways. And WGCNA was conducted to construct 13 gene modules. The highest correlations module is related to the regulation of cell adhesion, positive regulation of locomotion, PI3K-Akt, gamma response, epithelial-mesenchymal transition, and E2F target signaling pathway. Then we overlapped the DEGs, WGCNA, and scRNA-seq, SLIT3, PDE1A and CFH were screened as the closely related genes to DKD. In addition, the findings of immunological infiltration revealed a remarkable positive link between T cells gamma delta, Macrophages M2, resting mast cells, and the three critical genes SLIT3, PDE1A, and CFH. Neutrophils were considerably negatively connected with the three key genes. Comparatively to healthy controls, DKD patients showed high levels of SLIT3, PDE1A, and CFH. Despite this, higher SLIT3, PDE1A, and CFH were associated with an end point rate based on a median follow-up of 2.6 years. And with the gradual deterioration of DKD, the expression of SLIT3, PDE1A, and CFH gradually increased. Conclusions The 3 immune-associated genes could be used as diagnostic markers and therapeutic targets of DKD. Additionally, we found new pathogenic mechanisms associated with immune cells in DKD, which might lead to therapeutic targets against these cells.

/pdf/single-cell-rna-and-transcriptome-sequencing-profiles-got4e57g.pdf

Single-cell RNA and transcriptome sequencing profiles identify immune-associated key genes in the development of diabetic kidney disease

Immunoglobulin A nephropathy (IgAN) is a rare autoimmune disorder and the leading cause of biopsy-reported glomerulonephritis (GN) worldwide. Disease progression is driven by the formation and deposition of immune complexes composed of galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1 autoantibodies (anti-Gd-IgA1 antibodies) in the glomeruli, where they trigger complement-mediated inflammation that can result in loss of kidney function and end-stage kidney disease (ESKD). With the risk of progression and limited treatment options, there is an unmet need for therapies that address the formation of pathogenic Gd-IgA1 antibody and anti-Gd-IgA1 antibody-containing immune complexes. New therapeutic approaches target immunological aspects of IgAN, including complement-mediated inflammation and pathogenic antibody production by inhibiting activation or promoting depletion of B cells and CD38-positive plasma cells. This article will review therapies, both approved and in development, that support the depletion of Gd-IgA1-producing cells in IgAN and have the potential to modify the course of this disease. Ultimately, we propose here a novel therapeutic approach by depleting CD38-positive plasma cells, as the source of the autoimmunity, to treat patients with IgAN.

/pdf/new-treatment-strategies-for-iga-nephropathy-targeting-2am3116k.pdf

New Treatment Strategies for IgA Nephropathy: Targeting Plasma Cells as the Main Source of Pathogenic Antibodies

Decreased number of CD19+CD24hiCD38hi regulatory B cells in Diabetic nephropathy.

IgA nephropathy (IgAN) diagnosis remains largely based upon immunohistologic detection of IgA- and IgG-containing glomerular deposits in renal mesangial cells, and little is known about the underlying pathogenic mechanisms. This study examines the putative contribution of B cell types, including the Breg type, to IgAN pathogenesis. Twenty-four patients with IgAN and proteinuria (Group A: 3.5 g/24 h, n = 11) and 10 healthy controls were enrolled. The frequencies of B cell subtypes in venous blood were measured by flow cytometry. Galactose-deficient IgA1 was measurement by ELISA. Needle biopsies were analysed by histology and immunofluorescence microscopy. Correlation between clinical features and B cell subtypes, including the regulatory B (Breg) cells, and Breg cell-derived immunomodulatory cytokine IL-10 was assessed by Spearman's rank correlation test. IgAN patients had significantly higher frequencies of CD27(+) CD19(+) , CD38(+) CD19(+) , CD86(+) CD19(+) and CD5(+) CD19(+) B cells than the healthy controls, but significantly lower levels of Breg cells and intracellular expression of IL-10 protein in the Breg subtype. Serum IgA concentration positively correlated with CD27(+) CD19(+) B cell frequency and negatively correlated with IL-10(+) Breg cell frequency in IgAN patients, and the percentage of CD19(+) CD5(+) CD1d(+) in CD19(+) cells was negatively correlated with the level of serum Gd-IgA1. Furthermore, the frequencies of CD19(+) CD38(+) and CD19(+) CD86(+) in the CD19(+) subpopulation negatively correlated with the estimated glomerular filtration rate of IgAN patients. Several of the CD19(+) B cell subtypes and the IL-10(+) Breg cells are differentially expressed in IgAN patients and may contribute to the disease pathogenesis.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/sji.12128

Functional Implications of Regulatory B Cells in Human IgA Nephropathy

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Functional Implications of Regulatory B Cells in Human IgA Nephropathy