Glomerulonephritis and autoimmune vasculitis are independent of P2RX7 but may depend on alternative inflammasome pathways

P2RX7, an ionotropic receptor for extracellular ATP, is expressed on immune cells, including macrophages, monocytes and dendritic cells and is up-regulated on non-immune cells following injury. P2RX7 plays a role in many biological processes, including production of pro-inflammatory cytokines such as IL-1β via the canonical inflammasome pathway. P2RX7 has been shown to be important in inflammation and fibrosis and may also play a role in autoimmunity. We have developed and phenotyped a novel P2RX7 knock-out (KO) inbred rat strain and taking advantage of the human-resembling unique histopathological features of rat models of glomerulonephritis, we induced three models of disease: nephrotoxic nephritis, experimental autoimmune glomerulonephritis, and experimental autoimmune vasculitis. We found that deletion of P2RX7 does not protect rats from models of experimental glomerulonephritis or the development of autoimmunity. Notably, treatment with A-438079, a P2RX7 antagonist, was equally protective in WKY WT and P2RX7 KO rats, revealing its 'off-target' properties. We identify a novel ATP/P2RX7/K+ efflux-independent and caspase-1/8-dependent pathway for production of IL-1β in rat dendritic cells, which was absent in macrophages. Taken together, these results comprehensively establish that inflammation and autoimmunity in glomerulonephritis is independent of P2RX7 and reveals the off-target properties of drugs previously known as selective P2RX7 antagonists. Rat mononuclear phagocytes may be able to utilise an 'alternative inflammasome' pathway to produce IL-1β independently of P2RX7, which may account for the susceptibility of P2RX7 KO rats to inflammation and autoimmunity in glomerulonephritis. This article is protected by copyright. All rights reserved

B-cell numbers and phenotype at clinical relapse following rituximab therapy differ in SLE patients according to anti-dsDNA antibody levels

Objectives. To correlate the kinetics of B-cell repopulation with relapse after B-cell depletion therapy in SLE patients and address whether variation in relapse rate, B-cell numbers and phenotype are related to anti-dsDNA antibody levels

Live imaging of monocyte subsets in immune complex-mediated glomerulonephritis reveals distinct phenotypes and effector functions

Crescentic glomerulonephritis (GN) caused by deposition of immune complexes within the glomerular capillary wall is a common cause of rapidly progressive glomerulonephritis and an important cause of end-stage renal failure. Current treatment with generalised immunosuppression is suboptimal in terms of efficacy, and is associated with significant side effects and long-term toxicity. Monocytes and macrophages are important in mediating crescentic GN, but little work has been done to phenotype the subpopulations involved and determine their respective contributions to glomerular inflammation. I developed a live glomerular imaging model using confocal microscopy in order to monitor intravascular monocyte subset behaviour during nephrotoxic nephritis (NTN) in a novel WKYhCD68- GFP monocyte/macrophage reporter rat strain. Additionally, I used flow cytometry and gene expression analysis to analyse ex vivo the glomerular leukocyte infiltrate during NTN. Using live glomerular imaging, I showed that non-classical monocytes surveyed the glomerular endothelium via the b2 integrin LFA-1 in the steady state. During NTN, nonclassical monocytes were recruited first, but subsequent recruitment and retention of classical monocytes was associated with glomerular damage and the onset of proteinuria. Importantly, monocytes recruited to the glomerular vasculature during NTN did not undergo transendothelial migration. This finding suggests that inflammation in crescentic GN caused by immune complex formation within the glomerulus is predominantly intravascular, driven by dynamic interactions between intravascular blood monocytes and the endothelium. Glomerular endothelial cells and non-classical monocytes overexpressed a distinct chemokine axis, which may orchestrate inflammatory myeloid cell recruitment and expression of damage mediators. Lewis rats, that are inherently resistant to experimental GN, demonstrated reduced recruitment of classical monocytes during NTN, suggesting a role for CD16 in mediating glomerular damage. In conclusion, my data suggest that monocyte subsets with distinct phenotypes and effector functions may be important in driving inflammation in experimental crescentic GN caused by immune complex deposition within the glomerulus. LFA-1 dependent endothelial surveillance by non-classical monocytes may detect immune complexes through CD16, orchestrating the inflammatory response through intravascular retention of classical monocytes, which results in glomerular damage and proteinuria.Open Acces

Clinical characteristics and outcomes of HIV-associated immune complex kidney disease.

BACKGROUND The pathogenesis and natural history of HIV-associated immune complex kidney disease (HIVICK) is not well understood. Key questions remain unanswered, including the role of HIV infection and replication in disease development and the efficacy of antiretroviral therapy (ART) in the prevention and treatment of disease. METHODS In this multicentre study, we describe the renal pathology of HIVICK and compare the clinical characteristics of patients with HIVICK with those with IgA nephropathy and HIV-associated nephropathy (HIVAN). Poisson regression models were used to identify risk factors for each of these pathologies. RESULTS Between 1998 and 2012, 65 patients were diagnosed with HIVICK, 27 with IgA nephropathy and 70 with HIVAN. Black ethnicity and HIV RNA were associated with HIVICK, receipt of ART with IgA nephropathy and black ethnicity and CD4 cell count with HIVAN. HIVICK was associated with lower rates of progression to end-stage kidney disease compared with HIVAN and IgA nephropathy (P < 0.0001). Patients with HIVICK who initiated ART and achieved suppression of HIV RNA experienced improvements in estimated glomerular filtration rate and proteinuria. CONCLUSIONS These findings suggest a pathogenic role for HIV replication in the development of HIVICK and that ART may improve kidney function in patients who have detectable HIV RNA at the time of HIVICK diagnosis. Our data also suggest that IgA nephropathy should be viewed as a separate entity and not included in the HIVICK spectrum

Results from the IRoc-GN international registry of patients with COVID-19 and glomerular disease suggest close monitoring

The effects of SARS-CoV-2 infection on individuals with immune-mediated glomerulonephritis, who are often undergoing immunosuppressive treatments, are unknown. Therefore, we created the International Registry of COVID infection in glomerulonephritis (IRoc-GN) and identified 40 patients with glomerulonephritis and COVID-19 followed in centers in North America and Europe. Detailed information on glomerulonephritis diagnosis, kidney parameters, and baseline immunosuppression prior to infection were recorded, as well as clinical presentation, laboratory values, treatment, complications, and outcomes of COVID-19. This cohort was compared to 80 COVID-positive control cases from the general population without glomerulonephritis matched for the time of infection. The majority (70%) of the patients with glomerulonephritis and all the controls were hospitalized. Patients with glomerulonephritis had significantly higher mortality (15% vs. 5%, respectively) and acute kidney injury (39% vs. 14%) than controls, while the need for kidney replacement therapy was not statistically different between the two groups. Receiving immunosuppression or renin-angiotensin-aldosterone system inhibitors at presentation did not increase the risk of death or acute kidney injury in the glomerulonephritis cohort. In the cohort with glomerulonephritis, lower serum albumin at presentation and shorter duration of glomerular disease were associated with greater risk of acute kidney injury and need for kidney replacement therapy. No differences in outcomes occurred between patients with primary glomerulonephritis versus glomerulonephritis associated with a systemic autoimmune disease (lupus or vasculitis). Thus, due to the higher mortality and risk of acute kidney injury than in the general population without glomerulonephritis, patients with glomerulonephritis and COVID-19 should be carefully monitored, especially when they present with low serum albumin levels

COVID-19 in Patients with Glomerular Disease: Follow-Up Results from the IRoc-GN International Registry

The acute and long-term effects of severe acute respiratory syndrome coronavirus 2 infection in individuals with GN are still unclear. To address this relevant issue, we created the International Registry of COVID-19 infection in GN