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The NLRP3 inflammasome is an intracellular platform that converts the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 to their active forms in response to 'danger' signals, which can be either host or pathogen derived, and mediates a form of inflammatory cell death called pyroptosis. This component of the innate immune system was initially discovered because of its role in rare autoinflammatory syndromes called cryopyrinopathies, but it has since been shown to mediate injurious inflammation in a broad range of diseases. Inflammasome activation occurs in both immune cells, primarily macrophages and dendritic cells, and in some intrinsic kidney cells such as the renal tubular epithelium. The NLRP3 inflammasome has been implicated in the pathogenesis of a number of renal conditions, including acute kidney injury, chronic kidney disease, diabetic nephropathy and crystal-related nephropathy. The inflammasome also plays a role in autoimmune kidney disease, as IL-1β and IL-18 influence adaptive immunity through modulation of T helper cell subsets, skewing development in favour of Th17 and Th1 cells that are important in the development of autoimmunity. Both IL-1 blockade and two recently identified specific NLRP3 inflammasome blockers, MCC950 and β-hydroxybutyrate, have shown promise in the treatment of inflammasome-mediated conditions. These targeted therapies have the potential to be of benefit in the growing number of kidney diseases in which the NLRP3 inflammasome has been implicated. [ABSTRACT FROM AUTHOR]

Biological therapeutics (biologics) that target autoimmune responses and inflammatory injury pathways have a marked beneficial impact on the management of many chronic diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease, and ankylosing spondylitis. Accumulating data suggest that a growing number of renal diseases result from autoimmune injury - including lupus nephritis, IgA nephropathy, anti-neutrophil cytoplasmic antibody-associated glomerulonephritis, autoimmune (formerly idiopathic) membranous nephropathy, anti-glomerular basement membrane glomerulonephritis, and C3 nephropathy - and one can speculate that biologics might also be applicable to these diseases. As many autoimmune renal diseases are relatively uncommon, with long natural histories and diverse outcomes, clinical trials that aim to validate potentially useful biologics are difficult to design and/or perform. Some excellent consortia are undertaking cohort studies and clinical trials, but more multicentre international collaborations are needed to advance the introduction of new biologics to patients with autoimmune renal disorders. This Review discusses the key molecules that direct injurious inflammation and the biologics that are available to modulate them. The opportunities and challenges for the introduction of relevant biologics into treatment protocols for autoimmune renal diseases are also discussed. [ABSTRACT FROM AUTHOR]

Objective Myeloperoxidase (MPO) locally contributes to organ damage in various chronic inflammatory conditions by generating reactive intermediates. The contribution of MPO in the development of experimental lupus is unknown. The aim of this study was to define the role of MPO in murine lupus nephritis (LN). Methods LN was induced in C57BL/6 wild-type (WT) and MPO knockout (MPO-/-) mice by intraperitoneal injection of pristane. Autoimmunity and glomerulonephritis were assessed 20 and 40 weeks after pristane administration. Cell apoptosis, leukocyte accumulation, and cytokine levels in the peritoneal cavity of WT and MPO-/- mice were assessed 3 or 6 days after pristane injection. Results MPO-/- mice developed more severe nephritis than did WT mice 20 and 40 weeks after pristane injection, despite having reduced glomerular deposition of antibody and complement and diminished levels of markers of oxidative stress (oxidized DNA and glutathione sulfonamide). Enhancement of renal disease in MPO-deficient mice correlated with increased accumulation of CD4+ T cells and macrophages in glomeruli, which, in turn, was associated with augmented generation of CD4+ T cell responses and increased activation and migration of dendritic cells in secondary lymphoid organs. In addition, the enhanced renal injury in MPO-/- mice was associated with increased glomerular accumulation of neutrophils and deposition of neutrophil extracellular traps. MPO deficiency also increased early cell apoptosis, leukocyte accumulation, and proinflammatory cytokine expression in the peritoneum. Conclusion MPO attenuates pristane-induced LN by inhibiting early inflammatory responses in the peritoneum and limiting the generation of CD4+ T cell autoimmunity in secondary lymphoid organs. [ABSTRACT FROM AUTHOR]

Background. IL-1β has the potential to promote progressive renal disease by effects on macrophage recruitment and activation or by effects mediated through tubular cell transforming growth factor (TGF)-β production, previously demonstrated in vitro. [ABSTRACT FROM PUBLISHER]

Recent studies in experimental crescentic glomerulonephritis, using the technique of glomerular culture, have shown that the macrophage is a major cell type present within the glomeruli and developing crescents. It has been suggested that their accumulation is a consequence of glomerular fibrin deposition. The effect of defibrination with ancrod on the cellular events occurring in experimental crescentic glomeruhmephritis in the rabbit was therefore assessed in this disease using the techniques of culture of isolated glomeruli, electronmicroscopy of renal tissue, and light microscopy. Defibrinated animals developed only minimal renal impairment, virtually no fibrin deposition in Bowman's Space and only a mild degree of crescent formation, in contrast to the severe renal failure, fibrin deposition and crescent formation that occurred in the untreated animals. The culture of isolated glomeruli and electronmicroscopy of intact renal tissue demonstrated large numbers of macrophages within and emerging from glomeruli of both defibrinated and untreated animals. However, only in untreated animals were macrophages seen to migrate into Bowman's Space, phagocytose fibrin, transform into epithelioid cells and accumulate to form crescents. These studies suggest that fibrin deposition in Bowman's Space is the major stimulus to the macrophage migration from capillary loops and accumulation in Bowaman's Space. However, fibrin deposition does not appear to be the stimulus to macrophage accumulation within capillary loops as this event was not affected by defibrination. [ABSTRACT FROM AUTHOR]

The extent and timing of glomerular T lymphocyte infiltration was studied in acute serum sickness (AcSS) glomerulonephritis (GN) in rabbits. AcSS was initiated by a single intravenous injection of bovine serum albumin (BSA), Rabbits developed circulating BSA anti-BSA immune complexes, and rapid immune elimination of the circulating antigen was associated with the deposition of immune complexes in the kidney and the onset ofa diffuse endocapillary proliferative GN. On the day of immune elimination (defined as when < 1% of the injected antigen remained in the circulation), rabbits developed significant proteinuria (98 ± 36 mg/24 h; normal 14 ± 1 mg/24 h, P < 0.01). glomerular macrophage accumulation (44.3 ±21.1 macrophages per glomerulus [mac/glom]: normal 0,28 ±0.18 mac/glom. P < 0.01), and a significant glomerular T. lymphocyte influx (3.0 ±0.9 cells/glomerular cross-section [c/gcs); normal 0.47 ±0,13 c/gcs; P < 0.005), On the day prior to immune elimination, increased T cells numbers were observed in some rabbits (2.4 ± 2.1 c/gcs) together with a minor macrophage presence (7.6 ± 3.6 mac/glom) and minimal proteinuria (17.6 ± 3 mg/24 h). These studies demonstrate the influx of T lymphocytes together with macrophages at the onset of proteinuria in serum sickness nephritis and are consistent with a role for cell-mediated immunity in the pathogenesis of this lesion. [ABSTRACT FROM AUTHOR]

The relative contributions of chemo-attractant and terminal components of complement to heterologous phase glomerular injury was studied in anti-GBM glomerulonephritis in rabbits. Normal rabbits (complement intact) were given anti-GBM antibody at a dose which resulted in 140 Hg specific kidney-fixed antibody per gram of renal cortex, and developed significant proteinuria (1910 ± 327 mg/24 h; control 18.2 ± 6.1 mg/24 h; P < 0.01). Leucocyte depiction significantly reduced but did not abolish proteinuria (574 ± 186 mg/24 h, P < 0.05), Complement depletion of neutrophil-depleted rabbits resulted in a further significant reduction in proteinuria (50.1 ± 12.2 mg/24 h. P < 0.05; versus neutrophil-depleted, complement-intact rabbits), indicating that both neutrophil accumulation and complement activation independent of neutrophils contribute to injury in this model. Rabbits congenitally deficient in the sixth component of complement (C6D) developed similar levels of proteinuria (2099 ± 796 mg/24 h) to normal rabbits given an identical dose of antibody. However, after leucocyte depletion. C6D rabbits developed significantly less proteinuria (135 ± 56 mg/24 h) than did leucocyte-depleted, complement-intact rabbits (P<0 05). These studies show that terminal complement components are not necessary for the full expression of acute anti- GBM antibody-initiated injury in leucocyte-intact rabbits. However, in the absence of leucocytes, C6 and the terminal complement components are apparently responsible for the majority of the complement-dependent glomerular injury. [ABSTRACT FROM AUTHOR]

Since the first association between HLA and diseases of native kidneys was described almost 50 years ago, technological and conceptual advances in HLA biology and typing, together with better case ascertainment, have led to an improved understanding of HLA associations with a variety of renal diseases. A substantial body of evidence now supports the existence of HLA genetic associations in the field of renal disease beyond the role of HLA in allogeneic responses in transplant recipients. Allomorphs of HLA have emerged as important risk factors in most immune-mediated renal diseases, which, together with other genetic and environmental factors, lead to loss of tolerance and autoimmune-mediated renal inflammation. HLA associations have also been described for renal diseases that are less traditionally seen as autoimmune or immune-mediated. Here, we review essential concepts in HLA biology and the association of HLA with diseases of the native kidneys, and describe the current understanding of the epistatic and mechanistic bases of HLA-associated kidney disease. Greater understanding of the relationship between HLA and kidney function has the potential not only to further the understanding of immune renal disease at a fundamental level but also to lead to the development and application of more effective, specific and less toxic therapies for kidney diseases. [ABSTRACT FROM AUTHOR]

Reports that the intrinsic renal cell derived interleukin-12 (IL-12) is an effector of renal glomerular injury in crescentic glomerulonephritis. Attenuated crescent formation, leukocyte accumulation and renal injury in IL-12 chimeric mice; Required IL-12 intrinsic renal cell for full development of immune glomerular injury in model of crescentic glomerulonephritis.

Experimental autoimmune Goodpasture's disease: A pathogenetic role for both effector cells and antibody in injury.Background.Goodpasture's disease[antiglomerular basement membrane (GBM) glomerulonephritis] is a classic autoimmune disease and the only organ-specific autoimmune renal disease in which the antigen is well described. The importance of antibodies against the non-collagenous domain of theα3 chain of type IV collagen[α3(IV)NC1] is well established. However, observational human studies and studies in experimental systems also imply a role for cell-mediated effector injury.Methods.Active experimental autoimmune glomerulonephritis (EAG) was induced by immunization withα3-α5(IV)NC1 heterodimers in B cell intact C57BL/6 mice and B cell (μ chain-deficient) mice. Passive disease was induced by transferring sera from B cell intact and B cell deficient mice with EAG toRAG-1−/− mice (that lack adaptive immunity). Histologic and functional injury was studied.Results.Despite the absence of B cells and immunoglobulin in B-cell–deficient mice, histologic and functional injury developed in mice immunized withα3-α5(IV)NC1, with T cells and macrophages in glomeruli. Injury occurred to a similar degree to that found in B-cell–intact mice. Transfer of sera from B-cell–intact mice with EAG containing antibodies (but not from B-cell–deficient mice with EAG) toRAG-1−/− mice induced linear immunoglobulin deposits on the glomerular basement membrane (GBM) and pathologic proteinuria.Conclusion.Both cell-mediated and humoral effectors are capable of inducing renal injury in EAG. Given the similarity of the disease-initiating antigen in this model to the antigen in human anti-GBM glomerulonephritis, similar overlapping mechanisms are likely to operate in human disease. [ABSTRACT FROM AUTHOR]