The most prevalent severe manifestation of systemic lupus erythematosus (SLE) is nephritis which is characterized by immune complex deposition, inflammation, and scarring in both glomeruli and in the tubulointerstitium. Numerous studies indicate that glomerulonephritis results from a systemic break in B cell tolerance resulting in the local deposition of immune complexes containing antibodies reactive with ubiquitous self-antigens. However, the pathogenesis of SLE tubulointerstitial disease is not known. Herein, we demonstrate that in over half of a cohort of 68 lupus nephritis biopsies, the tubulointerstitial infiltrate was organized into either well-circumscribed T:B cell aggregates or germinal centers (GCs) containing follicular dendritic cells. Sampling of the in situ expressed immunoglobulin repertoire revealed that both histological patterns were associated with intrarenal B cell clonal expansion and ongoing somatic hypermutation. However, in the GC histology the proliferating cells were CD138−CD20+ centroblasts while in T:B aggregates, they were CD138+CD20low/− plasmablasts. The presence of either GCs or T:B aggregates was strongly associated with tubular basement membrane immune complexes. These data implicate tertiary lymphoid neogenesis in the pathogenesis of lupus tubulointerstitial inflammation.

These data implicate the Th17 axis and specifically IL-23 as mediators of more severe disease in AAV. Their persistence despite conventional treatment may contribute to high relapse rates.

Objective In lupus nephritis (LuN), severe tubulointerstitial inflammation (TII) predicts progression to renal failure. Severe TII is associated with tertiary lymphoid neogenesis and in situ antigen-driven clonal B cell selection. The autoantigen(s) driving in situ B-cell selection in TII are not known. This study aimed to identify the dominant driving autoantigen(s). Methods Single CD38+ or Ki-67+ B cells were laser captured from seven LuN diagnostic biopsies. Eighteen clonally expanded immunoglobulin heavy and light chain variable region pairs were cloned and expressed as monoclonal antibodies. Seven more antibodies were cloned from flow sorted CD38+ cells from an eighth biopsy. Antigen characterization was performed using a combination of confocal microscopy, ELISA, screening protoarrays, immunoprecipitation and mass spectrometry. Serum IgG titers to the dominant antigen were determined in 48 LuN and 35 non-nephritic lupus samples using purified antigen-coated arrays. Autoantigen expression was localized by immunohistochemistry and immunofluorescence on normal and LuN kidney. Results Eleven of 25 antibodies reacted with cytoplasmic structures, four reacted with nuclei, and none with dsDNA. Vimentin was the only autoantigen identified by both mass spectrometry and by protoarray. Ten of the 11 anti-cytoplasmic TII antibodies directly bound vimentin. Vimentin was highly expressed by tubulointerstitial inflammatory cells, and tested TII antibodies preferentially bound inflamed tubulointerstitium. Finally, high-titers of serum anti-vimentin antibodies were associated with severe TII (p = 0.0001). Conclusion Vimentin, an antigenic feature of inflammation, is a dominant autoantigen targeted in situ in LuN TII. This adaptive autoimmune response likely feeds forward to worsen TII and renal damage.

Percutaneous PD catheter insertion was associated with a very low complication rate and high primary success rate, and was highly efficient in use of resources and avoided the need for general anaesthesia.

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BackgroundMyeloperoxidase released after neutrophil and monocyte activation can generate reactive oxygen species, leading to host tissue damage. Extracellular glomerular myeloperoxidase deposition, seen in ANCA-associated vasculitis, may enhance crescentic GN through antigen-specific T and B cell activation. Myeloperoxidase-deficient animals have attenuated GN early on, but augmented T cell responses. We investigated the effect of myeloperoxidase inhibition, using the myeloperoxidase inhibitor AZM198, to understand its potential role in treating crescentic GN.MethodsWe evaluated renal biopsy samples from patients with various forms of crescentic GN for myeloperoxidase and neutrophils, measured serum myeloperoxidase concentration in patients with ANCA-associated vasculitis and controls, and assessed neutrophil extracellular trap formation, reactive oxygen species production, and neutrophil degranulation in ANCA-stimulated neutrophils in the absence and presence of AZM198. We also tested the effect of AZM198 on ANCA-stimulated neutrophil-mediated endothelial cell damage in vitro, as well as on crescentic GN severity and antigen-specific T cell reactivity in the murine model of nephrotoxic nephritis.ResultsAll biopsy specimens with crescentic GN had extracellular glomerular myeloperoxidase deposition that correlated significantly with eGFR and crescent formation. In vitro, AZM198 led to a significant reduction in neutrophil extracellular trap formation, reactive oxygen species production, and released human neutrophil peptide levels, and attenuated neutrophil-mediated endothelial cell damage. In vivo, delayed AZM198 treatment significantly reduced proteinuria, glomerular thrombosis, serum creatinine, and glomerular macrophage infiltration, without increasing adaptive T cell responses.ConclusionsMyeloperoxidase inhibition reduced neutrophil degranulation and neutrophil-mediated endothelial cell damage in patients with ANCA-associated vasculitis. In preclinical crescentic GN, delayed myeloperoxidase inhibition suppressed kidney damage without augmenting adaptive immune responses, suggesting it might offer a novel adjunctive therapeutic approach in crescentic GN.

Goodpasture's or anti-glomerular basement membrane (GBM) disease is classically characterised by the presence of circulating autoantibodies directed against the non-collagenous domain of the 3 chain of type IV collagen(3(IV)NC1), 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 proposed novel therapeutic options, 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 HLA-transgenic animals, while the association of anti-GBM antibodies with anti-neutrophil cytoplasm antibodies (ANCA) and their combined impact on disease phenotype is increasingly recognised, providing some insights into the basis of glomerular damage and autoimmunity.

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