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Objective: Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis, in which ANCA‐mediated neutrophil extracellular trap (NET) formation and subsequent endothelial cell necrosis occur. Cyclophilin D (CypD) plays an important role in mediation of cell necrosis and inflammation via the opening of mitochondrial permeability transition pores. This study was undertaken to examine the role of CypD in AAV pathogenesis. Methods: We assessed the role and mechanism of CypD in ANCA‐stimulated neutrophils in vitro by immunostaining and electron microscopy observation. We performed a comprehensive RNA‐sequencing analysis on ANCA‐treated murine neutrophils. To investigate the role of CypD in vivo, we assessed disease features in CypD‐knockout mice and wild‐type mice using 2 different murine AAV models: anti‐myeloperoxidase IgG transfer–induced AAV and spontaneous AAV. Results: In vitro experiments showed that pharmacologic and genetic inhibition of CypD suppressed ANCA‐induced NET formation via the suppression of reactive oxygen species and cytochrome c release from the mitochondria. RNA‐sequencing analyses in ANCA‐treated murine neutrophils revealed the involvement of inflammatory responses, with CypD deficiency reducing ANCA‐induced alterations in gene expression. Furthermore, analyses of upstream regulators revealed the relevance of intracellular calcium (CypD activator) and cyclosporin (CypD inhibitor) in ANCA stimulation, indicating that the CypD‐dependent opening of mitochondrial permeability transition pores is associated with ANCA‐induced neutrophil activation and NETosis. In both AAV mouse models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD‐dependent neutrophil and endothelial necrosis. Conclusion: CypD targeting is a novel and specific therapeutic strategy for AAV via the resolution of necrotizing vasculitis. [ABSTRACT FROM AUTHOR]

Competing Interests: The authors declare no conflict of interest.

Objectives: The aim of this study was to clarify the consequences of Mx1, one of the IFN-inducible proteins, in the peripheral blood as well as in renal tissues in patients with systemic lupus erythematosus (SLE)., Patients and Methods: Mx1 protein concentrations in (PBMCs) from 18 SLE patients mostly in their stable disease status, 11 IgA nephropathy (IgAN) patients, 5 ANCA-associated vasculitis (AAV) patients and 16 healthy controls were measured using enzyme-linked immunosorbent assay (ELISA). Mx1 expression in renal specimens from 18 patients with lupus nephritis (LN), 18 with IgAN and 10 with AAV were evaluated using immunohistochemistry., Results: Mx1 protein concentrations in lysates of PBMCs were significantly higher in SLE patients compared with those in other three groups. Mx1-positive area in renal tissues was significantly dominant in both glomeruli and renal tubules of LN compared with other renal diseases. Renal Mx1 protein levels were lower in LN after immunosuppressive treatment, compared with those from immunosuppressant-naïve patients., Conclusion: Mx1 levels were upregulated in lupus peripheral blood even when their disease activities were stable. On the other hand, Mx1 was highly expressed in kidneys from patients with LN before treatment, which was decreased after immunosuppressive treatment. These results suggest that Mx1 is a potential marker for the diagnosis of SLE in the peripheral blood and also for the activity of lupus nephritis in the kidney.

Targeted anticancer therapies have been developed to interfere with specific target molecules including those of downstream pathways required for tumor growth and progression. Mammalian target of rapamycin (mTOR) has been considered as one of the target molecules of cancer growth, and its inhibitors have been reported to exert an anticancer effect in various malignant tumors. The pulmonary disorder is one of the major side effects of anticancer drugs including mTOR inhibitor (mTORi), and the diagnosis of lung injury induced by medication is difficult because of non-specific nature of the radiological findings. In this study, we present the detailed autopsy findings of a patient who developed diffuse alveolar damage (DAD) following mTORi treatment for metastatic renal cell carcinoma. We also studied 19 cases of DAD derived from other diseases and 9 cases with non-pathological lung. Of interest, pneumocytes of the patients with DAD, who received other anticancer drugs or contacted bacteria, demonstrated significantly lower mTOR activities than pneumocytes of those with non-pathological lung tissue, as judged by the immunohistochemical analysis. In contrast, both pneumocytes and T cells in DAD tissues of the patient treated with mTORi showed higher mTOR activities than those of patients with DAD of other causes, suggesting that the enhanced mTOR signaling may be involved in the development of DAD after mTORi treatment. This unexpected finding needs to be confirmed in other patients treated with mTORi. In conclusion, the attenuated mTOR signaling in pneumocytes may contribute to the pathogenesis of DAD in patients without mTORi treatment.