Thrombospondin Type-1 Domain-Containing 7A in Idiopathic Membranous Nephropathy

Tomas, Nicola M.; Beck, Laurence H.; Meyer-Schwesinger, Catherine; Seitz-Polski, Barbara; Ma, Hong; Zahner, Gunther; Dolla, Guillaume; Hoxha, Elion; Helmchen, Udo; Dabert-Gay, Anne-Sophie; Debayle, Delphine; Merchant, Michael L.; Klein, Jon B.; Salant, David J.; Stahl, Rolf A.K.; Lambeau, Gérard

doi:10.1056/nejmoa1409354

Cited by 744 publications

(714 citation statements)

References 19 publications

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“…17 Despite various therapeutic strategies, the therapeutic effects are far from satisfactory. [18][19][20] Most of iMN cases will suffer from NS, posing a serious threat to human health. 21 And even worse, growing evidences have indicated that MN usually shows high rate of recurrence and long disease course, which may occur at any stage in life.…”

Section: Discussionmentioning

confidence: 99%

The clinicopathological features of patients with membranous nephropathy

Zhu

Han

Zhang

et al. 2018

IJNRD

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Background: Membranous nephropathy (MN) represents a distinct glomerular disease which has been considered as a major cause of nephrotic syndrome (NS) in adults. Evidences show that the clinicopathological features of MN are various among MN cases. This study aimed to summarize and analyze the clinicopathological features of patients with MN. Methods: A total of 231 MN patients were recruited in this study. Their clinical and pathological features were collected and analyzed according to their age, gender, pathological stages, and anti-phospholipase A2 receptor (anti-PLA2R) antibodies tests. Results: Among the 231 MN cases, the ratio of male to female was 1.47 and the mean age was 47.43±14.32 years. Altogether, 163 (70.6%) cases were positive for NS. Their serum antiPLA2R, body mass index, total cholesterol, triglyceride, low density lipoprotein cholesterol, D2, IgA, and IgE were increased, but IgG was decreased. The majority of the patients were middle aged and old aged. In addition, the pathological stage was significantly correlated with gender (P=0.038), creatinine, (P=0.021) and IgE (P=0.003). A total of 74.9% MN patients were found to be positive for anti-PLA2R antibodies, and they were more likely to have abnormal serum indices. Conclusion:The major clinicopathological characteristics of MN patients are summarized in this study. Male and elder MN cases are likely to have rapid disease progression. Advanced pathological stages and being positive for anti-PLA2R antibodies may be potential indicators for disease activity of MN.

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Section: Discussionmentioning

confidence: 99%

The clinicopathological features of patients with membranous nephropathy

Zhu

Han

Zhang

et al. 2018

IJNRD

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“…On one hand, elevated IgG4 levels may be an epiphenomenon associated with IgG4-RD-associated chronic inflammation, because this IgG subtype exhibits limited ability to bind to complement and FcgRs (5,6) and has been shown to have anti-inflammatory activity in experimental myasthenia gravis (7). On the other hand, enhanced IgG4 levels may play a vital immunopathologic role in this disease, because IgG4 Abs against autoantigens have also been shown to participate in the pathogenesis of autoimmunity (8,9).…”

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confidence: 99%

Plasmacytoid Dendritic Cell Activation and IFN-α Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis

Arai

Yamashita

Kuriyama

et al. 2015

The Journal of Immunology

132

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The abnormal immune response accompanying IgG4-related autoimmune pancreatitis (AIP) is presently unclear. In this study, we examined the role of plasmacytoid dendritic cell (pDC) activation and IFN-α production in this disease as well as in a murine model of AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid). We found that the development of AIP in treated MRL/Mp mice occurred in parallel with pancreatic accumulation of pDCs producing IFN-α, and with pDC depletion and IFN-α-blocking studies, we showed that such accumulation was necessary for AIP induction. In addition, we found that the pancreas of treated MRL/Mp mice contained neutrophil extracellular traps (NETs) shown previously to stimulate pDCs to produce IFN-α. Consistent with these findings, we found that patients with IgG4-related AIP also exhibited pancreatic tissue localization of IFN-α–expressing pDCs and had significantly higher serum IFN-α levels than healthy controls. In addition, the inflamed pancreas of these patients but not controls also contained NETs that were shown to be capable of pDC activation. More importantly, patient pDCs cultured in the presence of NETs produced greatly increased levels of IFN-α and induced control B cells to produce IgG4 (but not IgG1) as compared with control pDCs. These data suggest that pDC activation and production of IFN-α is a major cause of murine AIP; in addition, the increased pDC production of IFN-α and its relation to IgG4 production observed in IgG4-related AIP suggest that this mechanism also plays a role in the human disease.

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“…This protein shares different biochemical characteristics with PLA2R, such as N-glycosylation, transmembrane localization in glomerular podocytes and serum reactivity only in non-reducing conditions [37].…”

Section: Additional Candidate Antigensmentioning

confidence: 99%

Immunology of membranous nephropathy: from animal models to humans

Sinico

Mezzina

Trezzi³

et al. 2015

Clinical and Experimental Immunology

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SummaryMembranous nephropathy (MN), the leading cause of nephrotic syndrome in adults, is characterized by the deposition of subepithelial immune deposits that consist mainly of immunoglobulin (Ig)G and complement. Most of the cases are primary or idiopathic (iMN), while only approximately 25% of the cases are secondary to some known disease such as systemic lupus erythematosus, hepatitis B, drugs and malignancies. Most of our knowledge on the pathogenesis of iMN has relied upon old experimental models (i.e. Heymann nephritis) that have shown that immune deposits are formed in situ by the reaction of autoantibodies against the respective podocyte antigen. Recent findings indicate that podocyte proteins also act as an autoantigen in human iMN. The M-type phospholipase A2 receptor (PLA2R) has been identified as the main target antigen, as it can be found in approximately 70% of iMN patients but only rarely in other glomerulonephritides. Podocytes damage in the experimental model of Heymann nephritis is complementmediated. In humans, the presence of complement within the subepithelial deposits is well established, but IgG4, which does not activate complement by classical or alternative pathways, represents the predominant subclass of IgG anti-PLA2R. Some evidence suggests that IgG4 anti-PLA2R autoantibodies can bind mannan-binding lectin (MBL) and activate the lectin complement pathway. A genetic background for iMN has been demonstrated by genomewide association studies that have shown highly significant associations of the PLA2R1 and the human leucocyte antigen (HLA)-DQA1 loci with iMN. In addition to their diagnostic value, anti-PLA2R antibodies may be useful to monitor disease activity and predict response to treatment.

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Thrombospondin Type-1 Domain-Containing 7A in Idiopathic Membranous Nephropathy

Cited by 744 publications

References 19 publications

The clinicopathological features of patients with membranous nephropathy

The clinicopathological features of patients with membranous nephropathy

Plasmacytoid Dendritic Cell Activation and IFN-α Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis

Immunology of membranous nephropathy: from animal models to humans

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