Complement activation in experimental IgA nephropathy: An antigen-mediated process

Background and objectives: IgA nephropathy is the most common primary glomerulonephritis worldwide. Previous research demonstrated that collectin11, an initiator of complement lectin pathway, was involved in both acute kidney injury and chronic tubulointerstitial fibrosis. Here, we investigated the potential role of collectin11 in the pathogenesis of IgA nephropathy. Design, setting, participants, and measurements: The deposition of collectin11 and other complement proteins was detected in glomeruli of 60 participants with IgA nephropathy by immunofluorescence. In vitro, human mesangial cells were treated with IgA1-containing immune complexes derived from participants with IgA nephropathy. Then, the expression of collectin11 in mesangial cells was examined by RT-qPCR and immunofluorescence. The codeposition of collctin11 with IgA1 or C3 on mesangial cells was detected by immunofluorescence and proximity ligation assays. Results: 37% participants with IgA nephropathy (22/60) showed codeposition of collectin11 with IgA in the glomerular mesangium. Using an injury model of mesangial cells, we demonstrated that IgA1-immune complexes derived from participants with IgA nephropathy increased the secretion of collectin11 in mesangial cells with the subsequent deposition of collectin11 on the cell surface via the interaction with deposited IgA1-immune complexes. In vitro, we found that collectin11 bound to IgA1-immune complexes in a dose-dependent but calcium-independent manner. Furthermore, deposited collectin11 initiated the activation of complement and accelerated the deposition of C3 on mesangial cells. Conclusions: In situ-produced collectin11 by mesangial cells might play an essential role in kidney injury in a subset of patients with IgA nephropathy through the induction of complement activation.

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C4d deposits in IgA nephropathy: where does complement activation come from?

Pediatric Nephrology ◽

10.1007/s00467-016-3575-2 ◽

2017 ◽

Vol 32 (7) ◽

pp. 1097-1101 ◽

Cited By ~ 7

Author(s):

Rosanna Coppo

Keyword(s):

Iga Nephropathy ◽

Complement Activation

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Study of the variables associated with local complement activation in IgA nephropathy

Nefrología (English Edition) ◽

10.1016/j.nefroe.2017.03.003 ◽

2017 ◽

Vol 37 (3) ◽

pp. 320-329

Author(s):

Alfons Segarra-Medrano ◽

Clara Carnicer-Caceres ◽

Naiara Valtierra-Carmeno ◽

Irene Agraz-Pamplona ◽

Natalia Ramos-Terrades ◽

...

Keyword(s):

Iga Nephropathy ◽

Complement Activation

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The influences of α-hemolytic Streptococcus on class switching and complement activation of human tonsillar cells in IgA nephropathy

Immunologic Research ◽

10.1007/s12026-021-09223-2 ◽

2021 ◽

Author(s):

Muyao Ye ◽

Chang Wang ◽

Ling Li ◽

Qiulan Zhao ◽

Youming Peng ◽

...

Keyword(s):

Iga Nephropathy ◽

Complement Activation ◽

Class Switching ◽

Hemolytic Streptococcus ◽

Tonsillar Cells

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C4d in Native Glomerular Diseases

American Journal of Nephrology ◽

10.1159/000496059 ◽

2019 ◽

Vol 49 (1) ◽

pp. 81-92 ◽

Cited By ~ 4

Author(s):

Preeti Chandra

Keyword(s):

Iga Nephropathy ◽

Focal Segmental Glomerulosclerosis ◽

Complement Activation ◽

Immunoglobulin A ◽

Future Research ◽

Glomerular Diseases ◽

Segmental Glomerulosclerosis ◽

Native Kidney

Complement activation occurs in many glomerular diseases, the exact pathway(s) of activation has been studied in detail in some diseases but not in all. C4d is generated by the activation of classical and lectin pathways, and its presence can point to the activation of either of these pathways. This review aims to summarize the available data with regard to the deposition of glomerular C4d in native kidney biopsies in different glomerular pathologies that may be useful for future research into the role of complement activation in glomerular diseases. While there is more information on C4d in certain diseases (e.g., Immunoglobulin A (IgA) nephropathy), there is scant data in other diseases (such as focal segmental glomerulosclerosis).

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Complement activation in IgA nephropathy

Seminars in Immunopathology ◽

10.1007/s00281-021-00882-9 ◽

2021 ◽

Author(s):

Nicholas R. Medjeral-Thomas ◽

H. Terence Cook ◽

Matthew C. Pickering

Keyword(s):

Clinical Trials ◽

Iga Nephropathy ◽

Disease Severity ◽

Complement Activation ◽

Complement Activity ◽

Important Contributor ◽

Complement Inhibitors ◽

Growing Body ◽

Insight Into ◽

Disease Specific

AbstractIgA nephropathy pathogenesis is incompletely understood, and this limits the development of disease-specific biomarkers and effective therapies. Evidence of complement activity in IgA nephropathy is well established. However, a growing body of research indicates complement activity is an important contributor to IgA nephropathy pathology. In particular, multiple associations have been identified between complement alternative, lectin and terminal pathway proteins and IgA nephropathy severity. Recently, we have also gained insight into possible mechanisms that could link glomerular IgA deposition, complement activity, glomerular inflammation and disease severity. Ongoing clinical trials of therapeutic complement inhibitors will provide insight into the importance of complement activity to IgA nephropathy pathogenesis. Further research into mechanisms of complement activity is essential to improving our understanding and management of patients with IgA nephropathy.

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Determination of Severity of Murine IgA Nephropathy by Glomerular Complement Activation by Aberrantly Glycosylated IgA and Immune Complexes

American Journal Of Pathology ◽

10.1016/j.ajpath.2012.06.038 ◽

2012 ◽

Vol 181 (4) ◽

pp. 1338-1347 ◽

Cited By ~ 19

Author(s):

Azusa Hashimoto ◽

Yusuke Suzuki ◽

Hitoshi Suzuki ◽

Isao Ohsawa ◽

Rhubell Brown ◽

...

Keyword(s):

Iga Nephropathy ◽

Complement Activation ◽

Immune Complexes

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Complement Activation Is Associated With Crescents in IgA Nephropathy

Frontiers in Immunology ◽

10.3389/fimmu.2021.676919 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zi Wang ◽

Xinfang Xie ◽

Jingyi Li ◽

Xue Zhang ◽

Jiawei He ◽

...

Keyword(s):

Iga Nephropathy ◽

Complement Activation ◽

Predictive Ability ◽

Roc Curves ◽

Rapid Progression ◽

Crescent Formation ◽

Potential Biomarker ◽

Mannose Binding ◽

Progression Of Kidney Disease ◽

Binding Lectin

IntroductionCrescents, especially those found at a percentage greater than 50%, are often associated with rapid progression of kidney disease in IgA nephropathy (IgAN). The mechanism of crescents forming in IgAN is still unclear. In this study, we aimed to evaluate whether excess complement activation participates in the formation of crescents in IgAN.MethodsOne hundred IgAN patients with various proportions of crescents—24 with 1%–24%, 27 with 25%–49%, 21 with 50%–74% 12 with more than 75%, and 16 without crescents—were included. Urinary concentrations of mannose-binding lectin (MBL), Bb, C4d, C3a, C5a, and soluble C5b-9 (sC5b-9) were measured at the time of biopsy. Receiver operating characteristic (ROC) curves were performed to evaluate predictive ability of renal survival for urine complement activation. In addition, historical C4d, C5b-9, and C3d were stained by immunohistochemistry.ResultsIgAN patients with more than 50% crescent formation showed higher complement activation levels than the other patients (urinary C3a/creatinine (C3a/Cr): 6.7295 ng/mg, interquartile range (IQR) 1.4652–62.1086 ng/mg vs. 0.1055 ng/mg, IQR 0–1.4089 ng/mg; urinary C5a/Cr: 15.6202 ng/mg, 4.3127–66.7347 ng/mg vs. 0.3280 ng/mg, IQR 0.0859–2.4439 ng/mg; urinary sC5b-9/Cr: 98.6357 ng/mg, 8.8058–1,087.4578 ng/mg vs. 1.4262 ng/mg, 0.0916–11.0858 ng/mg, all p-values <0.001). The levels of urinary MBL and C4d representing lectin complement pathway showed a linear association with the proportion of crescents (r = 0.457 and 0.562, respectively, both p-values <0.001). Combined urine complement products could increase the predictive ability compared with crescents alone from 0.904 to 0.944 (p = 0.062) with borderline significance. Moreover, the glomerular C4d deposition rate elevated with the increase of proportions of crescents.ConclusionExcess complement activation may be involved in the formation of crescents, especially diffuse crescent formation, in patients with IgAN. Urinary C4d correlated with the proportion of crescents and was a potential biomarker for disease monitoring in crescentic IgAN.

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