Glomerular Activation of the Lectin Pathway of Complement in IgA Nephropathy Is Associated with More Severe Renal Disease

Roos, Anja; Rastaldi, Maria Pia; Calvaresi, Novella; Oortwijn, Beatrijs; Schlagwein, Nicole; Gijlswijk‐Janssen, Daniëlle J. van; Stahl, Gregory L.; Matsushita, Misao; Fujita, Teizo; Kooten, Cees van; Daha, Mohamed R.

doi:10.1681/asn.2005090923

Cited by 367 publications

(303 citation statements)

References 49 publications

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“…In our study, MBL staining was also not analyzed. However, it was previously shown that deposition of C4d was accompanied by deposits of MBL in 100% of patients (14). C4d in the absence of C1q is a marker for lectin pathway activation (Figure 1).…”

Section: Discussionmentioning

confidence: 83%

“…On the other hand, it is possible that IgA1-induced activation of the lectin pathway could specifically recruit other amplifying mechanisms, rendering the complement system activation more aggressive. Thus, positive costaining for C4-binding protein has been reported in patients with IgAN with a C4d-positive staining, but not in those with a C4d-negative staining (14,29). C4-binding protein behaves as a bridge between the complement system and coagulation (30), and this pathway could play a role in the formation of thrombotic microangiopathy lesions that some studies have reported (31,32) as well as in the pathogenesis of accelerated or malignant hypertension that some patients with IgAN develop (31,33).…”

Section: Discussionmentioning

confidence: 88%

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Association of C4d Deposition with Clinical Outcomes in IgA Nephropathy

Espinosa¹,

Ortega²,

Sánchez³

et al. 2014

Clinical Journal of the American Society of Nephrology

177

162

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Background and objectives Several studies have suggested that activation of the complement system is a contributing pathogenic mechanism in IgA nephropathy (IgAN). C4d staining is an inexpensive and easy-toperform method for the analysis of renal biopsies. This study aimed to assess the clinical and prognostic implications of C4d staining in IgAN.Design, setting, participants, & measurements This retrospective cohort study included 283 patients with IgAN in 11 hospitals in Spain who underwent a renal biopsy between 1979 and 2010. The primary predictor was mesangial C4d staining. Secondary predictors included demographic, clinical, and laboratory characteristics, and Oxford pathologic classification criteria. The primary end point was the cumulative percentage of patients who developed ESRD, defined as onset of chronic dialysis or renal transplantation. C4d was analyzed by immunohistochemical staining using a polyclonal antibody. Kaplan-Meier and Cox proportional hazards analyses were performed to evaluate the effect of C4d staining on renal survival.Results There were 109 patients (38.5%) and 174 patients (61.5%) who were classified as C4d positive and C4d negative, respectively. Renal survival at 20 years was 28% in C4d-positive patients versus 85% in C4d-negative patients (P,0.001). Independent risk factors associated with ESRD were as follows: proteinuria (hazard ratio [HR] per every 1 g/d increase. 1.16; 95% confidence interval [95% CI], 1.03 to 1.31; P=0.01), eGFR (HR per every 1 ml/min per 1.73 m 2 increase, 0.96; 95% CI, 0.94 to 0.97; P,0.001), T2 Oxford classification (tubular atrophy/ interstitial fibrosis, .50%; HR, 4.42; 95% CI, 1.40 to 13.88; P=0.01), and C4d-positive staining (HR, 2.45; 95% CI, 1.30 to 4.64; P=0.01).Conclusions C4d-positive staining is an independent risk factor for the development of ESRD in IgAN. This finding is consistent with the possibility that complement activation is involved in the pathogenesis of this disease.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 88%

Association of C4d Deposition with Clinical Outcomes in IgA Nephropathy

Espinosa¹,

Ortega²,

Sánchez³

et al. 2014

Clinical Journal of the American Society of Nephrology

177

162

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“…Due to its role in humoral immune system, acute MTB infection is correlated with a marked increase in serum IgA levels, which includes the presence of IgA antibodies against A-60 mycobacterial antigen, IgA immune complexes and mycobacterial antigens in the serum of patients with active TB (Solak et al 2013). Deposition of these complexes in turn may activate the alternative complement and the lectin pathway (Roos et al 2006), with resultant local injuries leading to IgA nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Early Diagnosis of Tuberculosis-Associated IgA Nephropathy with ESAT-6

Zhao

Sun

et al. 2017

Tohoku J. Exp. Med.

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IgA nephropathy (IgAN) is the most common cause of primary renal diseases worldwide, and the early secreted antigenic target of 6 (ESAT-6) which was secreted by Mycobacterium tuberculosis (MTB) may be involved in the development and progression of IgAN. This study aimed to investigate the role of ESAT-6 for early diagnosis of IgAN caused by MTB infection. From 2011 to 2014, 21 patients with renal tuberculosis (RTB), 25 with IgAN, and 46 with IgAN infected with MTB (IgAN/MTB) were enrolled. Serum levels of antibodies against Mycobacterium tuberculosis antigen 85A (Ag85A) were measured by ELISA. Urine culture and phage amplified biologically assay were performed to detect MTB. HE staining was used to observe the morphological changes in kidney tissues. Immunohistochemistry was applied to detect the expression of ESAT-6. Immunofluorescence staining was conducted to detect IgA1. Positive rates of serum anti-Ag85A antibody and urine culture for MTB were higher in the RTB and IgAN/MTB groups than those in the IgAN group. The positive rates of plaques were also higher in RTB and IgAN/MTB groups than the positive rate in the IgAN group. By contrast, the positive rate of ESAT-6 was lower in the IgAN group than that in the RTB group or the IgAN/MTB group, whereas the expression levels of IgA1 were higher in the IgAN and IgAN/MTB groups, compared with the RTB group. Our findings suggest that ESAT-6 and IgA1 may be helpful for early diagnosis of IgAN caused by MTB infection.

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“…The anti-CCP antibody response involves all IgG subclasses as well as IgM and IgA (35,36). The traditional view that the antibodies IgM and multivalent IgG can activate the complement system only directly via the classical pathway has recently been challenged by observations that differentially glycosylated forms of IgG (37), IgM (33), and IgA (38,39) can also activate the alternative pathway and/or lectin pathway of complement (33,34,(37)(38)(39)(40). In our experiments we did not observe any binding of MBL to immunoglobulins, not even in the patients who were positive for IgA or IgM, which are isotypes that have the ability to mediate such interaction.…”

Section: Discussionmentioning

confidence: 99%

Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways

Trouw¹,

Haisma²,

Levarht³

et al. 2009

Arthritis & Rheumatism

217

149

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Objective. It has been suggested that anticitrullinated protein antibodies (ACPAs) play an important role in the pathogenesis of rheumatoid arthritis (RA). To exert their pathologic effects, ACPAs must recruit immune effector mechanisms such as activation of the complement system. Mouse models of RA have shown that, surprisingly, arthritogenic antibodies activate the alternative pathway of complement rather than the expected classical pathway. This study was undertaken to investigate whether human anti-cyclic citrullinated peptide (anti-CCP) antibodies activate the complement system in vitro and, if so, which pathways of complement activation are used.Methods. We set up novel assays to analyze complement activation by anti-CCP antibodies, using cyclic citrullinated peptide-coated plates, specific buffers, and normal and complement-deficient sera as a source of complement.Results. Anti-CCP antibodies activated complement in a dose-dependent manner via the classical pathway of complement, and, surprisingly, via the alternative pathway of complement. The lectin pathway was not activated by anti-CCP antibodies. Complement activation proceeded in vitro up to the formation of the membrane attack complex, indicating that all activation steps, including the release of C5a, took place.Conclusion. Our findings indicate that anti-CCP antibodies activate the complement system in vitro via the classical and alternative pathways but not via the lectin pathway. These findings are relevant for the design of interventions aimed at inhibition of complement-mediated damage in RA.

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Glomerular Activation of the Lectin Pathway of Complement in IgA Nephropathy Is Associated with More Severe Renal Disease

Cited by 367 publications

References 49 publications

Association of C4d Deposition with Clinical Outcomes in IgA Nephropathy

Association of C4d Deposition with Clinical Outcomes in IgA Nephropathy

Early Diagnosis of Tuberculosis-Associated IgA Nephropathy with ESAT-6

Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways

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