Complement regulation in innate immunity and the acute-phase response: inhibition of mannan-binding lectin-initiated complement cytolysis by C-reactive protein (CRP)

Suankratay, Chusana; Mold, Carolyn; Zhang, Y; Potempa, Lawrence A.; Lint, Thomas F.; Gewürz, Henry

doi:10.1046/j.1365-2249.1998.00663.x

Cited by 44 publications

(29 citation statements)

References 31 publications

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“…In this context it is worth noting that we have previously shown an association of AER with the inflammatory markers CRP and IL-6 in diabetic patients with incipient or overt nephropathy [3]. One explanation for the lack of correlation between MBL and inflammatory markers could also come from the simple fact that CRP may inhibit the production of MBL [14,15]. On the other hand, it has been suggested that MBL and CRP are [15].…”

Section: Discussionmentioning

confidence: 91%

“…One explanation for the lack of correlation between MBL and inflammatory markers could also come from the simple fact that CRP may inhibit the production of MBL [14,15]. On the other hand, it has been suggested that MBL and CRP are [15]. Even if we could not confirm a relationship between MBL and eGDR in the multivariate analysis, there was a negative correlation between MBL and eGDR as well as between MBL and HDL cholesterol in the simple regression analysis, suggesting that MBL may be a marker of insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

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Increased levels of mannan-binding lectin in type 1 diabetic patients with incipient and overt nephropathy

et al. 2004

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Aims/hypothesis: Diabetic nephropathy is associated with insulin resistance, and low-grade inflammation and activation of the complement system may contribute to this cascade. Mannan-binding lectin (MBL) activates the complement system, and elevated MBL concentrations have been observed in normoalbuminuric type 1 diabetic patients. The aim of this study was to assess whether MBL is associated with diabetic nephropathy in type 1 diabetes, and whether there is an association between MBL and low-grade inflammatory markers or insulin resistance. Methods: A total of 191 type 1 diabetic patients from the Finnish Diabetic Nephropathy Study were divided into three groups based upon their AER. Patients with normal AER (n=67) did not take antihypertensive medication, while patients with microalbuminuria (n=62) or macroalbuminuria (n=62) were all treated with an ACE inhibitor. As a measure of insulin sensitivity we used estimated glucose disposal rate. MBL was measured by an immunofluorometric assay, C-reactive protein by a radioimmunoassay and IL-6 by high-sensitivity enzyme immunoassay. There was a significant correlation between MBL and estimated glucose disposal rate, but not between MBL and C-reactive protein or IL-6 levels in univariate analysis. However, in a multiple regression analysis, HbA1c was the single variable independently associated with MBL (β±SEM: 0.26±0.08; p=0.003). Conclusions/interpretation: MBL concentrations are increased in type 1 diabetic patients with diabetic nephropathy. MBL was not associated with low-grade inflammatory markers.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Increased levels of mannan-binding lectin in type 1 diabetic patients with incipient and overt nephropathy

et al. 2004

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“…When patients were divided according to the median level of MBL measured close to diabetes onset and before the development of microalbuminuria, there was a significantly higher cumulative incidence of persistent micro-or macroalbuminuria in patients with serum MBL above the median than in those patients with levels below the median (41% [CI 31-50] vs. 26% [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]; P ϭ 0.003). Furthermore, we have demonstrated for the first time that a high level of MBL early in the course of type 1 diabetes is significantly associated with later development of persistent micro-or macroalbuminuria, suggesting that MBL-initiated complement activation may be involved in the pathogenesis of microvascular complications in diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, adjustments for differences in CRP levels have had no impact on the association between MBL and microvascular complications (5). Even though CRP and MBL are closely interrelated in inflammation and CRP may inhibit MBL activity (26), the evaluation of these markers of inflammation gives rise to different information in the diabetic patients. The association of blood pressure, endothelial damage, and serum MBL remains to be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Mannose-Binding Lectin as a Predictor of Microalbuminuria in Type 1 Diabetes

et al. 2005

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A substantial portion of type 1 diabetic patients develop diabetic nephropathy, whereas others seem to be protected from this complication. Persistent microalbuminuria (urinary albumin excretion rate [UAER] of 30 -300 mg/24 h) is an established risk factor for the development of overt diabetic nephropathy, characterized by albuminuria Ͼ300 mg/24 h (1). Microalbuminuria may be regarded as an early marker of diabetic kidney disease, as early renal structural lesions can be detected at this stage (2). Genetic susceptibility, metabolic abnormalities, hemodynamic changes, upregulated growth factors, and cytokines may all play a part in the development of diabetic glomerulopathy, although the complex pathogenesis of diabetic nephropathy is not fully understood (1). It has been suggested that inflammation and complement activation are involved in the pathogenesis of diabetic microvascular complications (3-6). Mannose-binding lectin (MBL; also known as mannan-binding lectin) can activate the complement system independent of antibodies via MBL-associated serine proteases, thereby initiating the so-called MBL pathway of complement activation (7). Through this pathway, MBL plays an important role in the innate immune system. The level of MBL varies considerably among individuals, mainly because of frequently occurring polymorphisms within exon 1 as well as in the promoter region of the MBL2 gene on chromosome 10 (8). High levels of MBL are known to protect against invading microorganisms (9,10) and in other situations may mediate detrimental inflammation through exaggerated complement activation (11,12). In a recent cross-sectional study, it was demonstrated that in normoalbuminuric type 1 diabetic patients, circulating MBL levels correlate positively with the UAER (4). Higher levels of MBL have been found to be associated with micro-and macrovascular complications in type 1 diabetic patients (5). However, no prospective studies have evaluated the association between MBL and subsequent development of microvascular complications. In the present study, MBL was measured 3 years after diabetes onset in a large inception cohort of newly diagnosed type 1 diabetic patients. These patients were followed for a median of 18 years to evaluate in a prospective design the association between baseline MBL concentrations and the development of persistent microalbuminuria. The change in MBL levels during 15 years of diabetes was also assessed.

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“…17 Surface-bound CRP decreases the alternative complement pathway C3-convertase and C5-convertase activities, inhibits the alternative amplification loop and reduces deposition of C3b and lysis by the lectin pathway. [18][19][20] An important observation to understand the complex biological role of CRP-induced complement activation was the description of a direct binding of the complement regulatory proteins factor H (FH) 21 and C4b-binding protein (C4BP) 15 to CRP. These inhibitory effects result from an increased binding of complement regulatory protein FH to CRP-coated surfaces.…”

Section: Introductionmentioning

confidence: 99%

Studies on the interactions between C‐reactive protein and complement proteins

et al. 2007

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Studies on the interactions between C-reactive protein and complement proteins IntroductionThe classical acute-phase reactant C-reactive protein (CRP) is a pentameric, disc-shaped serum protein.1 Its basic features are the control of inflammation, the stimulation of clearance of damaged cell and tissue components, and the initiation of repair functions.2 CRP shows calcium-dependent affinity for phosphate monoesters, such as phosphatidylcholine, but several other ligands of CRP have been characterized, including damaged cell membranes, small ribonucleoprotein particles, apoptotic cells and fibronectin. Native CRP can undergo subunit dissociation into individual monomeric units, for example upon association with negatively charged lipid monolayers. 4 This modified form of CRP can be produced in vitro by urea chelation, acid treatment, heating or direct immobilization of native CRP onto polystyrene.5 This modified form of CRP (mCRP) has reduced solubility and exhibits different electrophoretic characteristics as the result of a decrease of isoelectric point (pI) from 6Á4 to 5Á4. 6 The structural changes releasing CRP subunits from the pentamer are correlated with expression of a new antigenic reactivity and formation of neo-epitopes. 7 The forms of CRP expressing SummarySeveral studies have investigated the interactions between C-reactive protein (CRP) and various complement proteins but none of them took into consideration the different structural forms of CRP. The aim of our study was to investigate whether the different antigenic forms of CRP are able to bind C1q, to trigger activation of the C1 complex and to study the ability of the various CRP forms to bind complement factor H (FH) and C4b-binding protein (C4BP). Interactions between various CRP forms and complement proteins were analysed in enzyme-linked immunosorbent assay and surface plasmon resonance tests and activation of the C1 complex was followed in a reconstituted system using purified C1q, C1r and C1s in the presence of C1-INH. Native, ligand-unbound CRP activated the classical pathway weakly. After binding to phosphocholine, native CRP bound C1q and significantly activated C1. Native CRP complexed to phosphocholine did not bind the complement regulatory proteins FH and C4BP. After disruption of the pentameric structure of CRP, as achieved by urea-treatment or by site-directed mutagenesis, C1q binding and C1 activation further increased and the ability of CRP to bind complement regulatory proteins was revealed. C1q binds to CRP through its globular head domain. The binding sites on CRP for FH and C4BP seemed to be different from that of C1q. In conclusion, in parallel with the increase in the C1-activating ability of different CRP structural variants, the affinity for complement regulatory proteins also increased, providing the biological basis for limitation of excess complement activation.

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Complement regulation in innate immunity and the acute-phase response: inhibition of mannan-binding lectin-initiated complement cytolysis by C-reactive protein (CRP)

Cited by 44 publications

References 31 publications

Increased levels of mannan-binding lectin in type 1 diabetic patients with incipient and overt nephropathy

Increased levels of mannan-binding lectin in type 1 diabetic patients with incipient and overt nephropathy

Mannose-Binding Lectin as a Predictor of Microalbuminuria in Type 1 Diabetes

Studies on the interactions between C‐reactive protein and complement proteins

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