Mannose-Binding Lectin Is a Regulator of Inflammation That Accompanies Myocardial Ischemia and Reperfusion Injury

Walsh, Mary F.; Bourcier, Todd; Takahashi, Kazue; Shi, Lei; Busche, Marc N.; Rother, Russell P.; Solomon, Scott D.; Ezekowitz, R. A. B.; Stahl, Gregory L.

doi:10.4049/jimmunol.175.1.541

Cited by 217 publications

(233 citation statements)

References 47 publications

(44 reference statements)

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“…MBL may enhance inflammation-mediated tissue injury during postischemic reperfusion by complement activation (14)(15)(16). MBL has also been suggested to be a mediator in the pathogenesis of microvascular complications in type 1 diabetes (36) as well as graft survival after kidney transplantation (37).…”

Section: Discussionmentioning

confidence: 99%

“…Lack of functional alleles in some populations is associated with increased risk of atherosclerosis and cardiovascular occlusion (9)(10)(11)(12)(13). However, experimental data and clinical observations suggest that MBL and the lectin pathway of complement may initiate the inflammatory reaction seen in relation to ischemia reperfusion injury (14)(15)(16). Moreover, subjects who are homozygous for the functional MBL2 genotype and have high serum levels of MBL have the highest rate of early restenosis after carotid eversion endarterectomy (17).…”

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confidence: 99%

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Genetically determined high serum levels of mannose-binding lectin and agalactosyl IgG are associated with ischemic heart disease in rheumatoid arthritis

Troelsen¹,

Garred²,

Madsen³

et al. 2006

Arthritis Rheum

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Objective. Patients with rheumatoid arthritis (RA) have excess morbidity and mortality due to ischemic heart disease. It has been suggested that high serum levels of mannose-binding lectin (MBL) and agalactosyl IgG (IgG-G0) are associated with increased inflammation in RA. MBL also enhances inflammationmediated tissue injury during postischemic reperfusion. This study was undertaken to examine whether these factors are associated with increased risk of ischemic heart disease in RA.Methods. MBL alleles were genotyped in 229 Danish patients with RA. In addition, serum levels of MBL and IgG-G0 were measured. Incidences of ischemic heart disease, myocardial infarction, and death due to ischemic heart disease after the diagnosis of RA were assessed in a prospective study.Results. During a median followup of 9.5 years, ischemic heart disease was diagnosed in 8 of 27 patients with genetically determined high serum levels of MBL, as compared with 24 of the remaining 192 patients (data not available on 10 patients). After correction for other known risk factors, the hazard ratio (HR) was 3.6 (95% confidence interval [95% CI] 1.4-9.2). The corrected HR for myocardial infarction was 9.0 (95% CI 2.2-36.4).High serum levels of MBL also conferred an increased risk of death due to ischemic heart disease (age-and sex-adjusted HR 10.5, 95% CI 2.7-41.3). However, further analyses showed that these associations were present only in patients with high serum levels of IgG-G0.Conclusion. Genetically determined high serum levels of MBL and high serum levels of IgG-G0 are associated with increased risk of ischemic heart disease, myocardial infarction, and premature death in patients with RA.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Genetically determined high serum levels of mannose-binding lectin and agalactosyl IgG are associated with ischemic heart disease in rheumatoid arthritis

Troelsen¹,

Garred²,

Madsen³

et al. 2006

Arthritis Rheum

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“…However, MBL plays a dual role in modifying inflammatory responses to injury [34]. Mice that lack MBL, and hence are devoid of MBL-dependent lectin pathway activation but have fully active alternative and classical complement pathways, are protected from cardiac reperfusion injury with resulting preservation of cardiac function [35]. In fact, variant MBL alleles that cause dominant low-serum concentrations have high frequencies in all populations studied; therefore, low MBL concentrations may confer selective advantages on individuals carrying the variant alleles [34].…”

Section: Discussionmentioning

confidence: 99%

Protection from inflammatory disease in insulin resistance: the role of mannan-binding lectin

Fernández-Real¹,

Strączkowski

Vendrell

et al. 2006

Diabetologia

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Aims/hypothesis Decreased sensing of the innate immune system may lead to chronic activation of the inflammatory cascade. We hypothesised that mannan-binding lectin (MBL) deficiency may confer risk of obesity and insulin resistance. Materials and methods We performed a cross-sectional study of MBL protein concentration (n=434) and MBL2 gene mutations (exon 1) (n=759) in association with obesity, markers of inflammation and insulin action (euglycaemic clamp, n=113), and a longitudinal study of MBL protein before and after weight loss in obese patients (n=10). We also studied the effects of MBL in vitro in muscle cells and circulating MBL-A (mouse equivalent of human MBL) in a mouse model. Results Among 434 consecutive non-diabetic men, the ageadjusted serum MBL concentration was lower in obese subjects than in lean subjects (median: 959 μg/ml [interquartile range: 116.8-2,044 μg/ml] vs 1,365 [467-2,513] μg/ml; p=0.01) and was accompanied by increased serum inflammatory markers. Insulin action correlated significantly with serum MBL (r=0.49, p<0.0001). Serum MBL concentration increased by a median of 110.2% after weight loss. The change in serum concentration of MBL was positively associated with the increase in insulin sensitivity (r=0.713, p=0.021). At least one MBL2 gene mutation was present in 48.2% of obese vs 39.3% of non-obese subjects (p=0.037). The plasma concentration of MBL-A was lower in insulinresistant obese ob/ob mice, as was the glucose/insulin ratio. Incubation of rat soleus muscle with human MBL markedly increased fatty acid oxidation. Conclusions/interpretation These findings suggest that MBL, previously thought only to be involved in inflammation and immune system function, affects metabolic pathways.

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“…A study (35) in a stroke model also found that the powerful neuroprotective action of C1 inhibitor (C1-INH) on brain I/R injury does not require C1q, an early component in the classical pathway of complement. Recently, Stahl and colleagues (36,37) reported that MBL-deficient mice displayed limited injury in the intestinal or myocardial I/R models. They showed that C2-knockout, but not C1q-deficient, mice were protected in the intestinal I/R model (36).…”

Section: Activation Of the Lectin Pathway By Natural Igm In A Modelmentioning

confidence: 99%

Activation of the Lectin Pathway by Natural IgM in a Model of Ischemia/Reperfusion Injury

Zhang

Takahashi

Alicot

et al. 2006

The Journal of Immunology

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128

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Reperfusion of ischemic tissues elicits an acute inflammatory response involving serum complement, which is activated by circulating natural IgM specific to self-Ags exposed by ischemia. Recent reports demonstrating a role for the lectin pathway raise a question regarding the initial events in complement activation. To dissect the individual roles of natural IgM and lectin in activation of complement, mice bearing genetic deficiency in early complement, IgM, or mannan-binding lectin were characterized in a mesenteric model of ischemia reperfusion injury. The results reveal that IgM binds initially to ischemic Ag providing a binding site for mannan-binding lectin which subsequently leads to activation of complement and injury.

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Mannose-Binding Lectin Is a Regulator of Inflammation That Accompanies Myocardial Ischemia and Reperfusion Injury

Cited by 217 publications

References 47 publications

Genetically determined high serum levels of mannose-binding lectin and agalactosyl IgG are associated with ischemic heart disease in rheumatoid arthritis

Genetically determined high serum levels of mannose-binding lectin and agalactosyl IgG are associated with ischemic heart disease in rheumatoid arthritis

Protection from inflammatory disease in insulin resistance: the role of mannan-binding lectin

Activation of the Lectin Pathway by Natural IgM in a Model of Ischemia/Reperfusion Injury

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