Mannose-binding lectin and the balance between immune protection and complication

Takahashi, Kazue

doi:10.1586/eri.11.136

Cited by 47 publications

(43 citation statements)

References 141 publications

(169 reference statements)

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“…Here we show that MBL, an LP equivalent to C1q, is also present in human AAA tissues. The LP is increasingly recognized as an essential regulator of hemostasis/ inflammation and a significant contributor to cardiovascular diseases (35)(36)(37)(38). Inhibitors of the LP pathway modulate coagulation disorders and protect against ischemia/reperfusion injury (38,39).…”

Section: Discussionmentioning

confidence: 99%

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Zhou

Yan

Bertram

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Abdominal aortic aneurysm (AAA) is a common vascular disease associated with high mortality rate due to progressive enlargement and eventual rupture. There is currently no established therapy known to alter the rate of aneurysmal expansion. Thus, understanding the processes that initiate and sustain aneurysmal growth is pivotal for the development of medical therapies aimed at halting disease progression. Using an elastase-induced AAA mouse model that recapitulates key features of human AAA, we previously reported that a natural IgG antibody directs alternative pathway complement activation and initiates the inflammatory process that culminates in aneurysmal development. The target of this natural antibody, however, was unknown. Herein we identify a natural IgG that binds to fibrinogen deposited in elastaseperfused aortic tissues, activates the complement lectin pathway (LP), and induces AAA. Moreover, we establish that alterations in the glycosylation patterns of this antibody critically affect its ability to activate the LP in vivo. We find that LP activation precedes the alternative pathway and absence of the LP complement protein mannan-binding lectin abrogates elastase-induced AAA. In human AAA tissues the mouse anti-fibrinogen antibody recognizes epitopes that localize to the same areas that stain positively for mannan-binding lectin, which suggests that the complement LP is engaged in humans as well. Lastly, we demonstrate that circulating antibodies in a subset of AAA patients react against fibrinogen or fibrinogen-associated epitopes in human aneurysmal tissues. Our findings support the concept that an autoimmune process directed at aortic wall self-antigens may play a central role in the immunopathogenesis of AAA.A bdominal aortic aneurysm (AAA) is a common vascular disorder that affects ∼5% of men and ∼1.5% of women ages 65 and older (1, 2). Rupture of AAA presents a medical emergency that accounts for 15,000 deaths annually in the United States (3). Currently, surgical repair represents the only treatment option for large AAAs, whereas surgery in small AAAs offers no clear overall long-term survival advantage (4, 5). Thus, medical management, to inhibit or reverse the progression of small AAAs, has received increasing attention. Major challenges remain in the development of therapeutic agents that impede aneurysm expansion, as our understanding of the pathophysiology underlying this disease is incomplete.One of the defining characteristics of AAA is inflammation accompanied by a cellular infiltrate that is predominantly lymphocytic (6-8). The elastase-induced AAA mouse model recapitulates many key features of human AAA, including the inflammatory response (9). We previously established with this model that aneurysm development requires factor B and properdin of the complement alternative pathway (AP) (10, 11). We showed that mice deficient in B cells (and hence antibodies), called μMT mice, are protected against aneurysm formation. Reconstitution with natural IgG, but not IgM, from wild-type mice res...

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Section: Discussionmentioning

confidence: 99%

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Zhou

Yan

Bertram

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…This may be explained by impaired clearance of cellular waste because low MBL was shown to compromise the immune response and to limit the capacity to remove waste products such as apoptotic cells. 7,8,27 Consequently, individuals with low MBL may be more prone to develop low-grade inflammation as a result of chronic infections and impaired turnover of dysfunctional tissues. MBL was not associated with endothelial dysfunction, which suggests that associations of low MBL with higher low-grade inflammation and cIMT may indeed be explained by a crucial role of MBL in clear-up processes inside the vessel wall rather than by effects on endothelial activation or damage.…”

Section: Discussionmentioning

confidence: 99%

“…At baseline, 28% of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) participants had CVD and 16% had CVE. In Table I 1,4,7,10 For this reason, the A/0 and 0/0 individuals were combined into 1 group in the regression analyses.…”

Section: Study Populationmentioning

confidence: 99%

“…[2][3][4][5] This harmful effect of low MBL was explained by its role as a pattern-recognition molecule in the clearance of pathogens and apoptotic cells in the vessel wall. [6][7][8] However,…”

mentioning

confidence: 99%

“…MBL circulates in plasma as a complex with MBL-associated proteases (MASPs) and MBL-associated proteins (MAps) that mediate or regulate downstream complement activation. 7,17,18 In humans, MASPs and MAps have been measured in case-control studies or during acute cardiovascular events (CVEs), [19][20][21] but longitudinal studies on the role of MASPs and MAps in CVD are not yet available.…”

mentioning

confidence: 99%

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Distinct Longitudinal Associations of MBL, MASP-1, MASP-2, MASP-3, and MAp44 With Endothelial Dysfunction and Intima–Media Thickness

Hertle

Arts

Kallen

et al. 2016

ATVB

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12associations with future CVD. When the effect of MBL on complications of established CVD was investigated, low MBL was in fact protective in most studies. [13][14][15] Thus, considerable discrepancy remains in the literature on whether MBL has beneficial or adverse effects in CVD.This reported discrepancy might be explained by a dual role of MBL in different etiologic aspects of CVD. Objective-Previous studies suggested that the lectin-complement pathway plays a complex role in cardiovascular disease (CVD). To date, no prospective human studies have investigated the relationship between the initiating factor of the lectin pathway, that is, mannose-binding lectin (MBL), and low-grade inflammation, endothelial dysfunction, or carotid intima-media thickness (cIMT). Moreover, MBL-associated proteases (MASPs) and MBL-associated proteins (MAps), which mediate downstream complement activation, have not been studied in the development of CVD. Approach and Results-In a prospective cohort (n=574; age 60±7 years; 7-year follow-up), we investigated longitudinal associations of plasma MBL, MASP-1, MASP-2, MASP-3, and MAp44 with biomarker scores that reflect low-grade inflammation and endothelial dysfunction, respectively, and with cIMT. We also investigated their associations with incident CVD (n=73). In adjusted analyses, low-grade inflammation was lowest in the middle tertile (T Middle )

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MBL2polymorphisms in women with atypical squamous cells of undetermined significance

et al. 2015

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Infection with high risk Human papillomavirus (HPV) is the main known cause of cervical cancer. HPV induces different grades of lesions: among them, Atypical squamous cells of undetermined significance are abnormal lesions that could evolve in pre-cancer lesions or spontaneously regress. The mannose binding lectin (MBL) is an innate immunity serum protein also found in cervico-vaginal mucosa, whose expression is known to be affected by polymorphisms in exon 1 and promoter of the MBL2 gene. In the present study the possible association between MBL2 functional polymorphisms and susceptibility to develop atypical squamous cells of undetermined significance was investigated in a group of women from North-East of Italy, stratified for HPV infection status. The MBL2 D and O alleles and the deficient producer combined genotypes, responsible for low MBL production, were more represented among atypical squamous cells of undetermined significance positive women than healthy controls and the results were confirmed when only HPV negative samples were considered. These results suggest a possible involvement of MBL2 functional polymorphisms in atypical squamous cells of undetermined significance susceptibility.

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Mannose-binding lectin and the balance between immune protection and complication

Cited by 47 publications

References 141 publications

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Distinct Longitudinal Associations of MBL, MASP-1, MASP-2, MASP-3, and MAp44 With Endothelial Dysfunction and Intima–Media Thickness

MBL2polymorphisms in women with atypical squamous cells of undetermined significance

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