Extremes of <scp>l</scp>-ficolin concentration in children with recurrent infections are associated with single nucleotide polymorphisms in the <i>FCN2</i> gene

Cedzyński, Maciej; Nuytinck, Lieve; Atkinson, Apm; Świerzko, Anna St.; Zeman, Krzysztof; Szemraj, Janusz; Szala, Agnieszka; Turner, M.; Dc, Kilpatrick

doi:10.1111/j.1365-2249.2007.03471.x

Cited by 53 publications

(52 citation statements)

References 21 publications

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“…Much like MBL, L-ficolin has been observed to be present in the bronchoalveolar lavage fluid following inflammation (J. D. Chalmers, personal communication; 37). L-Ficolin gene polymorphisms and insufficiencies have been acknowledged to have implications for allergic inflammation and recurrent respiratory infections (38,39). We therefore investigated whether ficolin-A and L-ficolin could modulate the association of A. fumigatus conidia with A549 airway epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Role of Ficolin-A and Lectin Complement Pathway in the Innate Defense against Pathogenic Aspergillus Species

et al. 2013

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Aspergillus species are saprophytic molds causing life-threatening invasive fungal infections in the immunocompromised host. Innate immune recognition, in particular, the mechanisms of opsonization and complement activation, has been reported to be an integral part of the defense against fungi. We have shown that the complement component ficolin-A significantly binds to Aspergillus conidia and hyphae in a concentration-dependent manner and was inhibited by N-acetylglucosamine and N-acetylgalactosamine. Calcium-independent binding to Aspergillus fumigatus and A. terreus was observed, but binding to A. flavus and A. niger was calcium dependent. Ficolin-A binding to conidia was increased under low-pH conditions, and opsonization led to enhanced binding of conidia to A549 airway epithelial cells. In investigations of the lectin pathway of complement activation, ficolin-A-opsonized conidia did not lead to lectin pathway-specific C4 deposition. In contrast, the collectin mannose binding lectin C (MBL-C) but not MBL-A led to efficient lectin pathway activation on A. fumigatus in the absence of ficolin-A. In addition, ficolin-A opsonization led to a modulation of the proinflammatory cytokine interleukin-8. We conclude that ficolin-A may play an important role in the innate defense against Aspergillus by opsonizing conidia, immobilizing this fungus through enhanced adherence to epithelial cells and modulation of inflammation. However, it appears that other immune pattern recognition molecules, i.e., those of the collectin MBL-C, are involved in the Aspergillus-lectin complement pathway activation rather than ficolin-A.

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Section: Discussionmentioning

confidence: 99%

Role of Ficolin-A and Lectin Complement Pathway in the Innate Defense against Pathogenic Aspergillus Species

et al. 2013

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“…Krarup et al [21] showed that L-ficolin binds to some capsulated S t reptococcus pneumoniae serotypes. Cedzynski et al [42] estimated serum L-ficolin concentrations in children with recurrent respiratory infections and predicted that high L-ficolin concentrations could confer enhanced protection from some infectious disorders. In this study, we found that the collectin molecule L-ficolin bound the envelope glycoproteins HA and NA and that L-ficolin enhanced mouse resistance to the influenza A virus.…”

Section: Discussionmentioning

confidence: 99%

L-Ficolin Binds to the Glycoproteins Hemagglutinin and Neuraminidase and Inhibits Influenza A Virus Infection Both in vitro and in vivo

Pan¹,

Chen²,

Wang³

et al. 2012

J Innate Immun

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L-ficolin, one of the complement lectins found in human serum, is a novel pattern recognition molecule that can specifically bind to microbial carbohydrates, thereby activating the lectin complement pathway and mounting a protective innate immune response. However, little is known about the role of L-ficolin during viral infections in vivo. In the present study, we used a mouse model of influenza A virus infection to demonstrate that the administration of exogenous L-ficolin or ficolin A (FCNA – an L-ficolin-like molecule in the mouse) is protective against the virus. Furthermore, FCNA-null mice have a greatly increased susceptibility to infection with the influenza A virus. Moreover, we found recombinant human L-ficolin inhibited influenza A virus entry into Madin-Darby canine kidney cells. More importantly, L-ficolin can recognize and bind hemagglutinin (HA) and neuraminidase (NA) glycoproteins and different subtypes of influenza A virus, and these interactions can be competitively inhibited by N-acetyl-D-glucosamine. In addition, the binding of L-ficolin and FCNA may lead to the activation of the lectin complement pathway. To our knowledge, this is the first report demonstrating that L-ficolin can block influenza virus infections both in vitro and in vivo using FCNA-knockout mice, possibly by interacting with the carbohydrates of HA and NA. Therefore, these data may provide new immunotherapeutic strategies based on the innate immune molecule L-ficolin against the influenza A virus.

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“…Unlike MBL2 polymorphisms, which produce substantial variation in the concentration and function of MBL over a 1,000-fold range, ficolin levels in the presence of these FCN2 and FCN3 polymorphisms vary at most by only a factor of 20 [74,75] , with no absolute deficiency identified. Associations between FCN2 [76] and FCN3 [74] single nucleotide polymorphisms and low or high serum levels are becoming apparent.…”

Section: Molecular and Clinical Comparisons Between Ficolins And Mblmentioning

confidence: 99%

Mannose-Binding Lectin Deficiency and Respiratory Tract Infection

Eisen¹

2009

J Innate Immun

119

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Mannose-binding lectin (MBL) is an innate immune system pattern recognition protein that kills a wide range of pathogenic microbes through complement activation. A substantial proportion of all human populations studied to date have MBL deficiency due to MBL2 polymorphisms, which potentially increases susceptibility to infectious disease. MBL binds numerous respiratory pathogens but the capsule of Streptococcus pneumoniae abrogates its efficient binding. Clinical studies in humans have shown that MBL deficiency appears to predispose to severe respiratory tract infection. A recent meta-analysis shows that MBL deficiency was associated with death in patients with pneumococcal infection after adjusting for bacteraemia and comorbidities. Human clinical studies have also shown associations between MBL deficiency and various less common respiratory infections. Intracellular infections like tuberculosis may be less common with MBL deficiency because of reduced opsonophagocytosis. Lung secretions contain small amounts of MBL that are potentially sufficient to activate complement, but their measurement is confounded by dilution inherent in collection techniques. Therefore, if this protein does play a role in pulmonary immunity it is presumably through prevention of haematogenous dissemination of respiratory pathogens while adding to mucosal defences. Ficolins are collectins that are structurally and functionally related to MBL and are either present in serum or expressed in tissues including the lung. Limited variation in serum levels of L- and H-ficolin result from the presence of FCN2 and FCN3 polymorphisms. Initial studies on the impact of FCN2 polymorphisms or low L-ficolin levels do not seem to show major associations with respiratory infection. MBL is being developed as a new immunotherapeutic agent for prevention of infection in immunocompromised hosts. The available literature suggests that it may also be of benefit in MBL deficient patients with severe pneumonia. This review concentrates on clinical associations between MBL deficiency and susceptibility to respiratory tract infection.

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Extremes of l-ficolin concentration in children with recurrent infections are associated with single nucleotide polymorphisms in the FCN2 gene

Cited by 53 publications

References 21 publications

Role of Ficolin-A and Lectin Complement Pathway in the Innate Defense against Pathogenic Aspergillus Species

Role of Ficolin-A and Lectin Complement Pathway in the Innate Defense against Pathogenic Aspergillus Species

L-Ficolin Binds to the Glycoproteins Hemagglutinin and Neuraminidase and Inhibits Influenza A Virus Infection Both in vitro and in vivo

Mannose-Binding Lectin Deficiency and Respiratory Tract Infection

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