Association of familial deficiency of mannose-binding lectin and meningococcal disease

Bax, Willem A.; Cluysenaer, O. J. J.; Bartelink, A. K. M.; Aerts, Piet C.; Ezekowitz, R. A. B.; Dijk, Hans van

doi:10.1016/s0140-6736(99)02563-5

Cited by 62 publications

(47 citation statements)

References 2 publications

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“…Genetic deficiencies and polymorphisms in PRM genes recently have been appreciated to have a role in susceptibility and response to infectious pathogens (38). CF patients lack functional CFTR and are hypersusceptible to lung infections with a variety of bacterial pathogens; P. aeruginosa is the predominant pathogen that is responsible for most of the morbidity and mortality in CF.…”

Section: Discussionmentioning

confidence: 99%

CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-κB translocation

Schroeder

Lee

Yacono

et al. 2002

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

127

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Immune cells are activated during cellular responses to antigen by two described mechanisms: (i) direct uptake of antigen and (ii) extraction and internalization of membrane components from antigen-presenting cells. Although endocytosis of microbial antigens by pattern recognition molecules (PRM) also activates innate immunity, it is not known whether this involves extraction and internalization of microbial surface components. Epithelial cells on mucosal surfaces use a variety of receptors that are distinct from the classical endocytic PRM to bind and internalize intact microorganisms. Nonclassical receptor molecules theoretically could act as a type of endocytic PRM if these molecules could recognize, bind, extract, and internalize a pathogen-associated molecule and initiate cell signaling. We report here that the interaction between the cystic fibrosis transmembrane conductance regulator (CFTR) and the outer core oligosaccharide of the lipopolysaccharide (LPS) in the outer membrane of Pseudomonas aeruginosa satisfies all of these conditions. P. aeruginosa LPS was specifically recognized and bound by CFTR, extracted from the organism's surface, and endocytosed by epithelial cells, leading to a rapid (5-to 15-min) and dynamic translocation of nuclear transcription factor NF-B. Inhibition of epithelial cell internalization of P. aeruginosa LPS prevented NF-B activation. Cellular activation depended on expression of wild-type CFTR, because both cultured ⌬F508 CFTR human airway epithelial cells and lung epithelial cells of transgenic-CF mice failed to endocytose LPS and translocate NF-B. CFTR serves as a critical endocytic PRM in the lung epithelium, coordinating the effective innate immune response to P. aeruginosa infection.

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Section: Discussionmentioning

confidence: 99%

CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-κB translocation

Schroeder

Lee

Yacono

et al. 2002

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

127

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“…A lack of SP-A in mice enhances infections originating from the respiratory tract, most notably Group B Streptococcus and Pseudomonas (41). In humans, deficient expression of MBL because of allelic variation has been associated with meningococcal disease (54,55) and severe cystic fibrosis complicated with Pseudomonas aeruginosa infection (56). A particular SP-A haplotype, on the other hand, associates with susceptibility to recurrent respiratory infections in infants (57).…”

Section: Discussionmentioning

confidence: 99%

“…The role of different TLRs in such diseases as cystic fibrosis as well as the efforts to ascertain whether polymorphisms in TLRs play a role in modifying the innate responses in this and other childhood diseases will inevitably attract a great deal of attention. Deficient or altered proteins involved in microbial binding or subsequent signaling potentially lead to an inappropriate acquired immune response (54,55,59). The role of innate immunity is critical during early childhood, when the clonal development of antibodies and other host defenses is inadequate.…”

mentioning

confidence: 99%

Toll-like Receptors as Sensors of Pathogens

2001

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“…In recent years, the association between genetic variations in MBL2 , and to a lesser extent FCN2 , and susceptibility to disease have been the subject of various studies 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31. An association between MBL2 polymorphisms and clinical outcome has been described in children with recurrent infections22 and in adult patients with meningococcal sepsis 17…”

Section: Introductionmentioning

confidence: 99%

“…An association between MBL2 polymorphisms and clinical outcome has been described in children with recurrent infections22 and in adult patients with meningococcal sepsis 1729 Behçet's disease,20 peritonitis in patients undergoing peritoneal dialysis28 and recurrent respiratory infections in children 16, 18.…”

Section: Introductionmentioning

confidence: 99%

Mannose‐binding lectin and l‐ficolin polymorphisms in patients with community‐acquired pneumonia caused by intracellular pathogens

et al. 2017

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SummaryCommunity‐acquired pneumonia (CAP) is the leading infectious disease requiring hospitalization in the western world. Genetic variability affecting the host response to infection may play a role in susceptibility and outcome in patients with CAP. Mannose‐binding lectin (MBL) and l‐ficolin (l‐FCN) are two important activators of the complement system and they can enhance phagocytosis by opsonization. In a prospective cohort of 505 Dutch patients with CAP and 227 control participants we studied whether polymorphisms in the MBL (MBL2) and FCN (FCN2) genes influenced susceptibility and outcome. No difference in frequency of these genotypes was found between patients with CAP in general and controls. However, the +6424G>T single nucleotide polymorphism (SNP) in FCN2 was more common in patients with a Coxiella burnetii pneumonia (P = 0·014). Moreover, the haplotypes coding for the highest MBL serum levels (YA/YA and YA/XA) predisposed to atypical pneumonia (C. burnetii, Legionella or Chlamydia species or Mycoplasma pneumoniae) compared with controls (P = 0·016). Furthermore, patients with these haplotypes were more often bacteraemic (P = 0·019). It can therefore be concluded that MBL2 and FCN2 polymorphisms are not major risk factors for CAP in general, but that the +6424G>T SNP in the FCN2 gene predisposes to C. burnetii pneumonia. In addition, patients with genotypes corresponding with high serum MBL levels are at risk for atypical pneumonia, possibly caused by enhanced phagocytosis, thereby promoting cell entry of these intracellular bacteria.

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Association of familial deficiency of mannose-binding lectin and meningococcal disease

Cited by 62 publications

References 2 publications

CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-κB translocation

CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-κB translocation

Toll-like Receptors as Sensors of Pathogens

Mannose‐binding lectin and l‐ficolin polymorphisms in patients with community‐acquired pneumonia caused by intracellular pathogens

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