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PubMed1993

Collectins: pattern recognition molecules involved in first line host defense.

A group of chimeric molecules comprising globular heads, which contain the carbohydrate recognition domain, and collagen tails are defined as collectins. The mannose-binding proteins, pulmonary surfactant apoproteins A and D and conglutinin all qualify as members of this family, whose function appears to be as pattern recognition molecules involved in the first line of defense in the pre-immune host.

Amino Acid Sequence↗
PubMed2004

A time-resolved immunofluorometric assay for quantification of the bovine collectin conglutinin.

A high capacity time-resolved immunofluorometric assay (TRIFMA) for the bovine collectin conglutinin was developed. The TRIFMA was constructed as a non-competitive sandwich assay based on polyclonal antibodies as the capture reagent and a novel monoclonal antibody raised against conglutinin as the detection reagent and was set up to run on an automatic analyzer designed for the TRIFMA detection system. Polyclonal antibodies immobilized on microtiter plate wells were incubated overnight at 4 degrees C with diluted plasma samples, including quality controls (QC) and dilutions of a plasma with known conglutinin concentration. Conglutinin was sandwiched between the capture antibodies and the monoclonal antibody and the detection optimised with biotin-labelled secondary antibodies and streptavidin-Eu(3+). Plates were washed four times between each step and finally incubated with enhancement solution before measuring the fluorescence. The assay detection limit was 0.34 ng/ml and the working range 0.80 ng/ml-0.20 microg/ml. Intra-plate and inter-plate coefficients of variation (CV) were in the range of 5.0-8.3% and 6.2-7.2%, respectively, at concentrations of 3.4 and 150 ng/ml. Recovery was 90.9+/-2.4% and 98.8+/-2.5% when samples were spiked with 20 ng/ml and 100 ng/ml purified bovine conglutinin (BK). No circadian rhythm (24-h variation) in conglutinin plasma levels was observed across animals, indicating that the plasma levels were not influenced by, e.g. feeding. Samples could be stored at -20 degrees Celsius and were not sensitive to repeated freezing and thawing. In conclusion, the developed TRIFMA for bovine conglutinin is specific and reliable over a measurement range covering most situations.

Animals↗
PubMed2003

By binding SIRPalpha or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation.

Surfactant proteins A and D (SP-A and SP-D) are lung collectins composed of two regions, a globular head domain that binds PAMPs and a collagenous tail domain that initiates phagocytosis. We provide evidence that SP-A and SP-D act in a dual manner, to enhance or suppress inflammatory mediator production depending on binding orientation. SP-A and SP-D bind SIRPalpha through their globular heads to initiate a signaling pathway that blocks proinflammatory mediator production. In contrast, their collagenous tails stimulate proinflammatory mediator production through binding to calreticulin/CD91. Together a model is implied in which SP-A and SP-D help maintain a non/anti-inflammatory lung environment by stimulating SIRPalpha on resident cells through their globular heads. However, interaction of these heads with PAMPs on foreign organisms or damaged cells and presentation of the collagenous tails in an aggregated state to calreticulin/CD91, stimulates phagocytosis and proinflammatory responses.

Animals↗
PubMed2000

Identification of a collectin-like protein in pig serum that binds a component in perienteric fluid from Ascaris suum.

A collectin-like protein (CLP) of the acute phase protein family that binds the polysaccharides mannan and alpha-1-6 dextran was isolated from the serum of pigs infected with Ascaris suum. A monoclonal antibody generated against this protein and used to characterize the CLP revealed on SDS-PAGE and western blot analysis that the protein had a molecular weight of approximately 48 kDa under reducing conditions and greater than 100 kDa under nonreducing conditions. Enzyme-linked immunosorbent assay (ELISA) showed that the CLP bound to substances in the perienteric fluid of Ascaris suum (APF). Molecular weight fractionation of APF demonstrated that CLP binds primarily to APF substances of greater than 100 kDa. Binding of CLP to APF was partially blocked by phosphatidylinositol. This is the first report of a porcine CLP and the binding of a CLP to components of the common nematode Ascaris suum.

Animals↗
PubMed2000

Importance of the carboxy-terminal 25 amino acid residues of lung collectins in interactions with lipids and alveolar type II cells.

Surfactant proteins A and D (SP-A and SP-D) are structurally related members of the collectin family found in the alveolar compartment of the lung. SP-A binds dipalmitoylphosphatidylcholine (DPPC) and galactosylceramide (GalCer), induces liposome aggregation, and regulates the uptake and secretion of surfactant lipids by alveolar type II cells in vitro. SP-D binds phosphatidylinositol (PI) and glucosylceramide. The purpose of this study was to identify a critical stretch of primary sequence in the SP-A region Cys(204)-Phe(228) and the SP-D region Cys(331)-Phe(355) that is involved in protein-specific lipid and type II cell interactions. Chimeras ad1 and ad2 were constructed with rat SP-A/SP-D splice junctions at Cys(218)/Gly(346) and Lys(203)/Cys(331), respectively. Chimera ad1 but not ad2 retained DPPC liposome binding activity. Both chimeras retained significant binding to GalCer liposomes. Chimera ad1 did not bind to PI, whereas chimera ad2 acquired a significant PI binding. Both chimeras failed to induce liposome aggregation and to interact with alveolar type II cells. In addition, monoclonal antibody 1D6 that blocks specific SP-A functions did not recognize either chimera. From these results, we conclude that (1) the SP-A region Leu(219)-Phe(228) is required for liposome aggregation and interaction with alveolar type II cells, (2) the SP-A region Cys(204)-Cys(218) is required for DPPC binding, (3) the SP-D region Cys(331)-Phe(355) is essential for minimal PI binding, and (4) the epitope for mAb 1D6 is located at the region contiguous to the SP-A region Leu(219)-Phe(228).

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2002

Heritability estimates for the constitutional levels of the collectins mannan-binding lectin and lung surfactant protein D. A study of unselected like-sexed mono- and dizygotic twins at the age of 6-9 years.

The collectins mannan-binding lectin (MBL) and lung surfactant protein D (SP-D) play a significant role in innate immunity. Structural as wells as promoter variants are known for MBL and different alleles correlate with low MBL concentrations in serum and predispose to infectious diseases. Structural variants are also known for SP-D but these have not been linked to disease states. The aim of the present study was to provide heritability estimates for the constitutional levels of MBL and SP-D in children. A population of 26 monozygotic (MZ) and 36 dizygotic (DZ) like-sexed twin pairs aged 6-9 years was studied. Intraclass correlations were significantly higher in MZ than in DZ twins, indicating substantial genetic influence on both MBL and SP-D levels. Biometric model fitting showed that the estimated heritability was 0.96 (95% CI 0.92-0.97) for MBL with the presence of non-additive genetic factors and non-shared environmental factors and 0.91 (95% CI 0.83-0.95) for SP-D with additive genetic and non-shared environmental factors. The data indicate quantitatively very strong genetic dependence for the serum levels of both MBL and SP-D.

Biometry↗
PubMed2001

The role of the collectin system in pulmonary defence.

The human collectin system comprises the serum protein, mannose- binding lectin and the hydrophilic surfactant proteins A and D. The three proteins possess structural and functional similarities and are important components of innate immunity. Through a variety of mechanisms, including direct opsonisation and complement activation, they assist in host defence against a wide array of micro-organisms. Investigation of the roles of the surfactant proteins in pulmonary disease has been assisted recently by the development of transgenic knockout mice. Animals deficient in these proteins display susceptibility to certain bacterial and viral pathogens, stimulating research into the role of polymorphisms in these genes in human respiratory disease. The role of MBL in human pulmonary disease is less well established, although accumulating evidence suggests that it is a modifier for lung disease in tuberculosis and cystic fibrosis.

Adult↗
PubMed1998

Analysis of chimeric proteins identifies the regions in the carbohydrate recognition domains of rat lung collectins that are essential for interactions with phospholipids, glycolipids, and alveolar type II cells.

Pulmonary surfactant proteins A (SP-A) and D (SP-D) are collectins in the C-type lectin superfamily. SP-A binds to dipalmitoylphosphatidylcholine and galactosylceramide, and it regulates the uptake and secretion of surfactant lipids by alveolar type II cells. In contrast, SP-D binds to phosphatidylinositol (PI) and glucosylceramide (GlcCer). We investigated the functional region in the carbohydrate recognition domain of rat SP-A and SP-D that is involved in binding lipids and interacting with alveolar type II cells by using chimeric proteins. Chimeras ad3, ad4, and ad5 were constructed with SP-A/SP-D splice junctions at Gly194/Glu321, Gln173/Thr300, and Met134/Cys261, respectively. All three chimeras lost SP-A-specific functions. Chimeras ad3, ad4, and ad5 bound to PI with increasing activity. In contrast, chimeras ad3 and ad4 did not bind to GlcCer, whereas ad5 avidly bound this lipid. From these results, we conclude that 1) the SP-A region of Glu195-Phe228 is required for lipid and type II cell interactions, 2) the SP-D region of Cys261-Phe355 is required for optimal lipid interactions, and 3) the structural requirement for the binding of SP-D to PI is different from that for GlcCer.

Animals↗
PubMed2005

Role of collectins in innate immunity against aspergillosis.

The protective role of lung surfactant proteins SP-A, SP-D and MBL in the host defense against both allergic and invasive aspergillosis was identified and established by a series of in vitro and in vivo studies. Therapeutic administration of SP-D and MBL proteins in a murine model of pulmonary invasive aspergillosis rescued mice from death. In mice mimicking human allergic bronchopulmonary aspergillosis, SP-A and SP-D suppressed IgE levels, eosinophilia, pulmonary cellular infiltration and cause a marked shift from a pathogenic Th2 to a protective Th1 cytokine profile. SP-A and SP-D knock-out mice studies made significant contributions in understanding the mechanisms by which SP-A and SP-D modulate the host defense response in patients suffering from pulmonary allergies and infections. The results suggested that individuals with any structural or functional defects in these innate immune molecules due to genetic variations might be susceptible to aspergillosis. SNPs in SP-A2 and MBL genes showed significant associations with patients of allergic bronchopulmonary aspergillosis in an Indian population. The patients carrying either one or both of GCT and AGG alleles of SP-A2 and patients with A allele at position 1011 of MBL had markedly higher eosinophilia, total IgE antibodies and lower FEV1 (the clinical markers of ABPA). Our results show that collectins play an important role in Aspergillus mediated allergies and infections.

Animals↗
PubMed2001

The pulmonary collectins and surfactant metabolism.

Lung surfactant covers and stabilizes a large, delicate surface at the interface between the host and the environment. The surfactant system is placed at risk by a number of environmental challenges such as inflammation, infection, or oxidant stress, and perhaps not surprisingly, it demonstrates adaptive changes in metabolism in response to alterations in the alveolar microenvironment. Recent experiments have shown that certain components of the surfactant system are active participants in the regulation of the alveolar response to a wide variety of environmental challenges. These components are capable not only of maintaining a low interfacial surface tension but also of amplifying or dampening inflammatory responses. These observations suggest that regulatory molecules are capable of both sensing the environment of the alveolus and providing feedback to the cells regulating surfactant synthesis, secretion, alveolar conversion, and clearance. In this review we examine the evidence from in vitro systems and gene-targeted mice that two surfactant-associated collectins (SP-A and SP-D) may serve in these roles and help modify surfactant homeostasis as part of a coordinated host response to environmental challenges.

Animals↗
PubMed2002

Alterations in lung collectins in an adaptive allergic immune response.

Although surfactant apoproteins are known to be mediators of innate responses, their relationship to adaptive responses has not been examined extensively. We investigated possible links between surfactant apoproteins and responses to allergens by studying alterations in surfactant apoproteins A, B, and D in a murine model of allergic pulmonary inflammation. Three murine strains (BALB/c, C57BL/6, and 129J) demonstrated increased immunostaining of surfactant apoproteins A and D in nonciliated epithelial cells of noncartilaginous airways after aerosolized challenge. In contrast, surfactant apoprotein B immunostaining was unchanged. Immunoblotting demonstrated increased surfactant A in bronchoalveolar lavage fluid after allergen sensitization and challenge. Surfactant apoprotein A and D induction required T and/or B lymphocyte responses to allergen, since the induction was absent in recombinase-activating gene-deficient mice, which lack functional lymphocytes. We conclude that increased immunoreactivity of two collectins, surfactant apoproteins A and D, occurs within the response to allergen. Our findings support a model in which surfactant apoproteins A and D are important to both innate immunity and adaptive immune responses to allergens.

Adaptation, Physiological↗
PubMed2006

Collectins and cationic antimicrobial peptides of the respiratory epithelia.

The respiratory epithelium is a primary site for the deposition of microorganisms that are acquired during inspiration. The innate immune system of the respiratory tract eliminates many of these potentially harmful agents preventing their colonization. Collectins and cationic antimicrobial peptides are antimicrobial components of the pulmonary innate immune system produced by respiratory epithelia, which have integral roles in host defense and inflammation in the lung. Synthesis and secretion of these molecules are regulated by the developmental stage, hormones, as well as many growth and immunoregulatory factors. The purpose of this review is to discuss antimicrobial innate immune elements within the respiratory tract of healthy and pneumonic lung with emphasis on hydrophilic surfactant proteins and beta-defensins.

Animals↗
PubMed2005

Collectin surfactant protein D binds antibodies and interlinks innate and adaptive immune systems.

Innate immune collectins, such as surfactant protein D (SP-D), contain fibrillar collagen-like regions and globular carbohydrate-recognition domains (CRDs). SP-D recognizes carbohydrate arrays present on microbial surfaces via its CRDs, agglutinates microbes and enhances their phagocytosis. In contrast, adaptive immune proteins such as immunoglobulins (Igs) recognize pathogens via binding to specific antigens. Here we show that: SP-D binds various classes of immunoglobins, including IgG, IgM, IgE and secretory IgA, but not serum IgA; the globular domains of SP-D bind both the Fab and Fc domains of IgG; SP-D recognizes IgG via calcium-dependent protein-protein interactions, aggregates IgG-coated beads and enhances their phagocytosis by murine macrophage RAW 264.7 cells. Therefore, we propose that SP-D effectively interlinks innate and adaptive immune systems.

Animals↗
PubMed2001

Pulmonary collectins and innate host defense of the lung.

Surfactant proteins A and D (SP-A and SP-D) are members of the collectin family of polypeptides expressed in the respiratory tract that bind bacterial, fungal and viral pathogens, enhancing their opsonization and killing by phagocytic cells. Clearance of bacterial pathogens including group B streptococci, Haemophilus influenza, Pseudomonas aeruginosa and viral pathogens, respiratory syncytial virus, adenovirus and influenza A virus, was deficient in SP-A(-/-) mice. SP-A deficiency was associated with enhanced inflammation and synthesis of proinflammatory cytokines. SP-D(-/-) mice cleared these bacteria as efficiently as wild-type mice; however, clearance of viral pathogens was deficient in SP-D(-/-) mice and associated with increased inflammation. SP-A and SP-D play critical and distinct roles in the regulation of alveolar macrophage function and inflammation, contributing to innate defense of the lung.

Animals↗
PubMed2005

Comparative signature-tagged mutagenesis identifies Pseudomonas factors conferring resistance to the pulmonary collectin SP-A.

The pulmonary collectin, surfactant protein A (SP-A), is a broad spectrum opsonin with microbicidal membrane permeabilization properties that plays a role in the innate immune response of the lung. However, the factors that govern SP-A's microbial specificity and the mechanisms by which it mediates membrane permeabilization and opsonization are not fully understood. In an effort to identify bacterial factors that confer susceptibility or resistance to SP-A, we used comparative signature-tagged mutagenesis to screen a library of 1,680 Pseudomonas aeruginosa mutants for evidence of differential pulmonary clearance in SP-A-sufficient (SP-A) and SP-A-deficient (SP-A) mice. Two SP-A-sensitive P. aeruginosa mutants harboring transposon insertions in genes required for salicylate biosynthesis (pch) and phosphoenolpyruvate-protein-phosphotransferase (ptsP) were recovered. The mutants were indistinguishable from the parental wild-type PA01 with regard to opsonization by SP-A, but they exhibited increased susceptibility to SP-A-mediated membrane permeabilization. These results suggest that bacterial gene functions that are required to maintain membrane integrity play crucial roles in resistance of P. aeruginosa to the permeabilizing effects of SP-A.

Journal Article↗
PubMed2003

Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-kappa B activation and TNF-alpha secretion are down-regulated by lung collectin surfactant protein A.

The lung collectin surfactant protein A (SP-A) has been implicated in the regulation of pulmonary host defense and inflammation. Zymosan induces proinflammatory cytokines in immune cells. Toll-like receptor (TLR)2 has been shown to be involved in zymosan-induced signaling. We first investigated the interaction of TLR2 with zymosan. Zymosan cosedimented the soluble form of rTLR2 possessing the putative extracellular domain (sTLR2). sTLR2 directly bound to zymosan with an apparent binding constant of 48 nM. We next examined whether SP-A modulated zymosan-induced cellular responses. SP-A significantly attenuated zymosan-induced TNF-alpha secretion in RAW264.7 cells and alveolar macrophages in a concentration-dependent manner. Although zymosan failed to cosediment SP-A, SP-A significantly reduced zymosan-elicited NF-kappaB activation in TLR2-transfected human embryonic kidney 293 cells. Because we have shown that SP-A binds to sTLR2, we also examined whether SP-A affected the binding of sTLR2 to zymosan. SP-A significantly attenuated the direct binding of sTLR2 to zymosan in a concentration-dependent fashion. From these results, we conclude that 1) TLR2 directly binds zymosan, 2) SP-A can alter zymosan-TLR2 interaction, and 3) SP-A down-regulates TLR2-mediated signaling and TNF-alpha secretion stimulated by zymosan. This study supports an important role of SP-A in controlling pulmonary inflammation caused by microbial pathogens.

Animals↗