16 research outputs found
Collectins and ficolins in neonatal health and disease
The immune system starts to develop early in embryogenesis. However, at birth it is still immature and associated with high susceptibility to infection. Adaptation to extrauterine conditions requires a balance between colonization with normal flora and protection from pathogens. Infections, oxidative stress and invasive therapeutic procedures may lead to transient organ dysfunction or permanent damage and perhaps even death. Newborns are primarily protected by innate immune mechanisms. Collectins (mannose-binding lectin, collectin-10, collectin-11, collectin-12, surfactant protein A, surfactant protein D) and ficolins (ficolin-1, ficolin-2, ficolin-3) are oligomeric, collagen-related defence lectins, involved in innate immune response. In this review, we discuss the structure, specificity, genetics and role of collectins and ficolins in neonatal health and disease. Their clinical associations (protective or pathogenic influence) depend on a variety of variables, including genetic polymorphisms, gestational age, method of delivery, and maternal/environmental microflora
Interaction of human mannose-binding lectin (MBL) with Yersinia enterocolitica lipopolysaccharide
tThe lipopolysaccharide (LPS) is involved in the interaction between Gram-negative pathogenic bacteriaand host. Mannose-binding lectin (MBL), complement-activating soluble pattern-recognition receptortargets microbial glycoconjugates, including LPS. We studied its interactions with a set of Yersinia ente-rocolitica O:3 LPS mutants. The wild-type strain LPS consists of lipid A (LA) substituted with an inner coreoligosaccharide (IC) which in turn is substituted either with the O-specific polysaccharide (OPS) or theouter core hexasaccharide (OC), and sometimes also with the enterobacterial common antigen (ECA). TheLPS mutants produced truncated LPS, missing OPS, OC or both, or, in addition, different IC constituentsor ECA. MBL bound to LA-IC, LA-IC-OPS and LA-IC-ECA but not LA-IC-OC structures. Moreover, LA-IC sub-stitution with both OPS and ECA prevented the lectin binding. Sequential truncation of the IC heptosesdemonstrated that the MBL targets the IC heptose region. Furthermore, microbial growth temperatureinfluenced MBL binding; binding was stronger to bacteria grown at room temperature (22âŠC) than to bac-teria grown at 37âŠC. In conclusion, our results demonstrate that MBL can interact with Y. enterocoliticaLPS, however, the in vivo significance of that interaction remains to be elucidated
The Role of Complement Activating Collectins and Associated Serine Proteases in Patients With Hematological Malignancies, Receiving High-Dose Chemotherapy, and Autologous Hematopoietic Stem Cell Transplantations (Auto-HSCT)
We conducted a prospective study of 312 patients (194 with multiple myeloma,
118 with lymphomas) receiving high-dose conditioning chemotherapy and autologous
hematopoietic stem cell transplantation (auto-HSCT). Polymorphisms of MBL2 and
MASP2 genes were investigated and serial measurements of serum concentrations
of mannose-binding lectin (MBL), CL-LK collectin and MASP-2 as well as activities
of MBL-MASP-1 and MBL-MASP-2 complex were made. Serum samples were
taken before conditioning chemotherapy, before HSCT and once weekly after (totally
4-5 samples); in minority of subjects also 1 and/or 3 months post transplantation.
The results were compared with data from 267 healthy controls and analyzed
in relation to clinical data to explore possible associations with cancer and with
chemotherapy-induced medical complications. We found a higher frequency of MBL
deficiency-associated genotypes (LXA/O or O/O) among multiple myeloma patients
compared with controls. It was however not associated with hospital infections or
post-HSCT recovery of leukocytes, but seemed to be associated with the most
severe infections during follow-up. Paradoxically, high MBL serum levels were a
risk factor for prolonged fever and some infections. The first possible association
of MBL2 gene 3âČ-untranslated region polymorphism with cancer (lymphoma) in
Caucasians was noted. Heterozygosity for MASP2 gene +359 A>G mutation was relatively frequent in lymphoma patients who experienced bacteremia during hospital
stay. The median concentration of CL-LK was higher in myeloma patients compared
with healthy subjects. Chemotherapy induced marked increases in serum MBL and
MASP-2 concentrations, prolonged for several weeks and relatively slighter decline in
CL-LK level within 1 week. Conflicting findings on the influence of MBL on infections
following chemotherapy of myeloma and lymphoma have been reported. Here we found
no evidence for an association between MBL deficiency and infection during the short
period of neutropenia following conditioning treatment before HSCT. However, we noted
a possible protective effect of MBL during follow-up, and suspected that to be fully
effective when able to act in combination with phagocytic cells after their recovery
Serological characterization of the enterobacterial common antigen substitution of the lipopolysaccharide of "Yersinia enterocolitica" O:3
Enterobacterial common antigen (ECA) is a polysaccharide present in all members of
Enterobacteriaceae anchored either via phosphatidylglycerol (PG) or LPS to the outer leaflet of
the outer membrane (ECAPG and ECALPS, respectively). Only the latter form is ECAimmunogenic.
We previously demonstrated that Yersinia enterocolitica O: 3 and its rough (Ospecific
polysaccharide-negative) mutants were ECA-immunogenic, suggesting that they
contained ECALPS; however, it was not known which part of the LPS core region was involved in
ECA binding. To address this, we used a set of three deep-rough LPS mutants for rabbit
immunization. The polyvalent antisera obtained were: (i) analysed for the presence of anti-LPS and
anti-ECA antibodies; (ii) treated with caprylic acid (CA) to precipitate IgM antibodies and protein
aggregates; and (iii) adsorbed with live ECA-negative bacteria to obtain specific anti-ECA
antisera. We demonstrated the presence of antibodies specific for both ECAPG and ECALPS in all
antisera obtained. Both CA treatment and adsorption with ECA-negative bacteria efficiently
removed anti-LPS antibodies, resulting in specific anti-ECA sera. The LPS of the ECALPS-positive
deepest-rough mutant contained only lipid A and 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo)
residues of the inner core, suggesting that ECALPS was linked to the Kdo region of LPS in Y.
enterocolitica O:3
Possible disease-modifying factors: the mannan-binding lectin pathway and infections in hereditary angioedema of children and adults
Association of low ficolin-2 concentration in cord serum with respiratory distress syndrome in preterm newborns
IntroductionFicolin-2 is a serum pattern recognition molecule, involved in complement activation via the lectin pathway. This study aimed to investigate the association of ficolin-2 concentration in cord blood serum with complications related to premature birth.Methods546 premature neonates were included. The concentration of ficolin-2 in cord blood serum was determined by a sandwich TRIFMA method. FCN2 genetic variants were analysed with RFLP-PCR, allele-specific PCR, Sanger sequencing or allelic discrimination using TaqMan probes method.FindingsCord blood serum ficolin-2 concentration correlated positively with Apgar score and inversely with the length of hospitalisation and stay at Neonatal Intensive Care Unit (NICU). Multivariate logistic regression analysis indicated that low ficolin-2 increased the possibility of respiratory distress syndrome (RDS) diagnosis [OR=2.05, 95% CI (1.24-3.37), p=0.005]. Median ficolin-2 concentration was significantly lower in neonates with RDS than in premature babies without this complication, irrespective of FCN2 gene polymorphisms localised to promoter and 3âuntranslated regions: for patients born <33 GA: 1471 ng/ml vs. 2115 ng/ml (p=0.0003), and for patients born â„33 GA 1610 ng/ml vs. 2081 ng/ml (p=0.012). Ficolin-2 level was also significantly lower in neonates requiring intubation in the delivery room (1461 ng/ml vs. 1938 ng/ml, p=0.023) and inversely correlated weakly with the duration of respiratory support (R=-0.154, p<0.001). Interestingly, in the neonates born at GA <33, ficolin-2 concentration permitted differentiation of those with/without RDS [AUC=0.712, 95% CI (0.612-0.817), p<0.001] and effective separation of babies with mild RDS from those with moderate/severe form of the disease [AUC=0.807, 95% CI (0.644-0.97), p=0.0002].ConclusionLow cord serum ficolin-2 concentration (especially in neonates born at GA <33 weeks) is associated with a higher risk of developing moderate/severe RDS, requiring respiratory support and intensive care
Evaluation of lectin pathway activity and mannan-binding lectin levels in the course of pregnancy complicated by diabetes type 1, based on the genetic background
Components of the Lectin Pathway of Complement in Solid Tumour Cancers
The complement system is an important branch of the humoral innate immune response that can be activated via three distinct pathways (classical, alternative, lectin), contributing to keeping/restoring homeostasis. It can also interact with cellular innate immunity and with components of acquired immunity. Cross-talk between the complement system and other enzyme-dependent cascades makes it a more influential defence system, but on the other hand, over- or chronic activation can be harmful. This short review is focused on the dual role of the lectin pathway of complement activation in human solid tumour cancers, including those of the female reproductive system, lung, and alimentary tract, with emphasis on the aforementioned cross-talk
Components of the Lectin Pathway of Complement in Haematologic Malignancies
The complement system is activated cascadically via three distinct major routes: classical pathway (CP), alternative pathway (AP) or lectin pathway (LP). The unique factors associated with the latter are collectins (mannose-binding lectin, collectin-10, collectin-11), ficolins (ficolin-1, ficolin-2, ficolin-3) and proteins of the mannose-binding lectin-associated serine protease (MASP) family (MASP-1, MASP-2, MASP-3, MAp19, MAp44). Collectins and ficolins are both pattern-recognising molecules (PRM), reactive against pathogen-associated molecular patterns (PAMP) or danger-associated molecular patterns (DAMP). The MASP family proteins were first discovered as complexes with mannose-binding lectin (MBL) and therefore named MBL-associated serine proteases, but later, they were found to interact with ficolins, and later still, collectin-10 and collectin-11. As well as proteolytic enzymes (MASP-1, MASP-2, MASP-3), the group includes non-enzymatic factors (MAp19, MAp44). In this review, the association-specific factors of the lectin pathway with haematologic malignancies and related infections are discussed
Association of Polymorphisms of MASP1/3, COLEC10, and COLEC11 Genes with 3MC Syndrome
The Malpuech, Michels, Mingarelli, Carnevale (3MC) syndrome is a rare, autosomal recessive genetic- disorder associated with mutations in the MASP1/3, COLEC1,1 or COLEC10 genes. The number of 3MC patients with known mutations in these three genes reported so far remains very small. To date, 16 mutations in MASP-1/3, 12 mutations in COLEC11 and three in COLEC10 associated with 3MC syndrome have been identified. Their products play an essential role as factors involved in the activation of complement via the lectin or alternative (MASP-3) pathways. Recent data indicate that mannose-binding lectin-associated serine protease-1 (MASP-1), MASP-3, collectin kidney-1 (collectin-11) (CL-K1), and collectin liver-1 (collectin-10) (CL-L1) also participate in the correct migration of neural crest cells (NCC) during embryogenesis. This is supported by relationships between MASP1/3, COLEC10, and COLEC11 gene mutations and the incidence of 3MC syndrome, associated with craniofacial abnormalities such as radioulnar synostosis high-arched eyebrows, cleft lip/palate, hearing loss, and ptosis