Factors of the Lectin Pathway of Complement Activation and Their Clinical Associations in Neonates

Factors of the Lectin Pathway of Complement Activation and Their Clinical Associations in Neonates

We looked for human herpesvirus 6 (HHV-6) and HHV-7 genomes in the cervixes of pregnant women in the late stages of their pregnancies. The virion consists of an icosahedral nucleocapsid which is surrounded by a lipid bilayer envelope. She was treated empirically for both bacterial and herpes simplex virus meningitis. “what to start”). To narrow your search, add additional relevant terms. DNA extracted from whole blood (QIAamp DNA Blood Mini Kit on the QIAcube instrument, both from Qiagen Sciences, Inc, Germantown, MD, USA) was used for viral detection. et al.: HBLV (or HHV-6) in human cell lines.

Our preliminary conclusion is that these soluble defense lectins play a protective role in the neonate, and that insufficiency of such factors contributes to the adverse consequences of prematurity and low birthweight. Newborns have to adapt to their postnatal environment. They are exposed to extrauterine conditions which are completely different from intrauterine conditions. This finding documents for the first time the perinatal transmission of a specific HHV-8 subtype. Innate immune mechanisms are particularly important at that time. The high susceptibility of newborns to infection results from the immaturity of the immune system, despite immunoglobulins obtained via the placenta or breast feeding. Innate immunity plays an especially important role when the repertoire of maternal IgG does not include specific antibodies for the infecting agent or when, due to premature delivery, immunoglobulins do not achieve a sufficient level in the infant’s circulation [1–3].

Infarct on prenatal ultrasound (p=.0065) and family history of seizures (p=.0093) were significantly associated with an earlier development of seizures after 6 months of age: median time 3.8 months with, vs 53.9 without, positive ultrasound; and 1.1 months with, vs 53.9 without, positive family history. The research group plan to follow this study with prospective and clinical investigations, looking also at interactions with other contributory factors. Low ability to produce specific antibodies to such components, often exposed on the microbial cell surface, may suggest an important role for serum defense lectins in the first period of life. p. Structures of such important organs as bone marrow, spleen, or lymph nodes are not fully developed [1, 2]. The complement system is a crucial mediator of the immune response, interacting with other innate as well as acquired immunity mechanisms. It contributes significantly to cell homeostasis, tissue development and repair, reproduction and crosstalk with other endogenous cascades, like the coagulation network [6–10].

Each of three major complement activation pathways (classical, CP; alternative, AP; lectin, LP) employs its specific recognition molecules and initiating serine proteases (). Until recently, it was believed that only one collectin (mannan-binding lectin, MBL) and three ficolins: M- (-1), L- (-2), and H- (-3) were capable of activating LP. However, it now seems the novel or non-classical collectin, CL-11 (collectin-11, known also as collectin kidney-1 or CL-K1) also has this property [12]. Richardson M, Elliman D, Maguire H, et al. These pathways differ crucially in their initiating events: the classical pathway depends on antibody recognition and binding to C1q; the alternative pathway depends on low-level spontaneous hydrolysis … HHV-8 was also shown to reactivate during pregnancy among HIV-1-co-infected women, and reactivation might play a role in vertical transmission [22]. To circumvent this bottleneck and to enable future investigations of rare mutant animals, we applied in vivo imaging technology to perform a time-course analysis of the viral dissemination in the brain upon peripheral injection of a recombinant MCMV expressing luciferase to C57Bl/6 neonates.

MASP-2 and MAp19 are products of alternative splicing of the MASP2 gene. Similarly, synthesis of MASP-1, -3 and MAp44 is under control of a single MASP1/3 gene [13–18]. Following primary infection, the virus enters sensory nerve endings at the site of inoculation, travels up the axon and establishes a latent infection in the ganglion supplying that area of skin. MASP-2 cleaves C4, releasing C4a and C4b fragments. In the C4b molecule, a thioester group is exposed. It may bind to hydroxyl or amide groups on the microbial surface. Next, in the process of C2 cleavage, the C2b fragment is released, while C2a remains bound to C4b.

J. The coating of microorganisms with C4b or C3b opsonins facilitates phagocytosis. The C4b2a3b is a C5 convertase that cleaves the C5 component. The C5a fragment is released, while C5b may bind other C’ cascade factors (common pathway), which allows the membrane attack complex (MAC, C5b-9) to form and, in consequence, to lyse the microbial cell. Six women began highly active antiretroviral therapy (HAART) after the first trimester to reduce the risk of teratogenicity, seven received HAART before and during pregnancy, and two remained untreated throughout their pregnanacies. Moreover, MASP are believed to participate in the coagulation cascade activation [21, 26–29]. In general, serum levels of mannan-binding lectin, ficolins, and MASP-2 are lower in neonates than in older children, teenagers or adults.

They moreover often positively correlate with gestational age and birthweight [30–32]. CSF glucose and protein levels were normal, and white cells were absent or normal in 8 and increased to 11 to 12xl06/L in 2. Mannan-binding lectin (mannose-binding lectin), like other collectins, possesses both a collagen-like triple helical region and a C-type carbohydrate recognition domain. It is a pattern-recognition molecule (PRM), binding with a high affinity to microbial polysaccharides or glycoconjugates rich in D-mannose, N-acetyl-D-glucosamine, or L-fucose. 2009;58(RR-4):55–60. Single-nucleotide polymorphisms (SNPs) in exon 1 of the MBL2 gene are responsible for altered MBL serum levels and impaired function. Individuals with the A/A wild-type genotype generally have high MBL serum concentrations, whereas individuals with the A/O and particularly the O/O genotypes (where O is the collective designation of the mutant dominant alleles D, B, and C corresponding to mutations in codons 52, 54, and 57, respectively) show lower MBL serum concentrations.

Factors of the Lectin Pathway of Complement Activation and Their Clinical Associations in Neonates
Polymorphisms in the promoter and the untranslated region of exon 1 (H/L, Y/X, and P/Q at positions –550, –221, and +4, respectively) influence the gene expression level and thus the serum protein concentration [37, 38]. O/O homo- or heterozygotes as well as LXPA/O heterozygotes are considered to be MBL deficient. A correlation between MBL concentrations and gestational age has been reported by Lau et al. [39], Kielgast et al. [40], Hilgendorff et al. [41], and Sallenbach et al. PCR analyses revealed the presence of HHV-8 DNA sequences in 3 placenta samples from Cameroonian women, whereas samples from Italian women were repeatedly negative.

Additionally, mouse embryonic fibroblasts (MEFs) isolated from these deficient mouse strains can be used to further dissect roles of these molecules during γHV68 lytic replication ex vivo. [30, 35], in by far the largest series reported of full MBL2 genotypes, MBL cord serum levels and MBL-dependent lectin pathway activities, did not find such a relationship. Bodamer et al. If infection is delayed until adulthood the disease may be more severe and complications such as pneumonia, are more frequent. In contrast, Frakking et al. [43] found no difference in the distribution of genotypes between premature and term neonates, while Swierzko et al. [30] demonstrated high-serum MBL-conferring A/A genotypes to be more frequent among premature babies.

Similarly, the role of maternal genotype still remains unclear. Infect. [44] postulated that codon 54 (B) variants in mothers contribute to the shortened gestational age. Van de Geijn et al. [45], however showed women carrying no exon 1 mutation to be liable to suffer a preterm delivery. Reaction mixtures were prepared as described previously (5), except for the use of a high-fidelity DNA polymerase (PfuTurbo DNA polymerase; Stratagene, La Jolla, CA). Both possibilities seem to be reasonable, depending on interplay with other endogenous and environmental factors.

Numerous studies address the influence of MBL deficiency on perinatal morbidity and mortality from serious infections such as sepsis or pneumonia, especially in premature infants [46–53]. Schlapbach et al. [54] suggested that low MBL concentrations are a risk factor for sepsis associated with infections with Gram-positive but not Gram-negative bacteria. Moreover, Wahab Mohamed and Saeed [52] found MBL deficiency to predict development of septic shock. Swierzko et al. [30] found a higher incidence of perinatal infections in general among babies having the MBL deficiency-associated genotypes (LXPA/O and O/O) and a higher frequency of the D variant (codon 52 mutation) among neonates with infections. Two MBL2 gene haplotypes, LYPA and HYPD, were suggested to increase a risk of childhood neurological disorder, cerebral palsy, after perinatal exposure to certain viruses (enteroviruses, herpes simplex viruses 1 and 2, Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and human herpesviruses 6, 7, 8) [55].

On the other hand, several reports demonstrated no association of mannan-binding lectin deficiency with neonatal sepsis or viral infections. It however may reflect the specificity of aethiological agents or the group studied: nosocomial fungal invasive infections in preterm babies [56], sepsis caused by coagulase-negative staphylococci in a similar group [57], sepsis in very low birthweight babies [58], and pre- or perinatal infections with cytomegalovirus [59]. The MBL2 gene B variant was shown to enhance susceptibility to such inflammatory disorders as bronchopulmonary dysplasia (BPD) and intraventricular haemorrhage (IVH) [53, 60]. In contrast, Capoluongo et al. [61] found low MBL-associated genotypes to be linked to a better outcome in BPD, while Koroglu et al. [50] did not observe an influence of MBL2 polymorphism on incidence of bronchopulmonary dysplasia, intraventricular haemorrhage, respiratory distress syndrome, periventricular leukomalacia or necrotizing enterocolitis. MASP-2 has an identical domain organization to other MASPs and the classical complement pathway serine proteases, C1r and C1s.

To our knowledge, this is the first report that describes in vitro and in vivo HHV-8 infection of placental cells. Viral immune evasion, entailing host defense and viral evasion, provides one of the most fascinating and dynamic interfaces to discern the host-virus interaction. However, only one has been demonstrated to be potentially important clinically: the rarely occurring homozygous C359A > G mutation, resulting in an exchange of aspartic acid for glycine at position 120 (D120G; 105th residue of the mature protein, D105G). Current knowledge about any disease associations of MASP-2 and other proteases of that family, especially in neonates, is much more limited than in the case of MBL. Therapy should be started as soon as possible (within 48 hours) of disease onset. [31] found a correlation between serum MASP-2 concentration and gestational age which accounted for the relationships with early delivery and low birthweight. This observation was further confirmed by Schlapbach et al.

[54] and Sallenbach et al. [32]. Microbiol. Schlapbach et al. [66] however reported higher MASP-2 levels in the cord sera of babies developing necrotising enterocolitis. There are few data concerning other lectin pathway serine proteases. On the whole, HHV-8 sequences were detected in 7 of the 15 pregnancies; the increased rate of viral detection and the increased viral load suggest that latent HHV-8 infection may reactivate in HIV-1-infected women during pregnancy.

[54] found a correlation between MASP-3 levels and gestational age as well as birthweight and no impact of its low concentrations on the risk of neonatal sepsis. The family of human ficolins comprises three collagen-related, oligomeric lectins: M-ficolin (ficolin-1), L-ficolin (ficolin-2, P35), and H-ficolin (ficolin-3, Hakata antigen). They recognize N-acetyl-D-glucosamine (GlcNAc) and related structures via their fibrinogen-like domains. Ficolins act as opsonins (L- and H-) or as a phagocytic receptor (M-ficolin). All of them activate complement via the lectin pathway [67, 68]. Data concerning M-ficolin in neonates are very limited. Its serum level was shown to increase with gestational age and to reach a maximum during childhood (1–8 years) [32, 69].

Schlapbach et al. [69] demonstrated that low M-ficolin is associated both with increased need for mechanical ventilation and mortality among premature infants suffering from necrotising enterocolitis. Although the distribution of the corresponding FCN1 gene single-nucleotide polymorphisms (including several leading to amino acid substitutions) has been reported [70, 71], there are no data concerning their importance during the neonatal period.

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