Biomedical subjects

Nigel J Klein

Publications and source records attributed to Nigel J Klein.

At least 19 recordsLinked to original sources

PubMed2006

Genetic polymorphism of the binding domain of surfactant protein-A2 increases susceptibility to meningococcal disease.

BACKGROUND: Meningococcal disease occurs after colonization of the nasopharynx with Neisseria meningitidis. Surfactant protein (SP)-A and SP-D are pattern-recognition molecules of the respiratory tract that activate inflammatory and phagocytic defences after binding to microbial sugars. Variation in the genes of the surfactant proteins affects the expression and function of these molecules. METHODS: Allele frequencies of SP-A1, SP-A2, and SP-D were determined by polymerase chain reaction in 303 patients with microbiologically proven meningococcal disease, including 18 patients who died, and 222 healthy control subjects. RESULTS: Homozygosity of allele 1A1 of SP-A2 increased the risk of meningococcal disease (odds ratio [OR], 7.4; 95% confidence interval [CI], 1.3-42.4); carriage of 1A5 reduced the risk (OR, 0.3; 95% CI, 0.1-0.97). An analysis of the multiple single-nucleotide polymorphisms in SP-A demonstrated that homozygosity for alleles encoding lysine (in 1A1) rather than glutamine (in 1A5) at amino acid 223 in the carbohydrate recognition domain was associated with an increased risk of meningococcal disease (OR, 6.7; 95% CI, 1.4-31.5). Carriage of alleles encoding lysine at residue 223 was found in 61% of patients who died, compared with 35% of those who survived (OR adjusted for age, 2.9; 95% CI, 1.1-7.7). Genetic variation of SP-A1 and SP-D was not associated with meningococcal disease. CONCLUSIONS: Gene polymorphism resulting in the substitution of glutamine with lysine at residue 223 in the carbohydrate recognition domain of SP-A2 increases susceptibility to meningococcal disease, as well as the risk of death.

Adult↗

PubMed2006

Platelet and soluble CD40L in meningococcal sepsis.

OBJECTIVE: To determine the influence of meningococcal sepsis on levels of platelet derived CD40L and on endothelial CD40 expression. DESIGN AND SETTING: Prospective observational study in two tertiary paediatric intensive care units. PATIENTS AND PARTICIPANTS: 63 children with meningococcal sepsis and 10 age-matched controls. MEASUREMENTS AND RESULTS: (a) sCD40L ELISA of plasma from patients with meningococcal sepsis (n = 49) and age matched controls (n = 10). This demonstrated higher sCD40L levels in patients (median 0.29 ng/ml, IQR 0.2-0.41) than controls (0.09 ng/ml, 0.08-0.12). However, there was no relationship between plasma sCD40L level and platelet count or disease severity. (b) Flow cytometry of fresh blood from patients with meningococcal sepsis (n = 11) and age-matched controls (n = 10) for membrane bound CD40L and CD62P on circulating platelets. This demonstrated low levels of CD40L and CD62P in patients and controls. CD40L+ platelets were 3.5% (3.0-4.8) in patients and 4.9% (3.5-4.3) in controls. CD62P+ platelets were 10.7% (6.4-12.8) in patients and 7.9% (5.9-13.0) in controls. (c) Immunohistochemistry of skin biopsy specimens from six patients, staining for endothelial CD40 expression at sites of microthrombus formation, which demonstrated preserved CD40 expression in vascular endothelium at sites of microthrombus formation. CONCLUSIONS: The elevated sCD40L level in meningococcal sepsis implies release of sCD40L from platelets. However, there was no relationship between plasma sCD40L level and the degree of thrombocytopenia or disease severity. Furthermore, platelet surface bound CD40L was similar in controls and patients. Thus, further investigation is needed to determine whether platelet CD40L contributes to inflammation and thrombosis in MCS.

CD40 Ligand↗

PubMed2006

Nucleotide-binding oligomerization domain-1 and epidermal growth factor receptor: critical regulators of beta-defensins during Helicobacter pylori infection.

Host-pathogen interactions that allow Helicobacter pylori to survive and persist in the stomach of susceptible individuals remain unclear. Human beta-defensins (hBDs), epithelial-derived antimicrobial peptides are critical components of host-defense at mucosal surfaces. The role of H. pylori-mediated NF-kappaB and epidermal growth factor receptor (EGFR) activation on beta-defensin expression was investigated. Transient transfection studies utilizing beta-defensin promoter constructs were conducted in gastric cells with contribution of individual signaling events evaluated by the addition of specific inhibitors, small interference nucleotide-binding oligomerization domain 1 (NOD1) RNA or plasmids encoding Vaccinia virus proteins that interrupt interleukin-1 and Toll-like receptor signaling. The role of individual MAPK pathways was further delineated in HEK-293 cells expressing conditional MAPK mutants. We found hBD2 expression exclusively dependent on the presence of the bacterial cag pathogenicity island, with NOD1 a critical host sensor. Impairment of murinebeta-defensin 4 (an orthologue of hBD2) expression in NOD1-deficient mice 7-days post-infection further confirmed the role of this cytoplasmic pattern-recognition receptor in eliciting host innate immunity. In contrast to hBD2, hBD3 expression was NOD1-independent but EGFR and ERK pathway-dependent. Importantly, Toll-like receptor signaling was not implicated in H. pylori-mediated hBD2 and hBD3 gene expression. The divergent signaling events governing hBD2 and hBD3 expression suggest temporal functional variation, such that hBD2 may contribute to antimicrobial barrier function during the inflammatory phase with hBD3 playing a greater role during the repair, wound healing phase of infection.

Animals↗

PubMed2006

Interleukin-10 and its role in clinical immunoparalysis following pediatric cardiac surgery.

OBJECTIVE: A systemic insult is associated with subsequent hyporesponsiveness to endotoxin (as measured by ex vivo tumor necrosis factor [TNF]-alpha production) and an increased risk of late nosocomial infection in some patients. When combined with low monocyte surface major histocompatibility complex class II expression, this state of altered host defense is now commonly referred to as immunoparalysis. This study was undertaken to delineate the relationship between observed levels of the anti-inflammatory cytokine interleukin-10, common genetic polymorphisms that influence these levels, and the occurrence and severity of endotoxin hyporesponsiveness in children following elective cardiac surgery requiring cardiopulmonary bypass. DESIGN: A prospective observational clinical study. SETTING: A tertiary pediatric cardiac center. PATIENTS: Thirty-six infants and children <2 yrs of age undergoing elective cardiac surgery requiring cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We investigated the production of TNF-alpha, interleukin-6, interleukin-8, interleukin-1 receptor antagonist, and interleukin-10 in whole blood in response to lipopolysaccharide (Neisseria meningitides 10 ng/mL) in samples drawn before, during, and up to 48 hrs after surgery. Patients were genotyped for the -1082, -819, and -592 interleukin-10 promoter polymorphisms. Whole blood cytokine response to lipopolysaccharide was reduced postoperatively to </=50% of preoperative levels for all cytokines measured. Stimulated cytokine production was lowest in cases with the highest postoperative plasma interleukin-10 levels, which were in turn associated with the GCC haplotype. Those patients in whom the whole blood response to endotoxin was maintained (TNF-alpha >100 pg/mL) over the first 48 hrs were more likely to have an uncomplicated short stay (odds ratio 4.7, 95% confidence interval 1-22). CONCLUSIONS: Immediately following cardiac surgery, many children become relatively refractory to lipopolysaccharide stimulation. This immunoparalysis appears to be related in part to high circulating levels of interleukin-10 and places these patients at increased risk of postoperative complications. Interleukin-10 genotype may be a risk factor for immunoparalysis.

Analysis of Variance↗

PubMed2006

Mannose-binding lectin polymorphisms in severe sepsis: relationship to levels, incidence, and outcome.

Mannose-binding lectin (MBL) genetic polymorphisms result in deficiency of the encoded protein and increased susceptibility to infection, especially in children and the immunocompromised. The objective of this study was to investigate the relationship between MBL-2 exon 1 and promoter -221 polymorphisms, plasma levels of the encoded protein, and the incidence and outcome of severe sepsis and septic shock. One hundred seventy-four white adult patients with severe sepsis or septic shock were recruited in a prospective multicenter study across eight intensive care units in the South of England, UK. Genotype and haplotype frequencies were compared between normal population controls and patients, and between survivors and nonsurvivors. Plasma levels of encoded protein were related to genotype and outcome. The exon 1 polymorphisms (A/O or O/O) were significantly more common in the patients with severe sepsis and septic shock than in normal healthy adults (54.6% vs. 39.7%, P = 0.001), and there was a significant difference in haplotype frequency between controls and septic patients (P < 0.0001). There was no significant difference in MBL-2 genotype or haplotype frequency between survivors and nonsurvivors. There was a strong relationship between MBL-2 haplotype and plasma MBL concentration (P < 0.001). Individual plasma levels were variable and increased between days 1 and 7. The mortality rate was higher in those with MBL levels <1000 microg/L than in those patients with levels >1000 microg/L (47.2 vs. 22.2%, P = 0.05). We conclude that genetic polymorphisms resulting in mannose-binding lectin deficiency are associated with increased susceptibility to sepsis. The close relationship between polymorphic variants and plasma MBL concentration persists during sepsis but individual levels vary widely. Lower circulating MBL levels are associated with a poor outcome.

Adolescent↗

PubMed2005

Early structural and functional changes of the vasculature in HIV-infected children: impact of disease and antiretroviral therapy.

BACKGROUND: Premature cardiovascular disease is increasingly recognized in HIV-infected patients, but the mechanisms involved are unclear. The purpose of this study was to determine the impact of HIV infection and antiretroviral therapy (ART) on markers of early vascular disease in children. METHODS AND RESULTS: We studied 83 HIV-infected children (56 had taken ART, of whom 31 received a regimen containing protease inhibitors [PIs]; 27 were never treated) and a control group of 59 healthy children. Carotid intima-media thickness (IMT) and brachial artery flow-mediated dilatation (FMD) were measured. IMT was significantly greater in HIV-infected children compared with the control subjects (P<0.001). Among the HIV-infected children, age and treatment were significantly associated with increased IMT. Children exposed to PIs had greater IMT compared with both non-PI-treated children and untreated children (P=0.02). FMD was also significantly reduced in the HIV-infected children compared with control subjects (P=0.02). Pairwise comparisons of different treatment exposure groups revealed that FMD was impaired by a mean of 3.6% (95% CI, 1.8 to 5.3; P<0.001) for children exposed to PIs compared with untreated children and by a mean of 1.8% (95% CI, 0.01 to 3.5; P=0.05) compared with non-PI-treated children. HIV-infected children had lipid abnormalities, but they did not account for the observed differences in either FMD or IMT. CONCLUSIONS: HIV infection in childhood is associated with adverse structural and functional vascular changes that are most pronounced in children exposed to PI therapy. Longitudinal studies are required to differentiate the relative impact of HIV disease and ART and to assess the potential for prevention.

Adolescent↗

PubMed2005

Endothelial dysfunction in childhood infection.

BACKGROUND: Atherosclerosis begins in early life, and endothelial dysfunction is recognized as a key initiating event in the development of atherosclerosis. Although infection has been implicated in endothelial dysfunction and atherogenesis, the impact of acute common childhood infections on the vascular endothelium is unknown. METHODS AND RESULTS: We studied 600 children aged 10 years drawn from the Avon Longitudinal Study of Parents and Children. The children were divided into 3 groups: those with current acute infection (AI; n=135; 73 boys and 62 girls); a convalescent group with infection in the past 2 weeks (n=166; 78 boys and 88 girls), and a healthy control group (n=299; 131 boys and 168 girls). Endothelial function was determined in all subjects by high-resolution ultrasound to measure brachial artery flow-mediated dilation (FMD) and was expressed as the percentage change in diameter from baseline after reactive hyperemia. FMD was repeated in 40 children in the AI group and 50 in the control group after a mean interval of 1 year. FMD was lower in both the AI group (6.3+/-2.7%, mean+/-SD) and the convalescent group (8.1+/-3.1%) than in the control group (9.7+/-2.5%; P<0.001 for both). The observed differences in FMD remained after adjustment for potential confounding variables. At the repeat visit, FMD was unchanged in controls (P=0.85) but improved in the AI group (P<0.001). CONCLUSIONS: Acute infection in childhood is associated with impaired endothelium-dependent vasodilation. These findings support a potential role for previously unsuspected extrinsic inflammatory stimuli in the pathogenesis of early atherosclerosis.

Arteriosclerosis↗

PubMed2005

Inflammatory response in children after laparoscopic vs open Nissen fundoplication: randomized controlled trial.

UNLABELLED: We performed a randomized controlled trial to compare the inflammatory and immune responses to Nissen fundoplication in infants and children undergoing either open or laparoscopic surgery. METHODS: Forty children undergoing Nissen fundoplication were randomized to laparoscopy or open surgery using minimization with respect to age, neurologic status, and operating surgeon. Intraoperative and postoperative analgesias were standardized. Inflammatory markers (plasma malondialdehyde, nitrate plus nitrite level, and cytokines) and monocyte class II major histocompatibility complex expression were measured preoperatively, at end of surgery, 4, 24, and 48 hours postoperatively. Postoperative changes were compared between open and laparoscopic groups. RESULTS: There were no significant changes in circulating malondialdehyde, nitrates plus/ nitrite, interleukin-10, or tumor necrosis factor alpha in the postoperative period in either group. Interleukin-1 receptor antagonist (IL-1rA) and IL-6 were significantly increased in both groups, with a tendency for greater elevation of IL-1rA in the open group. Monocyte major histocompatibility complex expression fell significantly in both groups; however, this fall appeared to be slightly more marked in the open group. CONCLUSIONS: The postoperative cytokine response is similar in children undergoing open and laparoscopic Nissen fundoplication. This trial indicates that laparoscopy may partly reduce postoperative immune suppression.

Child↗

PubMed2005

P-selectin expression, neutrophil infiltration, and histologic injury in neonates with necrotizing enterocolitis.

BACKGROUND/PURPOSE: P-selectin promotes adherence of leukocytes to the endothelium in inflammatory processes. The aim of this study was to investigate the expression of P-selectin and its role in the development of inflammation in neonates with necrotizing enterocolitis (NEC). METHODS: Twenty-nine intestinal specimens from 13 neonates with NEC and 7 control neonates with congenital gastrointestinal abnormalities were studied. Histologic damage, immunohistochemical expression of P-selectin, and polymorphonuclear cell infiltrate were graded blindly. Mann-Whitney U and Spearman rank tests were used to compare grades. RESULTS: Expression of P-selectin was increased in NEC compared with controls in both medium-sized vessels (P = .03) and in the microcirculation (P = .03). P-selectin expression on medium-sized vessels correlated with the degree of histologic injury (P = .02, r = 0.425). P-selectin expression was greatest in areas of active inflammation but markedly lower in necrotic areas. The degree of polymorphonuclear cell infiltration strongly correlated with P-selectin expression on both medium-sized vessels (P = .004, r = 0.513) and the microcirculation (P = .001, r = 0.578). CONCLUSIONS: Expression of P-selectin is increased in medium-sized vessels and in the microcirculation in intestinal specimens of neonates with NEC compared with neonatal controls. Expression of P-selectin is associated with the recruitment of polymorphonuclear cells and the severity of histologic injury, although P-selectin expression is lost in necrotic tissue.

Enterocolitis, Necrotizing↗

PubMed2005

Intestinal innate immunity to Campylobacter jejuni results in induction of bactericidal human beta-defensins 2 and 3.

Campylobacter jejuni is the most prevalent cause of bacterial diarrhea worldwide. Despite the serious health problems caused by this bacterium, human innate immune responses to C. jejuni infection remain poorly defined. Human beta-defensins, a family of epithelial antimicrobial peptides, are a major component of host innate defense at the gastrointestinal mucosal surface. In this study, the effect of two different C. jejuni wild-type strains on human intestinal epithelial innate responses was investigated. Up-regulation of beta-defensin gene and peptide expression during infection was observed and recombinant beta-defensins were shown to have a direct bactericidal effect against C. jejuni through disruption of cell wall integrity. Further studies using an isogenic capsule-deficient mutant showed that, surprisingly, the absence of the bacterial polysaccharide capsule did not change the innate immune responses induced by C. jejuni or the ability of C. jejuni to survive exposure to recombinant beta-defensins. This study suggests a major role for this family of antimicrobial peptides in the innate immune defense against this human pathogen.

Bacterial Capsules↗

PubMed2005

Role for mannose binding lectin in the prevention of Mycoplasma infection.

Polymorphisms in exon 1 of the MBL-2 gene, resulting in reduced plasma levels of mannose binding lectin, were significantly overrepresented in 23 patients with primary antibody deficiency and culture-proven mycoplasma infections (P = 0.0038). This association persisted with the inclusion of a further nine suspected (doxycycline-responsive) cases (P = 0.0087). The lectin was shown to bind to three strains of mycoplasma.

Flow Cytometry↗

PubMed2004

Mannose-binding lectin enhances phagocytosis and killing of Neisseria meningitidis by human macrophages.

Deficiency of mannose-binding lectin (MBL) is probably the most common human immunodeficiency and is associated with an increased risk of mucosally acquired infections including meningococcal disease. Tissue macrophages are an important component of mucosal defense, and so we determined the effect of MBL on uptake of meningococci by human monocyte-derived macrophages. Opsonization with MBL significantly increased the capture and doubled the amount of internalization of Neisseria meningitidis. Inhibition of f-actin polymerization indicated that MBL exerted this effect by a dose-dependent acceleration of uptake into phagosomes, which was maximal within the normal physiological concentration of MBL (1.5 microg/ml) and was independent of scavenger receptors. MBL accelerated the acquisition and subsequent loss of the early endosome marker, early endosomal antigen-1, and enhanced the acquisition of the late endosomal marker, lysosome-associated membrane protein-1. MBL reduced the survival of meningococci within macrophages by more than half, despite the increased uptake of organisms, and significantly reduced the number of viable extracellular bacteria by 80%. We conclude that MBL is a dependent opsonin able to accelerate microbial uptake and killing. These results suggest that MBL could modify disease susceptibility by modulating macrophage interactions with mucosal organisms at the site of initial acquisition.

Cells, Cultured↗

PubMed2004

Mannose binding lectin enhances IL-1beta and IL-10 induction by non-lipopolysaccharide (LPS) components of Neisseria meningitidis.

Mannose binding lectin (MBL) is a key molecule in the lectin pathway of complement activation, and likely of importance in our innate defence against meningococcal infection. We evaluated the role of MBL in cytokine induction by LPS or non-LPS components of Neisseria meningitidis, using a meningococcal mutant deficient for LPS. Binding experiments showed that MBL exhibited low, but significant binding to encapsulated LPS+ meningococci (H44/76) and LPS-deficient (LPS-) meningococci (H44/76lpxA). Experiments with human mononuclear cells (PBMCs) showed that MBL significantly augmented IL-1beta production after stimulation with LPS+ and LPS- meningococci, in a dose-dependent fashion. In addition, IL-10 production was enhanced after stimulation with LPS- meningococci. In contrast, TNFalpha, IL-6 and IFNgamma productions were unaffected. No effect of MBL was observed on cytokine induction by meningococcal LPS. MBL enhanced cytokine production at concentrations >10(7) meningococci. It is concluded that MBL interacts with non-LPS components of N. meningitidis and in this way modulates the cytokine response.

Cells, Cultured↗

PubMed2004

Increased incidence and severity of the systemic inflammatory response syndrome in patients deficient in mannose-binding lectin.

OBJECTIVE: To determine whether pediatric PICU patients with mannose-binding lectin (MBL) gene polymorphisms associated with low levels of the functional protein have an increased risk of developing sepsis and SIRS. DESIGN AND SETTING: A prospective, observational cohort study in a 22-bed PICU in a tertiary referral centre. PATIENTS: One hundred consecutive admissions to a PICU with at least one organ system failure longer than 12 h. Patients were classified into those with infectious or non-infectious insults as the primary reason for intensive care admission. Patients were followed to determine which developed sepsis or non-infection related SIRS using standard criteria. MEASUREMENTS AND RESULTS: Of the 100 patients 50 had infectious and 50 had non-infectious insults as the precipitant for admission. 42 patients had variant MBL alleles (determined by MBL-2 gene exon 1 and promoter polymorphisms) and were significantly over-represented amongst the 59 patients that developed SIRS. This effect was not explained by differences in age, sex or ethnicity and was seen in both the infection and non-infection subgroups. In patients with infection, variant MBL alleles were associated with increased systemic response (2/15 with localised infection, 10/19 with sepsis and 12/16 with septic shock). MBL serum levels showed close concordance with the genotype and indicated that MBL levels less than 1000 ng/ml are associated with a greatly increased risk of SIRS. CONCLUSIONS: MBL-2 exon 1 polymorphisms with low serum levels of functional MBL protein are associated with a greatly increased risk of developing SIRS and of progression from infection to sepsis and septic shock in paediatric ICU patients.

Adolescent↗

PubMed2004

Mannose-binding lectin binds to two major outer membrane proteins, opacity protein and porin, of Neisseria meningitidis.

Human mannose-binding lectin (MBL) provides a first line of defense against microorganisms by complement activation and/or opsonization in the absence of specific Ab. This serum collectin has been shown to activate complement when bound to repeating sugar moieties on several microorganisms, including encapsulated serogroup B and C meningococci, which leads to increased bacterial killing. In the present study, we sought to identify the meningococcal cell surface components to which MBL bound and to characterize such binding. Outer membrane complex containing both lipooligosaccharide (LOS) and proteins and LOS from Neisseria meningitidis were examined for MBL binding by dot blot and ELISA. MBL bound outer membrane complex but not LOS. The binding to bacteria by whole-cell ELISA did not require calcium and was not inhibited by N-acetyl-glucosamine or mannose. With the use of SDS-PAGE, immunoblot analysis, and mAbs specific for meningococcal opacity (Opa) proteins and porin proteins, we determined that MBL bound to Opa and porin protein B (porB). The N-terminal amino acid sequences of the two MBL binding proteins confirmed Opa and PorB. Purified PorB inhibited the binding of MBL to meningococci. Escherichia coli with surface-expressed gonococcal Opa bound significantly more MBL than did the control strain. The binding of human factor H to purified PorB was markedly inhibited by MBL in a dose-dependent manner. Meningococci incubated with human serum bound MBL as detected by ELISA. We conclude that MBL binds to meningococci by a novel target recognition of two nonglycosylated outer membrane proteins, Opa and PorB.

Bacterial Outer Membrane Proteins↗

PubMed2003

Persistent infection of human microvascular endothelial cells by coxsackie B viruses induces increased expression of adhesion molecules.

Numerous studies indicate that enteroviruses, such as the Coxsackievirus (CV) group, are linked to autoimmune diseases. Virus tropism and tissue access are modulated by vascular endothelial cells (ECs), mainly at the level of the microvasculature. Data on the permissiveness of ECs to CV are, however, scanty and derived from studies on large vessel ECs. To examine the susceptibility of microvascular ECs to infection of group B CV (CVB), human dermal microvascular ECs (HMEC-1) were infected with three CVB strains, and the immunological phenotype of the infected cells was analyzed. All CVB persistently infected the EC cultures without producing overt cytopathic effects. Infected ECs retained endothelial characteristics. Release of infectious particles in cell supernatants persisted for up to 3 mo of culture. Infection up-regulated expression of the adhesion molecules ICAM-1 and VCAM-1, with the highest values detected during the first 30 days of infection (p < 0.05 vs uninfected HMEC-1). CVB infection increased production of the proinflammatory cytokines, IL-6, IL-8, and TNF-alpha, which may account for the enhanced expression of adhesion molecules. Parallel infection of macrovascular HUVEC had less evident effects on induction of ICAM-1 and did not significantly increase expression of VCAM-1. Moreover, mononuclear cell adhesion to CVB-infected HMEC-1 monolayers was increased, compared with uninfected monolayers. These results provide evidence that small vessel ECs can harbor a persistent viral infection, resulting in quantitative modification of adhesion molecule expression, which may contribute to the selective recruitment of subsets of leukocytes during inflammatory immune responses. Furthermore, our data confirm that the behavior against a viral challenge of ECs in large vessels and microvessels may differ.

Cell Adhesion↗

PubMed2003

CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation.

CD40 is a 48-kDa phosphorylated transmembrane glycoprotein belonging to the TNF receptor superfamily. CD40 has been demonstrated on a range of cell types, and it has an important role in adaptive immunity and inflammation. CD40 has recently been described on platelets but platelet activation by CD40 has not been described. In the present study, we use flow cytometry and immunoblotting to confirm that platelets constitutively express surface CD40. CD40 mRNA was undetectable, suggesting that the protein is synthesized early in platelet differentiation by megakaryocytes. Ligation of platelet CD40 with recombinant soluble CD40L trimer (sCD40LT) caused increased platelet CD62P expression, alpha-granule and dense granule release, and the classical morphological changes associated with platelet activation. CD40 ligation also caused beta3 integrin activation, although this was not accompanied by platelet aggregation. These actions were abrogated by the CD40L blocking antibody TRAP-1 and the CD40 blocking antibodies M2 and M3, showing that activation was mediated by CD40L binding to platelet CD40. beta3 integrin blockade with eptifibatide had no effect, indicating that outside-in signaling via alphaIIbbeta3 was not contributing to these CD40-mediated effects. CD40 ligation led to enhanced platelet-leukocyte adhesion, which is important in the recruitment of leukocytes to sites of thrombosis or inflammation. Our results support a role for CD40-mediated platelet activation in thrombosis, inflammation, and atherosclerosis.

Blood Platelets↗

PubMed2003

Are there opportunities to decrease nosocomial infection by choice of analgesic regimen? Evidence for immunity and pain interactions.

BACKGROUND: Interactions suggest that anesthetic and analgesic strategies could be used to modulate immune function and reduce nosocomial infection in critically ill pediatric patients. However, this theory has yet to be adequately tested. OBJECTIVE: To present the evidence for interactions between nociceptive and immune pathways. DATA SOURCES: The MEDLINE database and hand searches of the English-language biomedical literature for the 1985-2003 period. DATA SYNTHESIS: Substantial evidence exists for numerous bidirectional relationships between nociceptive and immune pathways. Some studies suggest that surgical pain and stress may alter immune function in adults. Limited evidence indicates that anesthetic and analgesic immunomodulation may boost immune function to prevent nosocomial infection. However, unique aspects of immune function maturation and neurodevelopment must be considered. CONCLUSION: Research is urgently needed to determine if the interactions between nociceptive and immune function pathways in critically ill infants and children are similar to those in adults and if host defenses can be enhanced by optimal anesthetic and analgesic strategies.

Analgesia↗