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Peter Garred

Publications and source records attributed to Peter Garred.

36 records · Page 2Linked to original sources
PubMed2004

Mini-review: A pivotal role for innate immunity in the clearance of apoptotic cells.

Apoptotic cells can be recognized and taken up by both macrophages and dendritic cells. Phagocytosis of apoptotic cells generally leads to active suppression of cytokine production by professional phagocytes. This is different from the response towards cells that die by necrosis, which induce a pro-inflammatory cytokine profile. Uptake of apoptotic cells involves a large number of receptors and opsonins, which bind to cellular ligands exposed during the various stages of apoptotic cell death. Among the opsonins of apoptotic cells, complement factors, including C1q, and complement-activating members of the pentraxin family play an important role. This is indicated by in vitro phagocytosis studies and supported by the susceptibility to systemic autoimmunity of carriers of genetic deficiencies for early complement proteins. The present review summarizes the role of molecules of innate immunity in the handling of apoptotic cells by macrophages and dendritic cells. It is proposed that C1q and other opsonins prevent autoimmunity and maintain self-tolerance by supporting the efficient clearance of apoptotic material, as well as by actively modulating phagocyte function.

Animals↗
PubMed2004

Genetic Susceptibility to Sepsis: A Possible Role for Mannose-binding Lectin.

Sepsis is an increasing problem in modern medicine and the leading cause of death in noncoronary intensive care unit patients. Over the past few years, several studies have provided data indicating that relatively common polymorphisms in genes encoding proteins of importance for innate immune recognition, the inflammatory response, and for coagulation and fibrinolysis, are associated with susceptibility for and outcome of sepsis. Recently, several studies have shed light on the importance of deficiency of mannose-binding lectin (MBL) as a susceptibility factor for sepsis. This review summarizes the evidence that critically ill patients carrying MBL-variant alleles may be at increased risk for severe sepsis. The prospect for the future is that genetic profiling may guide in identifying critically ill patients at increased risk for sepsis and poor outcome, and in tailoring a more individual and effective therapy.

Journal Article↗
PubMed2003

Association of mannose-binding lectin polymorphisms with sepsis and fatal outcome, in patients with systemic inflammatory response syndrome.

Genetic factors may predispose critically ill patients to increased risk of developing sepsis. Mannose-binding lectin (MBL) is an important factor in innate immune defense. We investigated whether MBL gene polymorphisms causing low levels of MBL are associated with the development and progression of sepsis in adult patients in intensive care units. In 272 prospectively monitored patients with systemic inflammatory response syndrome, different MBL genotypes were compared, with respect to microbiology, sepsis development, and survival. The presence of MBL variant alleles was associated with the development of sepsis, severe sepsis, and septic shock. An increased risk of fatal outcome was observed in patients carrying variant alleles. These data show that MBL insufficiency plays an important role in the susceptibility of critically ill patients to the development and progression of sepsis and confers a substantial risk of fatal outcome.

Adolescent↗
PubMed2003

Mannose-binding lectin polymorphisms in clinical tuberculosis.

Mannose-binding lectin (MBL) mediates protection against infections by using the complement system, but certain microorganisms may increase infectivity by exploiting this host defense system. Thus, it has been speculated whether genetically determined low MBL levels may confer partial protection against certain intracellular microorganisms, such as Mycobacterium tuberculosis. We investigated MBL alleles in 109 culture-positive human immunodeficiency virus-uninfected patients with tuberculosis living in Denmark and 250 white control subjects. Patients and control subjects were divided into 3 different groups defined by undetectable, low, and high serum MBL concentrations, which correlates to deficient, low, and high expressing MBL genotypes. A significantly decreased frequency of patients with the low-expressing MBL genotype was observed in white patients compared to control subjects. The same tendency also was observed in patients of other ethnic origin. It may be hypothesized that heterozygosity for MBL variant alleles, which encodes low serum MBL levels, is associated with protection against clinical tuberculosis.

Adult↗
PubMed2003

[Genetic epidemiology].

Genetic epidemiology--i.e. studies of the interaction between genes and environment--has lead to the identification of monogenic disorders and more recently of genes involved in polygenic diseases by means of family (linkage) and populations (association) studies. The recent complete sequencing of the human genome combined with new methods such as gene expression analyses with microchip technology and proteome analyses including bioinformatics increases the possibility to find genes involved in various diseases and help to identify new targets for therapy and/or prevention.

Computational Biology↗
PubMed2003

Mannose-binding lectin engagement with late apoptotic and necrotic cells.

The serum opsonin mannose-binding lectin (MBL) has been shown to be involved in the handling of apoptotic cells. However, at what stage in the process this happens and whether this mediates activation of complement is unknown. Cells rendered apoptotic or necrotic were incubated with purified MBL/MBL-associated serine protease (MASP) complexes and assessed by flow cytometry and fluorescence microscopy. MBL bound specifically to late apoptotic cells, as well as to apoptotic blebs and to necrotic cells, but not to early apoptotic cells. Binding of MBL could be inhibited by EDTA as well as with an antibody against the CRD region. Addition of C1q, another serum opsonin involved in the handling of apoptotic cells, prior to MBL partly inhibited MBL binding to apoptotic cells and vice versa. MBL/MASP could initiate deposition of purified complement C4 on the target cells. However, addition of MBL/MASP to whole serum deficient for both C1q and MBL did not enhance deposition of C4, but MBL enhanced phagocytosis of apoptotic cells by macrophages. These results demonstrate that MBL interacts with structures exposed on cells rendered late apoptotic or necrotic and facilitates uptake by macrophages. Thus, MBL may promote non-inflammatory sequestration of dying host cells.

Apoptosis↗
PubMed2003

Mannose-binding lectin deficiency--revisited.

There is an emerging interest for mannose-binding lectin (MBL) due to its role in innate immunity. In this survey we present a mixture of old and new data describing the effect MBL polymorphisms may have on the level and function of the molecule. Three single nucleotide substitutions in exon 1 of the mbl2 gene cause a dominant decrease of functional MBL in the circulation. Additionally, promoter variants influence expression of MBL. It has been assumed that the structural variant alleles may disrupt the assembly of MBL trimers or accelerate the degradation of the protein, thereby causing the decrease in MBL serum concentrations. We have analysed 1183 different sera in a double sandwich antibody ELISA using the same antibody to capture and detect MBL and find the same results as have been presented previously showing that different MBL promoter alleles have profound effect of on the MBL serum concentration. The use of a new anti-MBL monoclonal antibody, however, has shown that the amount of MBL in the circulation is less dependent on the presence of structural variant alleles than previously anticipated. Molecular characterisation of MBL revealed that sera from donors homozygous for the normal MBL genotype predominantly contained high molecular weight MBL, while sera from individuals heterozygous for the variant alleles contained both high and low molecular weight MBL. The ratio between high and low molecular weight MBL was dependent on the MBL promoter type on the normal haplotype. Sera deriving from individuals homozygous for MBL variant alleles contained mainly low molecular weight MBL. Of the different oligomers of MBL only the high molecular weight forms bound mannan efficiently and activated complement. In contrast to a previous notion, we demonstrate that variant alleles give rise to relatively high levels of MBL in the circulation. However, the variant MBL has lower molecular weight and is dysfunctional compared to normal MBL. The physiological relevance of variant MBL remains to be established.

Alleles↗
PubMed2003

Mannose-binding lectin is a disease modifier in clinical malaria and may function as opsonin for Plasmodium falciparum-infected erythrocytes.

Variant alleles in the mannose-binding lectin (MBL) gene (mbl2) causing low levels of functional MBL are associated with susceptibility to different infections and are common in areas where malaria is endemic. Therefore, we investigated whether MBL variant alleles in 551 children from Ghana were associated with the occurrence and outcome parameters of Plasmodium falciparum malaria and asked whether MBL may function as an opsonin for P. falciparum. No difference in MBL genotype frequency was observed between infected and noninfected children or between children with cerebral malaria and/or severe malarial anemia and children with uncomplicated malaria. However, patients with complicated malaria who were homozygous for MBL variant alleles had significantly higher parasite counts and lower blood glucose levels than their MBL-competent counterparts. Distinct calcium-dependent binding of MBL to the membrane of P. falciparum-infected erythrocytes, which could be inhibited by mannose, was observed. Further characterization revealed that MBL reacted with a P. falciparum glycoprotein identical to the 78-kDa glucose-regulated stress protein of P. falciparum. MBL seems to be a disease modifier in clinical malaria and to function as an opsonin for erythrocytes invaded by P. falciparum and may thus be involved in sequestration of the parasite, which in turn may explain the association between homozygosity for MBL variant alleles and high parasite counts.

Adolescent↗
PubMed2002

[Acute respiratory tract infections and mannose-binding lectin insufficiency in small children].

INTRODUCTION: According to hospital-based studies, increased susceptibility to certain infections is associated with genotypes that cause low serum levels of the protein mannose-binding lectin (MBL). However, the contribution of MBL insufficiency to the incidence of common childhood infections on a population basis is unknown. To investigate the effect of MBL insufficiency on the risk of acute respiratory infections (ARI) in unselected children, we performed a prospective population-based study of ARI in young children in Sisimiut, Greenland. MATERIAL AND METHODS: An open cohort of children aged 0-2 years was formed in 1996, and followed up with weekly morbidity surveillance visits for a two-year period. Episodes of ARI were diagnosed on medical history and clinical examinations. MBL genotypes were determined from blood samples according to the presence of structural alleles and promoter alleles. RESULTS: Altogether 294 children participated and 44 refused. Blood samples were taken from 252 participants. A 2.1-fold (95% confidence interval 1.4-3.1) increased risk of ARI was found in MBL-insufficient children compared with MBL-sufficient children (p < 0.001). The risk association was largely restricted to the period 6 to 17 months of age, whereas less or no effect could be shown in younger and older children. DISCUSSION: These population-based data suggest that genetic factors such as MBL insufficiency play an important role in host defence, particularly during the vulnerable period of infancy between 6 and 17 months of age, when the adaptive immune system is immature.

Acute Disease↗
PubMed2002

Association of Chlamydia pneumoniae with coronary artery disease and its progression is dependent on the modifying effect of mannose-binding lectin.

BACKGROUND: The possible association between coronary artery disease (CAD) and Chlamydia pneumoniae (C pneumoniae) infection is controversial. On the basis of the recent suggestion that mannose-binding lectin (MBL) variant alleles are related to an increased risk of severe atherosclerosis, and on the in vitro interaction of MBL with C pneumoniae, we asked whether MBL might contribute to CAD in conjunction with C pneumoniae. METHODS AND RESULTS: Antibodies to C pneumoniae were measured by immunofluorescence and MBL alleles were determined by polymerase chain reaction technique in samples from 210 patients with CAD and 257 healthy subjects from Hungary collected between 1995 and 1996. A higher percentage of patients with CAD were anti-C pneumoniae positive as compared with the control group (P=0.058). However, at logistic regression analysis adjusted to age, sex, and serum lipid levels, this difference was confined only to subjects carrying MBL variant alleles (P=0.035, odds ratio 2.63, [95% CI: 1.07 to 6.45]). In contrast, no significant difference was seen in those homozygous for the normal MBL allele (P=0.412). During a 65+/-5.8-month follow-up period, major outcomes (new myocardial infarction, and/or bypass operation or cardiovascular death) occurred in 11 C pneumoniae positive and 3 C pneumoniae negative patients. In the C pneumoniae positive group, the odds ratio of development of outcomes was 3.27 (95% CI: 1.10 to 9.71, P=0.033) in the carriers of the MBL variant alleles compared with the homozygous carriers of the normal MBL allele. CONCLUSIONS: These results indicate that infection with C pneumoniae leads mainly to the development and progression of severe CAD in patients with variation in the MBL gene.

Alleles↗
PubMed2002

Natural resistance-associated macrophage protein 1 polymorphisms are associated with microscopy-positive tuberculosis.

The natural resistance-associated macrophage protein 1 (NRAMP1) is implicated in the pathophysiology of mycobacterial infections. We investigated by polymerase chain reaction previously published Nramp1 genotypes at 4 loci-INT4, N543D, 3'UTR, and 5'(CA)(n) microsatellite markers-in 104 human immunodeficiency virus-negative patients with tuberculosis and 176 healthy control subjects living in Denmark. No significant difference in genotype frequency was found between white patients with tuberculosis and control subjects (P>.16), but carriage of Nramp1 variant alleles at loci INT4 and 5'(CA)(n) conferred a significantly increased risk of having microscopy-positive compared with microscopy-negative tuberculosis (65% vs. 35% [P=.0004] and 63% vs. 38% [P=.047], respectively). The Nramp1 alleles were not associated with increased risk for the development of cavities seen on chest radiographs, or with extrapulmonary tuberculosis. These results indicate that variant alleles in the Nramp1 gene are associated with increased mycobacterial replication rather than susceptibility for tuberculosis and may thus confer increased risk of severe disease.

Adult↗
PubMed2002

Increased frequency of mannose-binding lectin insufficiency among children with acute lymphoblastic leukemia.

Epidemiological data indicate that acute lymphoblastic leukemia (ALL) could be induced by interactions between the immune system and early childhood infections. Mannose-binding lectin (MBL) plays a critical role in the immune response in early childhood before specific immune protection develops. We investigated whether there may be an association between childhood ALL and low-producing MBL genotypes. Serum MBL levels depend on normal (A) or defective (O) alleles, and on normal (Y) or reduced (X) promoter activities. For this study, 137 noninfants with ALL and 250 controls were classified into 3 MBL genotype groups according to their influence on the serum level of functional MBL: group I, YA/YA and YA/XA (higher levels); group II, XA/XA and YA/O (intermediate levels); and group III, MBL insufficiency with XA/O or O/O (MBL-deficient) genotypes. Compared with controls, cases more often had low-level genotypes (I/II/III: 63 [46%]/44 [32%]/30 [22%] vs 145 [58%]/65 [26%]/40 [16%]; P =.02) and MBL deficiency (8.8% vs 2.8%; P =.009). Thus, the ALL odds ratio for MBL-deficient versus nondeficient individuals was 3.3 (95% CI, 1.3-8.7), whereas the ALL odds ratio for group I versus group II/III genotypes was 0.62 (95% CI, 0.41-0.94). MBL group III patients were significantly younger at diagnosis than patients in group I/II (median, 3.9 vs 5.2 years; P =.04). The study shows that the presence of low-level MBL genotypes is associated with an increased risk of childhood ALL, particularly with early age at onset.

Adolescent↗
PubMed2002

Variant mannose-binding lectin alleles are not associated with susceptibility to or outcome of invasive pneumococcal infection in randomly included patients.

Invasive pneumococcal disease is a serious infection that primarily affects very young children and elderly or immunocompromised individuals but also affects previously healthy people. Variant mannose-binding lectin (MBL) alleles are associated with recurrent infections and may be a risk factor for pneumococcal infections. To assess the influence of MBL genotypes on the course and outcome of invasive pneumococcal disease, clinical data for 141 adult patients were collected prospectively and their genotypes were determined. All patients included had positive blood cultures for Streptococcus pneumoniae. The distribution of variant MBL alleles related to low MBL serum concentrations was similar among the patients and healthy individuals, and MBL genotype was not associated with infection outcome. Thus, in a random adult population with invasive pneumococcal infection, MBL does not seem to play a role in the pathophysiology, in contrast to earlier observations in patients with other concomitant immune abnormalities.

Adolescent↗
PubMed2002

Mannose-binding lectin (MBL) therapy in an MBL-deficient patient with severe cystic fibrosis lung disease.

Deficiency of mannose-binding lectin has been shown to be a risk factor for cystic fibrosis (CF) patients. We, therefore, decided to treat a patient with CF, mannose-binding lectin deficiency, severe bronchopulmonary Pseudomonas aeruginosa infection, and rapid deterioration of lung function with purified mannose-binding lectin in an attempt to ameliorate the course of the lung disease. The mannose-binding lectin used originated from pooled human donor plasma and was given as an intravenous infusion twice a week for a period of 3 months. The patients's clinical condition was stabilized during the treatment period, but was not improved. No adverse events were observed. However, the lung function assessed as percent forced expiratory volume in 1 sec (FEV1%) and percent forced vital capacirt (FVC%) correlated significantly with the mannose-binding serum lectin levels (rho=+0.68, P=0.008, and rho=+0.73, P=0.004). Additionally, an inverse correlation with the acute phase-reactant C-reactive protein and the proinflammatory cytokine IL-6 was observed (rho=-0.49, P=0.007 and rho=-0.41, P=0.04, respectively). The results emphasize the importance of mannose-binding lectin as a secondary disease modifier in CF. Moreover, purified mannose-binding lectin can safely be administered to chronically ill patients, and may be a potential treatment in CF and other diseases in which mannose-binding lectin deficiency plays a pathophysiological role.

Adult↗
PubMed2002

Mannose-binding lectin variant alleles and HLA-DR4 alleles are associated with giant cell arteritis.

OBJECTIVE: To determine whether variant alleles of the mannose-binding lectin (MBL) gene causing low serum concentrations of MBL and/or polymorphisms of HLA-DRB1 are associated with increased susceptibility to polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) or particular clinical phenotypes of PMR/GCA. METHODS: MBL and HLA-DRB1 alleles were determined by polymerase chain reaction in 102 Danish patients with PMR (n = 37) or GCA (n = 65). Two hundred fifty and 193 healthy individuals served as controls for MBL and HLA genotyping, respectively. RESULTS: The prevalence of MBL variant alleles in controls, patients with PMR only, and patients with GCA was 37, 32, and 53% (p = 0.01), respectively. HLA-DRB1*04 was found in 47% of patients with PMR only and in 54% of patients with GCA, which differed significantly from the 35% found in controls (p = 0.01). HLA-DR4 alleles were not associated with any clinical phenotypes of PMR/GCA, whereas MBL variant alleles were associated with cranial arteritis, high erythrocyte sedimentation rate, and low B-hemoglobin. CONCLUSION: We found MBL variant alleles and HLA-DR4 alleles to be weak susceptibility markers for GCA. In patients with PMR/GCA, MBL variant alleles were associated with signs of increased inflammatory activity and clinical signs of arteritic manifestations. This was not found for HLA-DR4 alleles. These findings indicate that HLA-DR4 and MBL are contributing to the pathophysiology of GCA at different levels in the disease process.

Aged↗