Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the course of the past two decennia, a 3rd route of complement activation (next to the classical and the alternative routes) has been identified: the lectin route in which mannose-binding lectin (MBL) plays an essential role. MBL is produced in the liver. From the phylogenetic and functional points of view, complement activation via MBL falls in between the alternative and the classical routes and combines the advantages of the former (an early response, without the intervention of antibodies) with those of the latter (high specificity). The binding of MBL to the surface of a microorganism results in the activation of two serine proteases (MASP1 and MASP2) that are coupled to MBL. These enzymes can activate C4 and C2 so that, via the MBL route, the C3-convertase of the classical route (C4b2b) is produced long before there are any specific antibodies. The gene for MBL is located on the long arm of chromosome 10 and consists of a promoter gene and 4 exons coding for the protein. The prevalence of mutations in the MBL gene is about 10%, but in Africa South of the Sahara it is as high as 30%. MBL deficiency predisposes both children and adults to all sorts of infectious diseases, chronic diarrhoea, tonsillitis, otitis media, pneumonia, (meningococcal) meningitis, sepsis and osteomyelitis. Remarkably, MBL deficiency may actually be advantageous in some infections, because certain microorganisms use MBL or complement to invade the cell.
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PMID:[Immunology in the medical practice. XXVII. Mannose-binding lectin, an important link for nonspecific or hereditary immune reaction]. 1107 14

The ficolins and mannose-binding lectin (MBL) create complexes with three different serine proteases (MASP-1, MASP-2 and MASP-3) and a truncated non-enzymatic form of MASP-2 (sMAP). MASP-2 is able to activate complement by cleavage of C4 and C2, while the physiological functions of MASP-1, MASP-3 and sMAP still are debated. MASP-1 and MASP-3 are alternative spliced forms of the same MASP gene. To gain insight in the molecular variation in the MASP-1/3 gene, we undertook a systematic study of the protein coding sequences of the MASP-1/3 gene. The coding regions of the MASP-1/3 gene were sequenced in 92 healthy Caucasian donors. A total of six nucleotide substitutions were detected. Five were detected only once. One polymorphism identified in exon 10 at position +50074 (rs 38343199) relative to the transcription start site resulting in the amino acid substitution of a glycine (GGG) with a glutamic acid residue (GAG) in the second complement control protein domain was observed. The frequency of this allele in 305 blood donors, 90 patients with systemic lupus erythematosus and 234 patients with the systemic inflammatory response syndrome (SIRS) and/or sepsis was 0.03, 0.017 and 0.03 respectively. No significant differences in genotype frequencies between the groups were observed (P > 0.45). However, the SIRS/sepsis group deviated from the Hardy-Weinberg expectations due to one variant allele homozygote (P = 0.07), which was not observed in the other groups. In conclusion, the MASP1/3 gene harbours a low-frequent polymorphic site resulting in an amino acid substitution, which may influence the function of the gene product.
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PMID:A novel mannose-binding lectin-associated serine protease 1/3 gene variant. 1744 53

Broadly speaking, C1 inhibitor plays important roles in the regulation of vascular permeability and in the suppression of inflammation. Vascular permeability control is exerted largely through inhibition of two of the proteases involved in the generation of bradykinin, factor XIIa and plasma kallikrein (the plasma kallikrein-kinin system). Anti-inflammatory functions, however, are exerted via several activities including inhibition of complement system proteases (C1r, C1s, MASP2) and the plasma kallikrein-kinin system proteases, in addition to interactions with a number of different proteins, cells and infectious agents. These more recently described, as yet incompletely characterized, activities serve several potential functions, including concentration of C1 inhibitor at sites of inflammation, inhibition of alternative complement pathway activation, inhibition of the biologic activities of gram negative endotoxin, enhancement of bacterial phagocytosis and killing, and suppression of the influx of leukocytes into a site of inflammation. C1 inhibitor has been shown to be therapeutically useful in a variety of animal models of inflammatory diseases, including gram negative bacterial sepsis and endotoxin shock, suppression of hyperacute transplant rejection, and treatment of a variety of ischemia-reperfusion injuries (heart, intestine, skeletal muscle, liver, brain). In humans, early data appear particularly promising in myocardial reperfusion injury. The mechanism (or mechanisms) of the effect of C1 inhibitor in these conditions is (are) not completely clear, but involve inhibition of complement and contact system activation, in addition to variable contributions from other C1 inhibitor activities that do not involve protease inhibition.
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PMID:Biological activities of C1 inhibitor. 1867 18

BACKGROUND. The incidence of bacterial sepsis during the neonatal period is high. Mannan-binding lectin (MBL), L-ficolin, and H-ficolin recognize microorganisms and activate the complement system via MBL-associated serine proteases (MASPs). This study investigated whether cord blood concentrations of the lectin pathway proteins are associated with neonatal sepsis. METHODS. This was a case-control study including 47 infants with culture-proven sepsis during the first month of life and 94 matched controls. MBL, L-ficolin, H-ficolin, MASP-2, and MASP-3 levels were measured in cord blood with use of enzyme-linked immunosorbent assay and time-resolved immunofluorometric assay. Multivariate logistic regression was performed. RESULTS. Infants with gram-positive sepsis had significantly lower H-ficolin cord blood concentrations than controls (multivariate odds ratio [OR], 4.00; 95% confidence interval [CI], 1.51-10.56; P = .005), whereas infants with gram-negative sepsis had lower MBL cord blood concentrations (OR, 2.99; 95% CI, 0.86-10.33; P = .084). When excluding patients with postoperative sepsis, multivariate analysis confirmed that low H-ficolin was associated with a significantly higher risk of gram-positive sepsis (OR, 3.71; 95% CI, 1.26-10.92; P = .017) and late-onset sepsis (OR, 3.14; 95% CI, 1.07-9.21; P = .037). In contrast, low MBL was associated with a significantly higher risk of gram-negative sepsis (OR, 4.39; 95% CI, 1.10-17.45; P = .036) and early-onset sepsis (OR, 3.87; 95% CI, 1.05-14.29; P = .042). The concentrations of all the lectin pathway proteins increased with gestational age (P < .01). CONCLUSIONS. These preliminary results indicate that low MBL concentrations are a susceptibility factor for gram-negative sepsis, and low H-ficolin concentrations indicate susceptibility to gram-positive sepsis. The decreased expression of lectin pathway proteins in neonates must be considered to be an additional form of neonatal immunodeficiency.
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PMID:Differential role of the lectin pathway of complement activation in susceptibility to neonatal sepsis. 2052 71

Ficolins activate the lectin pathway of the complement system upon binding to carbohydrate patterns on pathogens. To characterize the producer cells of ficolin-B the expression of mouse ficolin-B, the orthologue of human M-ficolin, was studied in macrophages and dendritic cells during differentiation from bone marrow cells, in primary granulocytes, and during differentiation of granulocytes derived from ER-Hoxb8 cells. Expression of ficolin-B mRNA declined in all myeloid cell types to low levels during terminal differentiation. However, in contrast to macrophages and dendritic cells, ficolin-B expression was enhanced upon activation in granulocytes. High expression of ficolin-B was observed in primary immature neutrophilic CD11b(+) Ly-6C(int) Ly-6G(high) granulocytes when isolated from the bone marrow, in particular during sepsis. Ficolin-B was demonstrated in lysates of primary granulocytes, ER-Hoxb8-derived granulocytes, bone marrow-derived macrophages, and dendritic cells. Native ficolin-B from cell lysates and supernatants of granulocytes activated the lectin pathway as measured by binding to MASP-2 and inducing C4 deposition. Specific staining demonstrated intra-cellular or cell associated ficolin-B protein in activated immature granulocytes deposited in a granular fashion. This study shows that ficolin-B is stored in and set free from immature granulocytic myeloid cells indicating a role in the early infection-induced cellular response of these inflammatory cells.
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PMID:Immature mouse granulocytic myeloid cells are characterized by production of ficolin-B. 2391 5

Trauma is a major public health problem worldwide. Infectious complications, sepsis, and multiple organ dysfunction syndrome (MODS) remain important causes for morbidity and mortality in patients who survive the initial trauma. There is increasing evidence for the role of genetic variation in the innate immune system on infectious complications in severe trauma patients. We describe a trauma patient with multiple infectious complications caused by multiple micro-organisms leading to prolonged hospital stay with numerous treatments. This patient had multiple single nucleotide polymorphisms (SNPs) in the MBL2, MASP2, FCN2 and TLR2 genes, most likely contributing to increased susceptibility and severity of infectious disease.
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PMID:Multiple Infectious Complications in a Severely Injured Patient with Single Nucleotide Polymorphisms in Important Innate Immune Response Genes. 2631 21

Infectious complications, sepsis, and multiple organ dysfunction syndrome (MODS) remain important causes for morbidity and mortality in patients who survive the initial trauma. Increasing evidence suggests that genetic variants, particularly single nucleotide polymorphisms (SNPs), are critical determinants for interindividual differences in both inflammatory responses and clinical outcome in sepsis patients. Although the effect of SNPs on sepsis and MODS has been studied in many populations and diseases, this review aimed to summarize the current knowledge on the effect of SNPs on infectious complication specifically in trauma patients. A review of available literature was performed in PubMed database. The following genes have been studied in populations of trauma patients: CD14, HMGB1, IFNG, IL1A, IL1B, IL1RN, IL4, IL6, IL8, IL10, IL17F, IL18, MBL2, MASP2, FCN2, TLR1, TLR2, TLR4, TLR9, TNF, LTA, GR, MYLK, NLRP3, PRDX6, RAGE, HSPA1B, HSPA1L, HSP90, SERPINE1, IRAK1, IRAK3, VEGFA, LY96, ANGPT2, LBP, MicroRNA, and mtDNA. In this review, we discuss the genes of the Pattern Recognition Receptors, Signal Transducing Adaptor Proteins, and Inflammatory Cytokines of the innate immune system. A number of genetic variations have so far been studied in cohorts of trauma patients. Studies are often unique and numbers sometimes small. No definitive conclusions can be reached at this time about the influence of specific sequence variations on outcome in trauma patients.
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PMID:Effects of Sequence Variations in Innate Immune Response Genes on Infectious Outcome in Trauma Patients: A Comprehensive Review. 2647 37

Infections are a major cause of childhood mortality. We investigated components of the lectin pathway of complement activation in the context of sepsis at both genetic and protein levels in neonates, infants and older children. Major components of the lectin pathway and two genes for Toll-like receptors were studied in 87 neonates with confirmed sepsis and compared with 40 babies with infections who did not develop sepsis (disease controls) and 273 infection-free neonatal controls. A second cohort comprised 47 older children with sepsis and 87 controls. Low MBL-conferring genotypes (LXA/O+O/O) were more frequent in sepsis patients than in healthy controls but no significant differences in the frequency of SNPs of other lectin pathway genes (FCN1, FCN2, FCN3, MASP1/3, MASP2) or TLR receptor genes (TLR2, TLR4) were found. One case of primary MASP-2 deficiency was found among healthy pre-terms and one neonate suffering from SIRS was heterozygous for the rare FCN1 gene mutation, +6658 G>A. Generally, sepsis was associated with low serum MBL and low ficolin-2 concentrations on admission. Among neonates, ficolin-1 and MASP-2 levels were elevated in sepsis relative to healthy, but not disease, controls. Unlike neonates, ficolin-3 and MASP-2 levels were lower in older patients than in healthy controls while no difference was found for ficolin-1. With the possible exception of MBL, inherited lectin pathway insufficiencies do not seem to predispose to sepsis, rather changes in protein concentrations reflect alterations in disease course.
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PMID:Components of the lectin pathway of complement activation in paediatric patients of intensive care units. 2685 Mar 22

Genetic variants are associated with altered clinical outcome of patients with sepsis and cardiovascular diseases. Common gene signaling pathways may be involved in the pathophysiology of these diseases. A better understanding of genetic commonality among these diseases may enable the discovery of important genes, signaling pathways, and therapeutic targets for these diseases. We investigated the common genetic factors by a systematic search of the literature. Twenty-four genes (ADRB2, CD14, FGB, FV, HMOX1, IL1B, IL1RN, IL6, IL10, IL17A, IRAK1, MASP2, MBL, MIR608, MIF, NOD2, PCSK9, PPARG, PROC, SERPINE1, SOD2, SVEP1, TF, TIRAP, TLR1) were extracted as reported genetic variations associated with altered outcome of both sepsis and cardiovascular diseases. Of these genes, the adverse allele (or combinations) was same in nine (ADRB2, FV, HMOX1, IL6, MBL, MIF, NOD2, PCSK9, SERPINE1), and the effect appears to be in the same direction in both sepsis and cardiovascular disease. Shared gene signaling pathways suggest that these are true biological results and could point to overlapping drug targets in sepsis and cardiovascular disease.
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PMID:Genetic Polymorphisms in Sepsis and Cardiovascular Disease: Do Similar Risk Genes Suggest Similar Drug Targets? 3066 Jul 82