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)

Destruction of the skin barrier by thermal injury removes the major local defense barrier to bacteria. To determine whether a local defect in immunity also existed, the opsonic activity of blister fluid against Staphylococcus aureus and Pseudomonas aeruginosa as well as neutrophil chemotaxis were measured. The results of these studies indicated that blister fluid could not opsonize Pseudomonas. A series of repletion experiments indicated that the opsonic defect for Pseudomonas was not due to the presence of inhibitors but was due to the lack of normal serum factor(s). Although both the level of immunoglobulins and complement components in the blister fluid was depressed, the cause of the opsoninopathy appeared to be due to local consumption of complement in the burn wounds. In addition to the opsoninopathy, both neutrophil chemotaxis and random migration were also depressed. In conclusion, a burn injury appears to cause severe impairment of both cellular and humoral local immunity, which could predispose these patients to burn wound sepsis.
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PMID:Failure of local immunity. A potential cause of burn wound sepsis. 391 65

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

Despite significant progress in intensive care medicine, the mortality of septic shock has not changed in recent years. Early recognition of subtle signs in favor of meningococcal sepsis, early antibiotic treatment, and aggressive hemodynamic support remains the cornerstone of therapy of severe meningococcal shock in children. Recent work has emphasized the role of genetic polymorphisms in various systems to explain the most severe cases: anti-inflammatory cytokine profile IL-10/TNF-alpha, elevated levels of plasminogen activator inhibitor type-1, variants of the gene for mannose-binding lectin complement pathway. This may explain the disillusionment of pediatric intensivists, and the general failure of immunotherapy for sepsis. Reasonable hope lies upon new meningococcal vaccines.
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PMID:[Meningococcal purpura fulminans: untoward result of genetic polymorphism?]. 1152 16

Despite systematic antibiotic therapy, severe infections (septicemia, meningitis, or osteomyelitis) are a major cause of mortality and morbidity in children with sickle cell disease (SCD). In this study, we explored the possibility that polymorphism at the human leukocyte antigen (HLA) locus might constitute an immunogenetic modifying factor to the intrinsic susceptibility to infection in patients with SCD. A cohort of 80 SCD patients living in Paris, 43 with at least one major infectious complication and 37 without infections, were typed for HLA class II loci by polymerase chain reaction-sequence-specific primers (PCR-SSP). We found that significantly more patients without infections carry the HLA class II DRB1*15 specificity than did patients with infections (21.6% in the first group, versus 4.7% in the second group; chi(2) = 10.47, p(c) = 0.01), supporting a protective effect of this allele. Conversely, significantly more patients were found to carry the DQB1*03 specificity within the group of severe infections, supporting a negative effect (34.9% versus 12.2%, chi(2) = 9.41, p(c) = 0.01). These findings suggest a direct involvement of HLA polymorphism in the development of major infections in SCD. Together with previous data on polymorphism of the Fc receptor and of the mannose-binding lectin, they provide evidence for a polygenic immunomodulation of the constitutively increased infectious risk in SCD.
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PMID:Infectious complications in sickle cell disease are influenced by HLA class II alleles. 1187 37

The complement system is an important component of the innate immune response to bacterial pathogens, including Streptococcus pneumoniae. The classical complement pathway is activated by antibody-antigen complexes on the bacterial surface and has been considered predominately to be an effector of the adaptive immune response, whereas the alternative and mannose-binding lectin pathways are activated directly by bacterial cell surface components and are considered effectors of the innate immune response. Recently, a role has been suggested for the classical pathway during innate immunity that is activated by natural IgM or components of the acute-phase response bound to bacterial pathogens. However, the functional importance of the classical pathway for innate immunity to S. pneumoniae and other bacterial pathogens, and its relative contribution compared with the alternative and mannose-binding lectin pathways has not been defined. By using strains of mice with genetic deficiencies of complement components and secretory IgM we have investigated the role of each complement pathway and natural IgM for innate immunity to S. pneumoniae. Our results show that the proportion of a population of S. pneumoniae bound by C3 depends mainly on the classical pathway, whereas the intensity of C3 binding depends on the alternative pathway. Furthermore, the classical pathway, partially targeted by the binding of natural IgM to bacteria, is the dominant pathway for activation of the complement system during innate immunity to S. pneumoniae, loss of which results in rapidly progressing septicemia and impaired macrophage activation. These data demonstrate the vital role of the classical pathway for innate immunity to a bacterial pathogen.
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PMID:The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice. 1247 26

Adverse outcome of critical illness is often caused by systemic inflammation and sepsis. A recent study showed that mortality is significantly reduced by maintenance of normoglycemia using intensive insulin therapy. We examined whether the beneficial effects of intensive insulin therapy involve modulations of mannose-binding lectin (MBL) and C-reactive protein (CRP) levels. From a study of 1548 patients randomly assigned to either conventional treatment or intensive insulin therapy at an intensive care unit (ICU) we included all 451 patients who needed prolonged intensive care (>5 d). CRP and MBL concentrations were measured on admission, d 5, d 15, and the last day in the ICU. In all patients, serum MBL concentrations increased with time in the ICU (P < 0.0001). This acute phase response was suppressed by intensive insulin therapy at all time points studied (P < 0.02). Selectively in patients receiving conventional therapy, MBL concentrations at baseline were almost 3 times higher in survivors than in nonsurvivors (P = 0.04). Baseline CRP concentrations were elevated, but decreased with time in ICU (P < 0.0001). The decrease in CRP was significantly more pronounced in the intensive insulin-treated patients compared with the conventionally treated patients (P </= 0.02) at all time points. Multivariate logistic regression analysis, corrected for all other determinants of outcome, revealed that the antiinflammatory action on CRP, but not on MBL, largely explained the beneficial effects of intensive insulin therapy on morbidity and mortality. In conclusion, intensive insulin therapy exerts a powerful antiinflammatory effect during critical illness which at least partially explains improvement in morbidity and mortality. Possible adverse effects of low baseline MBL are overcome by intensive insulin therapy.
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PMID:Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. 1262 88

Infections are common in systemic lupus erythematosus (SLE), and remain a source of mortality. The types of infections (such as pneumonia, urinary tract infection, cellulitis, and sepsis) in SLE patients are similar to the general population and include the same pathogens (Gram-positive and Gram-negative). SLE patients may also develop opportunistic infections, especially when treated with immunosuppressive agents. As a high-risk population, identification and treatment of chronic infections such as tuberculosis, hepatitis B, or human immunodeficiency virus (HIV), are important prior to the institution of immunosuppression to prevent reactivation or exacerbation of the infection. A common caveat is to distinguish between a lupus flare and an acute infection; judicious use of corticosteroids and cytotoxic drugs is critical in limiting infectious complications. The risk factors associated with susceptibility to disease include severe flares, active renal disease, treatment with moderate or high doses of corticosteroids and/or immunosuppressive agents, and others. Genetic factors (complement deficiencies, mannose-binding lectin, Fcgamma III, granulocyte macrophage colony-stimulating factor [GM-CSF], osteopontin) may predispose certain SLE patients to develop infections. Parameters including C-reactive protein (CRP) and adhesion molecules may help to differentiate an infectious disease from an exacerbation of the disease. Finally, the mechanism of molecular mimicry by specific microbial agents may play a role in the induction of SLE.
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PMID:SLE and infections. 1279 59

Mutations of genes involved in the innate immune system have been reported to be associated with an increased sepsis rate in adults. We determined the -159T mutation of the CD14 gene, the 896G mutation of the toll-like receptor 4 gene, the 3020insC mutation of the NOD2 gene (NOD2-3020insC), the IL-6 174G/C promoter polymorphism (IL6-174G/C), and the mannose-binding lectin genotype and their association to the subsequent development of neonatal sepsis in a large cohort of very low birth weight (VLBW) infants. Fifty (14%) of 356 VLBW infants developed blood culture-proven sepsis during their stay in the hospital. VLBW infants carrying the NOD2-3020insC allele (n =15) and the IL6-174G allele (n =121) had a significantly higher rate of blood culture-proven sepsis (33% and 19.8%, respectively) than VLBW infants without these genotypes (p = 0.046 and 0.035, respectively). In a multivariate logistic regression analysis, gestational age less than 28 wk (odds ratio, 3.2; 95% confidence interval, 1.7-6.0; p < 0.001) and the homozygous IL6-174G allele (odds ratio, 1.9; 95% confidence interval, 1.0-3.9; p = 0.039) were predictive for the development of sepsis, whereas the NOD2-3020insC allele was only of borderline significance (odds ratio, 3.2; 95% confidence interval, 1.0-10.4; p = 0.052). VLBW infants with repeated episodes of sepsis had higher frequencies of the NOD2-3020insC and IL6-174G allele. The increased sepsis rate of homozygous IL6-174G carriers was especially related to an increase in Gram-positive infections, and was not observed in VLBW infants who received prophylaxis with teicoplanin (frequency of Gram-positive sepsis in homozygous IL6-174G carriers without prophylaxis 16.5% versus 2.4% in homozygous IL6-174G carriers with prophylaxis; p = 0.033).
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PMID:Mutations of genes involved in the innate immune system as predictors of sepsis in very low birth weight infants. 1473 67

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.
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PMID:Genetic Susceptibility to Sepsis: A Possible Role for Mannose-binding Lectin. 1546 87

There are only few clinical studies on complement in well-defined (or characterized) paediatric HIV patients. Aim of this study was to evaluate the complement system and immunoglobulins in HIV-infected children and to correlate data to stage of disease. Blood samples of 127 HIV-infected children (11-134 months; 62 male : 65 female) were collected in order to evaluate humoral immunity. The patients were classified according to CDC clinical (N-asymptomatic; A-mild symptoms such as common recurrent infections; B-moderate symptoms such as Candidiasis and herpes infections, meningitis, sepsis and anaemia; C-severe symptoms such as opportunistic infections and neoplasia) and with respect to immunological criteria (T CD4(+) cell count). Analysis of complement system included the classical (CH50), alternative (APH50) pathway activities and plasma concentrations of mannan-binding lectin (MBL), of the C4 allotypic variants C4A and C4B. (ELISA), and of the C3 split product C3d (rocket immunoeletrophoresis). Immunodiagnosis also included CD4(+) and CD8(+) lymphocyte count and immunoglobulin concentrations. Complement activation and consumption was observed in all patients correlating with disease activity. Activated classical and alternative pathways and elevated C3d were significantly correlated with immunologic category 3. C3d levels were also significantly correlated with immunologic category 1. Undetectable CH50 and APH50 were found in two (group C) and 10 patients (n = 2, A = 2, B = 2, C = 4), respectively. Low MBL values were found in 13/127 but without correlation to disease severity. Undetectable C4B levels were observed in three patients, favouring the diagnosis of a complete deficiency. Although not related to clinical symptomatology, a strong ongoing complement activation can be observed in all stages of HIV infection. In contrast to earlier reports MBL could not be considered as a risk factor for HIV.
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PMID:Immunological analysis in paediatric HIV patients at different stages of the disease. 1558 73


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