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PubMed2000

Tissue factor pathway of coagulation in sepsis.

OBJECTIVE: To review the role of the tissue factor pathway of coagulation in experimental sepsis. DATA SOURCES: Studies published in biomedical journals. STUDY SELECTION: Studies on the role of the tissue factor pathway in animal or human models for sepsis. DATA EXTRACTION AND SYNTHESIS: Variables reflecting tissue factor pathway activation in the various models are discussed; the effects of administration of tissue factor pathway inhibitors on these and inflammatory variables, as well as on the course and outcome, are analyzed. CONCLUSION: Activation of coagulation during experimental sepsis occurs mainly, if not exclusively, via the tissue factor pathway; inhibitors of this pathway improve mortality, presumably by a combined attenuating effect on coagulative and inflammatory responses.

Animals↗
PubMed2004

Inflammatory cytokines and fatty acids regulate endothelial cell heparanase expression.

Heparan sulfates, the carbohydrate chains of heparan sulfate proteoglycans, play an important role in basement membrane organization and endothelial barrier function. We explored whether endothelial cells secrete a heparan sulfate degrading heparanase under inflammatory conditions and what pathways were responsible for heparanase expression. Heparanase mRNA and protein by Western blot were induced when cultured endothelial cells were treated with cytokines, oxidized low-density lipoprotein (LDL) or fatty acids. Heparanase protein in the cell media was induced 2-10-fold when cells were treated with tumor necrosis factor alpha (TNFalpha) or interleukin 1beta (IL-1beta). Vascular endothelial growth factor (VEGF), in contrast, decreased heparanase secretion. Inhibitors to nuclear factor-kappaB (NFkappaB), PI3-kinase, MAP kinase, or c-jun kinase (JNK) did not affect TNFalpha-induced heparanase secretion. Interestingly, inhibition of caspase-8 completely abolished heparanase secretion induced by TNFalpha. Fatty acids also induced heparanase, and this required an Sp1 site in the heparanase promoter. Immunohistochemical analyses of cross sections of aorta showed intense staining for heparanase in the endothelium of apoE-null mice but not wild-type mice. Thus, heparanase is an inducible inflammatory gene product that may play an important role in vascular biology.

Animals↗
PubMed2005

Molecular rationale for the pharmacological treatment of Alzheimer's disease.

Cerebral deposition of amyloid plaques containing amyloid beta-peptide (Abeta) has traditionally been considered the central feature of Alzheimer's disease (AD). Abeta is derived from amyloid precursor protein (APP), which is cleaved by several different proteases: alpha-, beta- and gamma-secretase. In the past decade, however, the molecular pathogenesis of AD has been shown to involve alterations in several neurotransmitter, inflammatory, oxidative, and hormonal pathways that represent potential targets for AD prevention and treatment. Much research has shown a direct link between cholinergic impairment and altered APP processing as a major pathogenetic event in AD. Three highly probable mechanisms of APP regulation through inhibition of acetylcholinesterase are thus current topics of investigation. Indeed, acetylcholinesterase inhibitors appear to cause selective muscarinic activation of alpha-secretase and to induce the translation of APP mRNA; they may also restrict amyloid fibre assembly. Activation of N-methyl-D-aspartate receptors is considered a probable cause of chronic neurodegeneration in AD, and memantine has been widely used in some countries in AD patients to block cerebral N-methyl-D-aspartate receptors that normally respond to glutamate. Further studies are needed to determine whether antioxidants such as vitamins C and E are effective, through various mechanisms, in patients with mild-to-moderate AD. Additional data are also required for non-steroidal anti-inflammatory drugs, some of which appear to possess experimental effects that may ultimately prove favourable in AD patients. Statins also warrant further investigation, since they have activated alpha-secretase and they reduced Abeta generation and amyloid accumulation in a transgenic mouse model. beta-Secretase would seem to be an ideal target for anti-amyloid therapy in AD, but potential clinical and pharmacological issues, such as ensuring selectivity of inhibition, stability, and ease of blood-brain barrier penetration and cellular uptake, remain to be addressed for beta-secretase inhibitors. gamma-Secretase is not an easy candidate for pharmacological manipulation. Immunotherapeutic strategies have targeted Abeta directly; however, intensive investigation of indirect approaches to the management of AD with immunotherapy is now underway.

Alzheimer Disease↗
PubMed1998

Nonsteroidal anti-inflammatory drugs and cognitive function: do they have a beneficial or deleterious effect?

Studies suggest that high dose NSAID use may be associated with a reversible impairment of cognition in the elderly. Prolonged NSAID use, on the other hand, may prevent the decline in cognition associated with aging. However, it has yet to be to be definitively determined whether this protection arises from an anti-inflammatory effect that modifies pathways involved in Alzheimer's dementia, or is mediated by a platelet effect that decreases the risk of cerebrovascular disease. Further large-scale, randomised, controlled trials using NSAIDs are needed before patients can be advised that the known risks of NSAIDs are outweighed by their potential long term benefits on cognition. While clinicians await the results of such studies, they should continue to be alert to the possibility of acute CNS adverse effects in their elderly patients who are receiving NSAIDs and to prescribe the minimum dose that is necessary to control pain and inflammation.

Aged↗
PubMed2006

Magnesium sulfate suppresses inflammatory responses by human umbilical vein endothelial cells (HuVECs) through the NFkappaB pathway.

Dysfunctional endothelial cell activation and cytokines are implicated in preterm labor, a condition commonly treated with the tocolytic agent, magnesium sulfate (MgSO(4)). Based on recent findings showing the inflammatory effects of magnesium deficiency, we examined the effect of MgSO(4) on human umbilical vein endothelial cell (HuVEC) inflammatory responses in vitro. HuVECs isolated from term umbilical cords were incubated with MgSO(4) prior to stimulation with lipopolysaccharide (LPS) and then assessed for endothelial cell activation. Endothelial cell supernatants were assayed for inflammatory mediator production (interleukin-8; IL-8), and endothelial cell-associated intercellular adhesion molecule (ICAM-1) expression was determined. In the absence of LPS stimulation, MgSO(4) had no effect on HuVEC responses. Treatment of HuVECs with MgSO(4) prior to LPS stimulation inhibited inflammatory mediator production (p<0.05) and cell adhesion molecule expression (p<0.05) in a dose-dependent manner. Mechanistic studies showed that MgSO(4) reduced NFkappaB nuclear translocation and protected cytoplasmic IkappaBalpha from degradation in LPS-treated HuVECs. In conclusion, MgSO(4) inhibits endothelial cell activation, as measured by levels of IL-8 and ICAM-1 expression, via NFkappaB. Our results support the hypothesis that MgSO(4) treatment may function as an anti-inflammatory agent during preterm labor.

Active Transport, Cell Nucleus↗
PubMed2006

Anti-inflammatory effects of short chain fatty acids in IFN-gamma-stimulated RAW 264.7 murine macrophage cells: involvement of NF-kappaB and ERK signaling pathways.

The overactivation of macrophages causes abnormal cell death and chronic inflammatory diseases. Therefore, the modulation of macrophage-mediated cytotoxicity is expected to become a new therapeutic strategy for various inflammatory diseases. In this study, three types of short chain fatty acids (sodium butyrate (NaB), sodium phenylbutyrate (NaPB), sodium phenylacetate (NaPA)) were found to have anti-inflammatory effects in IFN-gamma-stimulated RAW 264.7 cells. They inhibited the expression of iNOS, TNF-alpha, and IL-6 induced by IFN-gamma, while they enhanced the expression of the anti-inflammatory cytokine, IL-10. Their potency as anti-inflammatory agents was in the order of NaB>NaPB>NaPA. Further mechanistic studies revealed these three agents to repress the DNA binding and transcriptional activities of NF-kappaB, which is an important modulator of inflammation. In addition, these agents repressed the IFN-gamma-induced ERK1/2 phosphorylation without affecting the Jak/STAT activities. The potency of NF-kappaB and ERK inhibition was also in the order of NaB>NaPB>NaPA. The results suggest that the NF-kappaB and ERK signaling pathways are at least in part involved in the anti-inflammatory activities of these SCFAs. Considering that SCFAs are normally present in the body and have few side effects, they might be promising agents for the prevention and/or treatment of various inflammatory diseases.

Animals↗
PubMedDate not supplied

Putative role of proteolysis and inflammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi-threat medical countermeasures.

Despite the contrasts in chemistry and toxicity, for blister and nerve chemical warfare agents there may be some analogous proteolytic and inflammatory mediators and pathological pathways that can be pharmacological targets for a single-drug multi-threat medical countermeasure. The dermal-epidermal separation caused by proteases and bullous diseases compared with that observed following exposure to the blister agent sulfur mustard (2,2'-dichlorodiethyl sulfide) has fostered the hypothesis that sulfur mustard vesication involves proteolysis and inflammation. In conjunction with the paramount toxicological event of cholinergic crisis that causes acute toxicity and precipitates neuronal degeneration, both anaphylactoid reactions and pathological proteolytic activity have been reported in nerve-agent-intoxicated animals. Two classes of drugs already have demonstrated multi-threat activity for both nerve and blister agents. Serine protease inhibitors can prolong the survival of animals intoxicated with the nerve agent soman and can also protect against vesication caused by the blister agent sulfur mustard. Poly (ADP-ribose) polymerase (PARP) inhibitors can reduce both soman-induced neuronal degeneration and sulfur-mustard-induced epidermal necrosis. Protease and PARP inhibitors, like many of the other countermeasures for blister and nerve agents, have potent primary or secondary anti-inflammatory pharmacology. Accordingly, we hypothesize that drugs with anti-inflammatory actions against either nerve or blister agent might also display multi-threat efficacy for the inflammatory pathogenesis of both classes of chemical warfare agent.

Animals↗
PubMed2005

Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction.

Minocycline, a tetracycline with anti-inflammatory properties, has been reported to down-regulate the activity of microglia, whose activation occurs in inflammatory and degenerative diseases of the central nervous system, such as multiple sclerosis and Alzheimer's disease. In these disorders, a T cell component is also evident, and we have demonstrated previously that the interaction of activated T cells with microglia led to the substantial increase in tumor necrosis factor alpha (TNF-alpha) levels. Here, we report that minocycline decreases TNF-alpha levels produced in human T cell-microglia interaction. This effect is mediated by a direct action of minocycline on the activated T cells and on microglia, which resulted in the decreased ability of T cells to contact microglia. In correspondence, minocycline decreased the expression on T cells of the CD40 ligand (CD40L), a key molecule regulating the contact-mediated interaction of T cells with microglia. These results demonstrate that the mechanism of action of minocycline involves not only microglia but also T cells and their subsequent activation of microglia. The capacity of minocycline to down-regulate CD40L on T cells may provide a new means to target the CD40-CD40L pathway, which regulates several inflammatory processes.

Adult↗
PubMed2005

Effect of neostigmine on organ injury in murine endotoxemia: missing facts about the cholinergic antiinflammatory pathway.

Electrical and pharmacologic stimulation of the efferent cholinergic antiinflammatory pathway suppress the systemic inflammatory response and can prevent lethal endotoxemia. Neostigmine, a cholinergic agent, has not been tested to determine if it can prevent histopathologic organ injury in endotoxemia. In the present study, the effects of neostigmine treatment on the histopathologic organ injury inflicted by Escherichia coli endotoxin in a mouse model of septic shock was investigated. Endotoxemia in mice caused weight loss and increased spleen, liver, and lung weight. When the organs were examined for histopathologic injury, endotoxemia increased interstitial inflammation in the lungs, liver injury, and organ injury in general terms; neostigmine, at a dose of 0.1 mg/kg, failed to attenuate these effects. Although the simultaneous administration of neostigmine at a dose of 0.3 mg/kg and endotoxin decreased interstitial inflammation in the lungs, vacuolar degeneration in the liver, and total liver injury, mortality was increased with this dose in the presence of endotoxemia. We conclude that neostigmine at a dose of 0.1 mg/kg was not protective against histopathologic organ injury in mice with endotoxemia, and a higher dose (0.3 mg/kg) was not tolerated probably owing to nonspecific parasympathetic action including cardiovascular effects. Further studies are required to determine the contribution of sites in the cholinergic antiinflammatory pathway.

Animals↗
PubMed2006

A new arthritis therapy with oxidative burst inducers.

BACKGROUND: Despite recent successes with biological agents as therapy for autoimmune inflammatory diseases such as rheumatoid arthritis (RA), many patients fail to respond adequately to these treatments, making a continued search for new therapies extremely important. Recently, the prevailing hypothesis that reactive oxygen species (ROS) promote inflammation was challenged when polymorphisms in Ncf1, that decrease oxidative burst, were shown to increase disease severity in mouse and rat arthritis models. Based on these findings we developed a new therapy for arthritis using oxidative burst-inducing substances. METHODS AND FINDINGS: Treatment of rats with phytol (3,7,11,15-tetramethyl-2-hexadecene-1-ol) increased oxidative burst in vivo and thereby corrected the effect of the genetic polymorphism in arthritis-prone Ncf1(DA) rats. Importantly, phytol treatment also decreased the autoimmune response and ameliorated both the acute and chronic phases of arthritis. When compared to standard therapies for RA, anti-tumour necrosis factor-alpha and methotrexate, phytol showed equally good or better therapeutic properties. Finally, phytol mediated its effect within hours of administration and involved modulation of T cell activation, as injection prevented adoptive transfer of disease with arthritogenic T cells. CONCLUSIONS: Treatment of arthritis with ROS-promoting substances such as phytol targets a newly discovered pathway leading to autoimmune inflammatory disease and introduces a novel class of therapeutics for treatment of RA and possibly other chronic inflammatory diseases.

Animals↗
PubMed2001

[Activation of NF-kappa B and its effect on induction of platelet-derived growth factor-B transcription by angiotensin II in ECV304 cell line].

OBJECTIVES: The renin-angiotensin system may contribute to the pathogenesis of atherosclerosis. The transcription factor nuclear factor-kappa B (NF-kappa B) participates in most signal pathways involved in the inflammatory process. In this project the effect of angiotensin II (Ang II) on NF-kappa B activation and the promotion of PDGF-B mRNA expression in human endothelial cell line ECV304 was studied. METHODS: Electrophoretic mobility shift assay, immunofluorescence and immunoelectronic microscope techniques, including confocal microscopy and gold particle labelled electronic microscopy were applied to investigate the mechanism by which Ang II activates NF-kappa B, ECV304 cells were transiently transfected with an NF-kappa B/luciferase reporter gene and catalytically inactive NIK, IKK alpha, IKK beta mutants respectively. Northern blot was carried out to detect PDGF-B mRNA. RESULTS: By the findings of immunofluorescence confocal microscopy, immunoelectronic microscopy and Northern blot, Ang II was effective in stimulating NF-kappa B activation and there was definited cytoplasmic-to-nuclear translocation of NF-kappa B subunits p50 and p65 and overexpression of PDGF-B mRNA expression. Over-expression of the transiently transfected IKK alpha-KM, IKK beta-KM and NIK-KM mutant genes enabled to block the reporter gene activation induced by ang II. CONCLUSION: Ang II is effective to activate NF-kappa B through a pathway dependent on NIK, IKK alpha and IKK beta, and induces PDGF-B transcription in the endothelial cell line ECV304.

Angiotensin II↗
PubMed2026

IL-33 Drives Inflammatory Changes and Extracellular Trap Formation in Eosinophils Involving Oxidised LDL and Complement Pathways.

BACKGROUND: IL-33 levels are elevated in the airways of patients with eosinophilic diseases, and IL-33 receptor expression on eosinophils is upregulated in type 2-high environments. However, the role of IL-33 in the regulation of human eosinophils remains unclear. OBJECTIVE: To elucidate the inflammatory effects of IL-33 on the cellular function of human eosinophils. METHODS: Blood eosinophils were stimulated with IL-33, TNF-&#x3b1;, oxidised low-density lipoprotein (oxLDL) and complement fragments (C3a and C5a). Multi-omics analyses, including transcriptomics and proteomics, were performed. Extracellular trap formation (ETosis) was assessed by SYTOX nucleic acid staining and was visualised by immunofluorescence and transmission electron microscopy. RESULTS: Multi-omics analyses revealed an IL-33- and TNF-&#x3b1;-induced inflammatory gene signature characterised by the upregulation of cell surface markers (oxLDL receptor 1, CD22, CD4 and ICAM-1) and inflammatory mediators (C3, CCL3/4 and IL1A/B). CD22 upregulation was specific to IL-33 stimulation. Eosinophils derived from nasal polyps exhibited a gene expression profile similar to that of IL-33-stimulated eosinophils. Functional assays demonstrated that oxLDL and complement fragments differentially prolonged eosinophil survival and altered the expression of adhesion molecules. OxLDL- and complement fragment-induced gene signatures were partly detected in eosinophils derived from nasal polyps. Furthermore, IL-33 triggered ETosis via NADPH oxidase, mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. CONCLUSIONS: IL-33, in conjunction with oxLDL and the complement cascade, induces inflammatory changes in eosinophils, promoting an ETosis-prone phenotype. These pathways represent potential therapeutic targets in refractory eosinophilic diseases.

Humans↗
PubMed1988

Mechanisms for post-inflammatory hyperpigmentation and hypopigmentation.

Many other mediators of inflammation or biochemical pathways must be involved in producing post-inflammatory hyper and hypopigmentation. Most of these mechanisms remain to be identified. We hope the ideas presented in this report stimulate some future investigation, the results of which will improve both our own understanding of the epidermis and the role of the melanocyte as an integral part of this important issue.

Animals↗
PubMed2003

Dual roles for lipolysis and oxidation in peroxisome proliferation-activator receptor responses to electronegative low density lipoprotein.

Low density lipoprotein (LDL) exists in various forms that possess unique characteristics, including particle content and metabolism. One circulating subfraction, electronegative LDL (LDL(-)), which is increased in familial hypercholesterolemia and diabetes, is implicated in accelerated atherosclerosis. Cellular responses to LDL(-) remain poorly described. Here we demonstrate that LDL(-) increases tumor necrosis factor alpha (TNFalpha)-induced inflammatory responses through NF kappa B and AP-1 activation with corresponding increases in vascular cell adhesion molecule-1 (VCAM1) expression. LDL receptor overexpression increased these effects. In contrast, exposing LDL(-) to the key lipolytic enzyme lipoprotein lipase (LPL) reversed these responses, inhibiting VCAM1 below levels seen with TNFalpha alone. LPL is known to act on lipoproteins to generate endogenous peroxisomal proliferator-activated receptor alpha (PPAR alpha) ligand, thus limiting inflammation. These responses varied according to the lipoprotein substrate triglyceride content (very low density lipoprotein >> LDL > high density lipoprotein). The PPAR alpha activation seen with LDL, however, was disproportionately high. We show here that MUT LDL activates PPAR alpha to an extent proportional to its LDL(-) content. As compared with LDL(-) alone, LPL-treated LDL(-) increased PPAR alpha activation 20-fold in either cell-based transfection or radioligand displacement assays. LPL-treated LDL(-) suppressed NF kappa B and AP-1 activation, increasing expression of the PPAR alpha target gene I kappa B alpha, although only in the genetic presence of PPAR alpha and with intact LPL hydrolysis. Mass spectrometry reveals that LPL-treatment of either LDL or LDL(-) releases hydroxy-octadecadienoic acids (HODEs), potent PPAR alpha activators. These findings suggest LPL-mediated PPAR alpha activation as an alternative catabolic pathway that may limit inflammatory responses to LDL(-).

Animals↗
PubMed2025

Natural, safety immunomodulatory derivatives of lactobacillus biofilms promote diabetic wound healing by metabolically regulating macrophage phenotype and alleviating local inflammation.

INTRODUCTION: Long-term inflammatory microenvironment further impairs the healing process of diabetic wounds. Many studies have shown that Lactobacillus can regulate immune function and promote injured tissue repair. However, the immunomodulatory function and safety of Lactobacillus biofilm (LB) on wounds need further investigation. OBJECTIVES: In this present research, we proposed a "bacteria-free biofilm derivative therapy" and successfully extracted Lactobacillus biofilm derivatives (LBDs) by ultrasonic separation and filtration technology for the natural and safe treatment of diabetic wounds. METHODS: The study first cultured Lactobacillus anaerobically and extracted LBDs using ultrasound separation combined with filtration technology. LBDs were characterized via scanning electron microscopy, Concanavalin A fluorescence staining, and protein gel electrophoresis. In vivo diabetic wound model, wound closure rates were dynamically monitored, and tissue sections were analyzed using hematoxylin-eosin and immunofluorescence staining to evaluate LBDs' healing effects. An in vitro macrophage inflammation model was established, employing immunofluorescence, flow cytometry, and Western blotting techniques to explore the molecular mechanisms underlying LBDs' effects on macrophage phenotypes. Furthermore, whole-genome sequencing and proteomics of LBDs-treated macrophages were performed to further elucidate the intrinsic molecular mechanisms through which LBDs regulate macrophage phenotypes. RESULTS: LBDs were effectively extracted utilizing ultrasonic separation coupled with filtration technology. Studies revealed that LBDs modulate the systemic metabolic reprogramming in wound-site macrophages, suppress JAK-STAT1 signaling pathway, alleviate the local inflammatory microenvironment, promote neovascularization and ultimately accelerate wound healing. CONCLUSION: The LBDs retains most bioactive components of the LB. As a natural, safe and immunomodulatory agent, LBDs promote diabetic wound healing by metabolically reprogramming macrophage phenotypes and improving the local immune microenvironment, offering promising potential for regenerative applications in diabetic wound management.

Wound Healing↗
PubMed2001

A catechol antioxidant protocatechuic acid potentiates inflammatory leukocyte-derived oxidative stress in mouse skin via a tyrosinase bioactivation pathway.

The modifying effects of topical application of a catechol antioxidant protocatechuic acid (PA) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammatory responses in mouse skin were investigated. Treatment with a high dose (20,000 nmol) of PA, based on time of application, modifies inflammatory responses in the skin of the B6C3F(1) mouse, a resistant strain to inflammatory response induction by TPA, but shows much higher tyrosinase expression than that of an albino mouse. The responsibility of a large amount of PA-induced leukocyte infiltration to an inflamed region in a B6C3F(1) mouse is more sensitive than that of an ICR albino mouse. When ICR mice were treated with TPA (1.6 nmol) twice weekly for 5 weeks to induce chronic inflammatory responses, pretreatment with 1600 nmol PA 30 min prior to each TPA treatment significantly enhanced the inflammatory responses including edema formation, leukocyte infiltration, and the level of thiobarbituric acid-reacting substances. The dose-dependency was closely parallel to the results of a tumor promotion study of PA previously reported. Further, the treatment of PA alone resulted in tyrosinase-dependent contact hypersensitivity in ICR mouse skin. In addition, the in vitro study of cytotoxicity demonstrated that bioactivation by tyrosinase but not myeloperoxidase of PA significantly enhanced cytotoxicity and intracellular glutathione consumption. We conclude that the tyrosinase-derived reactive quinone intermediate(s) of PA, which binds nucleophilic residues of proteins including sulfhydryl group and conjugates of which are recognized as haptens, was partially involved in alteration of the cellular immune functions including oxygen radical-generating leukocytes migration to inflamed regions.

Animals↗
PubMed2006

Arachidonic acid pathways in nociception.

The metabolism of arachidonic acid may follow multiple, inter-related pathways, leading to the generation or release of a wide variety of biologically active substances (including bradykinins, serotonin, histamine, prostaglandins, and cytokines) that produce pain and/or inflammation. Therapeutic agents that directly affect one particular pathway, such as cyclooxygenase inhibitors (typically, nonsteroidal anti-inflammatory agents), may indirectly affect one or more other pathways, as well as the resolution of inflammation. Rather than taking the traditional approach to treating multiple types of pain by inhibiting a single pathway, future treatments of pain and inflammation may target specific pathways and pain mechanisms and/or address two or more pathways simultaneously. A thorough understanding and appreciation of the mechanisms contributing to various pain and inflammatory states, the metabolic fates of arachidonic acid, the functions of its many metabolites, and the interrelatedness of the various metabolic pathways involved in nociception may lead to more rational and optimal approaches to addressing patient suffering.

Analgesics↗
PubMed2003

Host genetic determinants of Neisseria meningitidis infections.

The clinical presentation of infections caused by Neisseria meningitidis is highly diverse. Some patients develop meningitis, and others present with sepsis or even septic shock. After invasion of the bloodstream by the bacteria, three main cascade pathways are activated. These are the complement system, the inflammatory response, and the coagulation and fibrinolysis pathway. These pathways do not act independently but are able to interact with each other. Genetic polymorphisms among components of these pathways have been shown to be involved in the susceptibility, severity, and outcome of meningococcal disease. We review knowledge of genetic variations associated with susceptibility to and severity of meningococcal infection. Complement deficiencies and defects in sensing or opsonophagocytic pathways, such as the rare Toll-like receptor 4 single nucleotide polymorphisms (SNPs) and combinations of inefficient variants of Fcgamma-receptors, seem to have the most important role in genetically established susceptibility. Effect on severity has repeatedly been reported for FcgammaRIIa and plasminogen activator inhibitor type 1 (PAI1) polymorphisms. Outcome effects have been confirmed for SNPs in properdin deficiencies, PAI1 and combination of the -511C/T SNP in interleukin 1beta, and the +2018C/T SNP in interleukin RN. Conflicting results are reported for the effect of the -308G/A promoter polymorphism in tumour necrosis factor (TNF) alpha. These differences may reflect discrepancies in group definitions between studies or the influence of additional SNPs in the TNFalpha promoter, which can form haplotypes representing different cytokine production capacity. For several SNPs, the potential effect on susceptibility, severity, or outcome has not yet been confirmed in an independent study.

Child↗