Pathogen Recognition and Innate Immunity

Living in an oxygenated environment has required the evolution of effective cellular strategies to detect and detoxify metabolites of molecular oxygen known as reactive oxygen species. Here we review evidence that the appropriate and inappropriate production of oxidants, together with the ability of organisms to respond to oxidative stress, is intricately connected to ageing and life span.

Oxidants, oxidative stress and the biology of ageing.

Background: Pulmonary endothelial injury is a critical process in the pathogenesis of acute lung injury (ALI) during sepsis Heat shock protein A12B (HSPA12B) is

/pdf/heat-shock-protein-a12b-protects-vascular-endothelial-cells-3qj3tex105.pdf

Heat Shock Protein A12B Protects Vascular Endothelial Cells Against Sepsis-Induced Acute Lung Injury in Mice

Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

http://www.chem.uwec.edu/Chem454/BiochemDiabetes.pdf

Biochemistry and molecular cell biology of diabetic complications

▪ Abstract The innate immune system is a universal and ancient form of host defense against infection. Innate immune recognition relies on a limited number of germline-encoded receptors. These receptors evolved to recognize conserved products of microbial metabolism produced by microbial pathogens, but not by the host. Recognition of these molecular structures allows the immune system to distinguish infectious nonself from noninfectious self. Toll-like receptors play a major role in pathogen recognition and initiation of inflammatory and immune responses. Stimulation of Toll-like receptors by microbial products leads to the activation of signaling pathways that result in the induction of antimicrobial genes and inflammatory cytokines. In addition, stimulation of Toll-like receptors triggers dendritic cell maturation and results in the induction of costimulatory molecules and increased antigen-presenting capacity. Thus, microbial recognition by Toll-like receptors helps to direct adaptive immune responses ...

/pdf/innate-immune-recognition-3eedeqyq83.pdf

Innate Immune Recognition

Lipopolysaccharides of Salmonella minnesota rough mutants were treated with 20 mM acetate buffer pH 44 at 70°C/3 h After dialysis of the hydrolysates about one third of the total 3-deoxy-d-mannooctulosonic acid (dOclA) content but no neutral sugars were found in the dialysate By high-voltage paper electrophoresis, a compound with the mobility of 12 relative to dOclA could be isolated from the dialysate It was identified as a dOclA disaccharide by hydrolysis without or after reduction with sodium borohydride and by analysis with the thiobarbituric acid assay under different conditions The ketosidic linkage in the disaccharide is assumed to be 24 or 25

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1983.tb07250.x

Isolation of a 3-Deoxy-d-mannooctulosonic Acid Disaccharide from Salmonella minnesota Rough-Form Lipopolysaccharides

The course of cutaneous leishmaniasis was ex- amined in mice from two genetically closely related strains, C57BL/10ScCr (Cr) and C57BL/10ScSn (Sn). Sn mice are able to heal Leishmania majorinfections, while Cr mice are unable to heal. The cutaneous lesions of the Cr mice progressed continuously and the increase in lesion size was paralleled by an unrestricted growth of the para- sites in vivo. Cr mice, in contrast to their Sn counterparts, are highly resistant to all effects of lipopolysaccharide (LPS). The nonhealing L. major infection in Cr mice is in sharp contrast to the course of infection in another endo- toxin-nonresponder mouse strain, C3H/HeJ, which heal in- fections with L. major. Cr mice exhibit, in addition to the defective LPS responsiveness, an impaired interferon- γ (IFN-γ) response after infection with a variety of microor- ganisms. The insufficient activation of parasitized macro- phages to kill intracellular L. major could be due to the in- ability of splenocytes from infected Cr mice to secrete IFN-γ upon restimulation with L. major. IFN-γ is essen- tial for the efficient activation of parasitized macrophages to kill intracellular L. major by producing nitric oxide (NO). Although bone marrow-derived Cr macrophages do not produce NO in response to LPS, both Sn and Cr mac-

http://link.springer.com/content/pdf/10.1007/s004300050048.pdf

Leishmania major infection in C57BL/10 mice differing at the Lps locus: a new non-healing phenotype ORIGINAL INVESTIGA T ION

A preparation consisting essentially of lipid A or alkali-treated lipid A sorbed on a particulate organic carrier material and an immunizing agent containing same being useful against diseases caused by gram-negative enterobacteriaceae.

Lipid A-preparation

Mice infected with bacteria develop an interferon-γ (IFN-γ) dependent hypersensitivity to lipopolysaccharide (LPS) and other bacterial components. The broader aim of this study is to find out whether such hypersensitivity also occurs in patients suffering from bacterial infections. The capacity of stimulated peripheral blood cells from infected, intensive-care patients to produce cytokines (IFN-γ, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)) was compared to that of healthy donors. Culturing of the cells was carried out preferentially in whole blood diluted 1:3. Whole blood cultures (WBC) were stimulated with lipopolysaccharide (LPS), whole killedSalmonella typhimurium andStaphylococcus aureus and concanavalin A (ConA), and the cytokine production was determined. Two main findings emerged from this study: The IFN-γ production by WBC of patients was, compared to healthy donors, markedly suppressed, regardless of stimulus used. Further, patients' WBC exhibited a suppressed TNF-α production after stimulation with LPS. Surprisingly, following stimulation with bacteria (S. typhimurium andS. aureus) an elevated TNF-α and IL-6 response was obtained. Thus, in severely infected patients the cytokine responses of peripheral blood cells to LPS may be suppressed, while the response to other bacterial components is enhanced.

/pdf/differential-cytokine-production-in-stimulated-blood-21u1qd3c4m.pdf

Differential cytokine production in stimulated blood cultures from intensive care patients with bacterial infections

Blood monocytes (MO) undergo maturation into macrophages (MAC) upon migration from the capillary bed to tissue sites of inflammation where they are exposed to environmental signals. Functional competence and phenotype heterogeneity is the result of both differentiation-inducing and -activating events. In vitro, MO to MAC maturation is induced by serum factors, can be followed by the expression of specific maturation-associated antigens and is accompanied by a characteristic change in the secretory repertoire of MAC in comparison to MO. Here we report that bacterial lipopolysaccharides (LPS) at subnanogram quantities very effectively inhibited the serum-induced maturation of human MO in vitro. At the same time LPS induced the up-regulation of CD14 antigens. The lipid A moiety was shown to be responsible for this novel biological activity of the LPS molecule. Inhibition of maturation was not due to secondary LPS-induced signals like interleukin (IL)-1, IL-6, tumor-necrosis factor (TNF)-alpha or interferon (IFN)-alpha--even though the latter by itself suppressed MAC maturation in vitro. The inhibitory activity of IFN-alpha could be abolished by neutralizing anti-IFN-alpha antibodies whereas these antibodies had no effect on LPS-induced suppression of MAC maturation. Functional analysis of LPS-treated MO long-term cultures showed that the pattern of secretory products released was similar to that of freshly-isolated immature blood MO: compared with mature MAC, LPS-treated MO released high amounts of IL-6 but significantly less TNF-alpha, neopterin, lysozyme and beta-2-microglobulin. At the same time, in LPS-treated MO cultures the MAC maturation-associated molecules alpha-2-macroglobulin and fibronectin could be detected only in trace amounts. The ability to secrete IL-1, however, was lost both in control as well as in LPS-treated MO cultures. The results indicate that endotoxins may influence the biology of the MO/MAC system distinctively: they not only induce a functional activation but also interfere with the ontogeny of this cell family.

Inhibition of in vitro differentiation of human monocytes to macrophages by lipopolysaccharides (LPS): phenotypic and functional analysis

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