Pathogen Recognition and Innate Immunity

At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

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Free Radicals in the Physiological Control of Cell Function

▪ 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 ...

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Innate Immune Recognition

One of the mechanisms by which the innate immune system senses the invasion of pathogenic microorganisms is through the Toll-like receptors (TLRs), which recognize specific molecular patterns that are present in microbial components. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also instructs the development of antigen-specific acquired immunity. Here, we review the rapid progress that has recently improved our understanding of the molecular mechanisms that mediate TLR signalling.

Toll-like receptor signalling

ObjectiveTo determine the incidence, cost, and outcome of severe sepsis in the United States.DesignObservational cohort study.SettingAll nonfederal hospitals (n = 847) in seven U.S. states.PatientsAll patients (n = 192,980) meeting criteria for severe sepsis based on the International Classification

Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.

Nucleotide-binding oligomerization domain (Nod)-containing proteins Nod1 and Nod2 play important roles in the innate immune response to pathogenic microbes, but mounting data suggest these pattern recognition receptors might also play key roles in adaptive immune responses. Targeting Nod1 and Nod2 signaling pathways in T cells is likely to provide a new strategy to modify inflammation in a variety of disease states, particularly those that depend on Ag-induced T cell activation. To better understand how Nod1 and Nod2 proteins contribute to adaptive immunity, this study investigated their role in alloantigen-induced T cell activation and asked whether their absence might impact in vivo alloresponses using a severe acute graft versus host disease model. The study provided several important observations. We found that the simultaneous absence of Nod1 and Nod2 primed T cells for activation-induced cell death. T cells from Nod1 × 2-/- mice rapidly underwent cell death upon exposure to alloantigen. The Nod1 × 2-/- T cells had sustained p53 expression that was associated with downregulation of its negative regulator MDM2. In vivo, mice transplanted with an inoculum containing Nod1 × 2-/- T cells were protected from severe graft versus host disease. The results show that the simultaneous absence of Nod1 and Nod2 is associated with accelerated T cell death upon alloantigen encounter, suggesting these proteins might provide new targets to ameliorate T cell responses in a variety of inflammatory states, including those associated with bone marrow or solid organ transplantation.

Lack of Both Nucleotide-Binding Oligomerization Domain-Containing Proteins 1 and 2 Primes T Cells for Activation-Induced Cell Death.

Therapeutic strategies to block LPS interactions with its receptor.

Rabbit prekallikrein (RPK) was purified from rabbit plasma by ion exchange and lectin column chromatography and preparative polyacrylamide gel electrophoresis. A 1500-fold purification was routinely achieved with a final yield of 5-10%. The purified RPK was found to be a glycoprotein with an apparent molecular weight of 88,000. Activation of RPK with either trypsin or rabbit Hageman factor (active) occurs by limited proteolytic cleavage, producing two disulfide-linked polypeptide chains with molecular weights of 55,000 and 35,000. Both chains contain carbohyrate and the 35,000-molecular-weight polypeptide was shown to incorporate [3H]DFP. Activation of RPK in kaolin-treated plasma was shown to proceed by an analogous mechanism yielding 55,000- and 35,000-molecular-weight polypeptide chains.

Rabbit prekallikrein. Purification, biochemical characterization, and mechanism of activation.

The invention provides methods for the use of agents that increase or decrease the expression or activity of IKKi to regulate cellular processes, such as inflammation, cellular differentiation, cellular proliferation, tissue regeneration, neurodegeneration and complement activation. In addition, the invention provides a method to identify agents that increase or decrease the expression or activity of IKKi.

METHOD TO IDENTIFY AGENTS THAT ACTIVATE OR INHIBIT IKKi

The present invention concerns a method of treating LBP-mediated LPS-induced myeloid cell activation comprising administering a therapeutically effective amount of an anti-LBP monoclonal antibody molecule. A therapeutic composition comprising anti-LBP antibody molecules in a pharmaceutically acceptable excipient is also contemplated.

Richard J. Ulevitch

Papers

Lack of Both Nucleotide-Binding Oligomerization Domain-Containing Proteins 1 and 2 Primes T Cells for Activation-Induced Cell Death.

Therapeutic strategies to block LPS interactions with its receptor.

Rabbit prekallikrein. Purification, biochemical characterization, and mechanism of activation.

METHOD TO IDENTIFY AGENTS THAT ACTIVATE OR INHIBIT IKKi

Monoclonal antibodies immunoreactive with lipopolysaccharide binding protein (LBP) and methods of their use