▪ 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

In the mid 1990s, immunoassays for C-reactive protein (CRP), with greater sensitivity than those previously in routine use, revealed that increased CRP values, even within the range previously considered normal, strongly predict future coronary events. These findings triggered widespread interest, especially, remarkably, in the US, where the clinical use of CRP measurement had been largely ignored for about 30 years. CRP production is part of the nonspecific acute-phase response to most forms of inflammation, infection, and tissue damage and was therefore considered not to provide clinically useful information. Indeed, CRP values can never be diagnostic on their own and can only be interpreted at the bedside, in full knowledge of all other clinical and pathological results. However, they can then contribute powerfully to management, just as universal recording of the patient’s temperature, an equally nonspecific parameter, is of great clinical utility.

The present torrent of studies of CRP in cardiovascular disease and associated conditions is facilitated by the ready commercial availability of automated CRP assays and of CRP itself as a research reagent. However, unlike the earlier rejection in the US of CRP as an empirical test because of its perceived lack of specificity, the current enthusiasm over CRP in cardiovascular disease is widely characterized by failure to recognize appropriately the nonspecific nature of the acute-phase response, and by lack of critical biological judgment. Quality control of the source, purity, and structural and functional integrity of the CRP, and the relevance of experimental design before ascribing pathophysiological functions, are also often ignored.

This article provides information about CRP as a protein and an acute-phase reactant, and a knowledge-based framework for interpretation and analysis of clinical observations of CRP in relation to cardiovascular and other diseases. We also review the properties of CRP, its possible role in pathogenesis of disease, and our own observations that identify it as a possible therapeutic target.

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C-reactive protein: a critical update

The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.

Long-Circulating and Target-Specific Nanoparticles: Theory to Practice

White adipose tissue is now recognised to be a multifunctional organ; in addition to the central role of lipid storage, it has a major endocrine function secreting several hormones, notably leptin and adiponectin, and a diverse range of other protein factors. These various protein signals have been given the collective name 'adipocytokines' or 'adipokines'. However, since most are neither 'cytokines' nor 'cytokine-like', it is recommended that the term 'adipokine' be universally adopted to describe a protein that is secreted from (and synthesised by) adipocytes. It is suggested that the term is restricted to proteins secreted from adipocytes, excluding signals released only by the other cell types (such as macrophages) in adipose tissue. The adipokinome (which together with lipid moieties released, such as fatty acids and prostaglandins, constitute the secretome of fat cells) includes proteins involved in lipid metabolism, insulin sensitivity, the alternative complement system, vascular haemostasis, blood pressure regulation and angiogenesis, as well as the regulation of energy balance. In addition, there is a growing list of adipokines involved in inflammation (TNFalpha, IL-1beta, IL-6, IL-8, IL-10, transforming growth factor-beta, nerve growth factor) and the acute-phase response (plasminogen activator inhibitor-1, haptoglobin, serum amyloid A). Production of these proteins by adipose tissue is increased in obesity, and raised circulating levels of several acute-phase proteins and inflammatory cytokines has led to the view that the obese are characterised by a state of chronic low-grade inflammation, and that this links causally to insulin resistance and the metabolic syndrome. It is, however, unclear as to the extent to which adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and whether there is a generalised or local state of inflammation. The parsimonious view is that the increased production of inflammatory cytokines and acute-phase proteins by adipose tissue in obesity relates primarily to localised events within the expanding fat depots. It is suggested that these events reflect hypoxia in parts of the growing adipose tissue mass in advance of angiogenesis, and involve the key controller of the cellular response to hypoxia, the transcription factor hypoxia inducible factor-1.

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Adipokines: inflammation and the pleiotropic role of white adipose tissue.

Background—Inflammatory reactions in coronary plaques play an important role in the pathogenesis of acute atherothrombotic events; inflammation elsewhere is also associated with both atherogenesis ...

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C-Reactive Protein, a Sensitive Marker of Inflammation, Predicts Future Risk of Coronary Heart Disease in Initially Healthy Middle-Aged Men Results From the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992

Human C-reactive protein: expression, structure, and function.

These combined data have permitted the conclusion that complement consumption was attributable to CRP complexes and that it proceeded via the classical pathway independent of the presence of specific antibody or immunoglobulin. The specificity of CRP for choline phosphatides and its capacity to activate the complement system are considered in relation to the possible functions of CRP in the inflammatory process.

Interaction of C-Reactive Protein Complexes with the Complement System I. Consumption of Human Complement Associated with the Reaction of C-Reactive Protein with Pneumococcal C-Polysaccharide and with the Choline Phosphatides, Lecithin and Sphingomyelin

Introduction and Historical Notes, Michael M Frank Molecular Architecture Overview of the Complement System, John E Volanakis Clq and Mannose-Binding Lectin, Kenneth B M Reid Complement Enzymes, John E Volanakis and Gerard J Arlaud The Chemistry and Biology of C3, C4, and C5, John D Lambris, Arvind Sahu, and Rick A Wetsel Proteins of the Membrane Attack Complex, Mnason E Plumb and James M Sodetz Regulatory Proteins of Complement, M Kathryn Liszewski and John P Atkinson Complement Receptors, Joseph M Ahearn and Ariella M Rosengard Phylogeny of the Complement System, Masaru Nonaka Regulation of Complement Protein Gene Expression, Harvey R Colten and Gerard Garnier Biology Characterization of Complement Anaphylatoxins and Their Biological Responses, Julia A Ember, Mark A Jagels, and Tony E Hugli Complement-Mediated Phagocytosis, Melvin Berger Cellular Responses to the Membrane Attack Complex, Carolyn Mold Regulation by Complement of Acquired Immunity, Michael C Carroll and Douglas T Fearon Endothelial Cell Responses to Complement Activation, Soheyla Saadi and Jeffrey L Platt The Complement System in Reproduction, Teresa J Oglesby Bacteria and Complement, Franz Petry and Michael Loos Complement and Viruses, Neil R Cooper Complement and Disease Complement Deficiencies and Infection, Peter Densen Processing and Clearance of Immune Complexes by Complement and the Role of Complement in Immune Complex Diseases, Kevin A Davies and Mark J Walport C1 Inhibitor Gene and Hereditary Angioedema, Alvin E Davis III Paroxysmal Nocturnal Hemoglobinuria and Complement, Wendell F Rosse Complement in Central Nervous System Disorders, Moon L Shin, Horea Rus, and Florin Niculescu Development of Clinically Useful Agents to Control Complement-Mediated Tissue Damage, Eric Wagner and Michael M Frank Autoimmune Hemolytic Anemia, Alan D Schreiber Complement and Glomerular Diseases, Clark West Role of Complement in Diseased and Normal Human Skin, Kim B Yancey and Thomas J Lawley Complement and Neuromuscular Diseases, Milan Basta and Marinos C Dalakas

The human complement system in health and disease

The structure of the classical acute phase reactant human C-reactive protein provides evidence that phosphocholine binding is mediated through calcium and a hydrophobic pocket centred on Phe 66. The residue Glu 81 is suitably positioned to interact with the choline group. A cleft on the pentameric face opposite to that containing the calcium site may have an important functional role. The structure provides insights into the molecular mechanisms by which this highly conserved plasma protein, for which no polymorphism or deficiency state is known, may exert its biological role.

Three dimensional structure of human C-reactive protein

These combined data indicated that the consumption of guinea pig complement by CRP complexes required participation of human Clq, and that these complexes presumably do not interact with guinea pig Clq.

Interaction of C-Reactive Protein Complexes with the Complement System II. Consumption of Guinea Pig Complement by CRP Complexes: Requirement for Human Clq

John E. Volanakis

Papers

Human C-reactive protein: expression, structure, and function.

Interaction of C-Reactive Protein Complexes with the Complement System I. Consumption of Human Complement Associated with the Reaction of C-Reactive Protein with Pneumococcal C-Polysaccharide and with the Choline Phosphatides, Lecithin and Sphingomyelin

The human complement system in health and disease

Three dimensional structure of human C-reactive protein

Interaction of C-Reactive Protein Complexes with the Complement System II. Consumption of Guinea Pig Complement by CRP Complexes: Requirement for Human Clq