▪ 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

A large number of changes, distant from the site or sites of inflammation and involving many organ systems, may accompany inflammation. In 1930 interest was focused on these changes by the discovery of C-reactive protein (so named because it reacted with the pneumococcal C-polysaccharide) in the plasma of patients during the acute phase of pneumococcal pneumonia.1 Accordingly, these systemic changes have since been referred to as the acute-phase response,2 even though they accompany both acute and chronic inflammatory disorders. New acute-phase phenomena continue to be recognized, and the mechanisms mediating them are becoming better understood. This review summarizes much of . . .

Acute-Phase Proteins and Other Systemic Responses to Inflammation

Toll-like receptors have a crucial role in the detection of microbial infection in mammals and insects. In mammals, these receptors have evolved to recognize conserved products unique to microbial metabolism. This specificity allows the Toll proteins to detect the presence of infection and to induce activation of inflammatory and antimicrobial innate immune responses. Recognition of microbial products by Toll-like receptors expressed on dendritic cells triggers functional maturation of dendritic cells and leads to initiation of antigen-specific adaptive immune responses.

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Toll-like receptors and innate immunity

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

Sixteen years have passed since the description of the nuclear factor-кB (NF-кB) as a regulator of к light-chain gene expression in murine B lymphocytes (Sen & Baltimore, 1986a) During that time, over 4,000 publications have appeared, characterizing the family of Rel/NF-кB transcription factors involved in the control of a large number of normal and pathological cellular processes The physiological functions of NF-кB proteins include immunological and inflammatory responses, developmental processes, cellular growth and modulating effects on apoptosis In addition, these factors are activated in a number of diseases, including cancer, arthritis, acute and chronic inflammatory states, asthma, as well as neurodegenerative and heart diseases

Activators and target genes of Rel/NF-kappaB transcription factors.

C-reactive Protein

Avery never discussed the C-reactive protein without turning the conversation to what he was wont to call “the chemistry of the host.” Although he never spelled out what he meant by that expression, he clearly had in mind all the unidentified body substances and mechanisms of a nonimmunological nature, both protective and destructive, that come into play in the course of infectious processes.+ Rene J. Dubos

The phenomenon of the acute phase response

C-reactive protein (CRP) is a plasma protein of hepatic origin whose concentration may rapidly increase to levels more than 1000 times normal following tissue injury or infection.’ While the precise biologic role of this protein is unclear, recent evidence has shown that it can exhibit recognition and activation functions with the potential for influencing inflammation.’ The potential clinical usefulness of estimation of CRP in serum has been appreciated for some time. Until recently, however, the methods in widespread use for detection of CRP were semiquantitative at best, limiting their ~ s e f u l n e s s . ~ ~ ~ In early studies employing such methods (e.g., 5, 6) , serum CRP was often reported as simply “absent” or “present” or “elevated.” The use of such terms was consistent with previously held views that CRP was normally absent from the serum of healthy individuals and that its mere presence had pathological significance. However, it has been shown in the last decade that CRP can be detected in serum from all normal individ~als.~.’ It is thus clear that the critical clinical question about CRP is not whether it is present, but how much is present. Two recently introduced methods, radial immun~diffusion~ and nephelomepermit precise quantitative assessment of serum CRP levels in the range of clinical importance. The availability of this quantitative capability has underscored our relative lack of information about the clinical significance of differing degrees of CRP elevation in man. Since published reports of quantitative CRP data have been confined to relatively few specific disease states, the present study was undertaken to provide further information about the varying degrees of CRP elevation in a broad spectrum of hospitalized patients with different diseases. In addition, we will review some published reports of the usefulness of quantitative CRP determination in diagnosis of management of various specific diseases.

Serum c‐reactive protein levels in disease*

: Since its discovery approximately fifty years ago, CRP has been recognized as the prototype acute phase reactant. Now appreciated as a trace serum protein that elevates markedly in concentration in association with inflammation and tissue necrosis, CRP also has been found deposited at sites of cell injury. Together with its long appreciated ability to initiate precipitation, agglutination, and capsular swelling reactions, these considerations early led to the surmise that CRP may play a role in the host adaptive response. Studies of its binding specificities have indicated that CRP has reactivity with (a) phosphocholine and phosphate esters, and hence with lipids widely distributed in mammalian and microbial cells; and (b) with multiple widely distributed polycations, including those derived from leukocyte granules. Interaction with either of these ligands has been shown to alter CRP in such a way that it can bring about activation of the complement system with generation of all the known C-dependent reactivities, including component consumption, adherence, phagocytosis, and cytolysis. Similarly, modified CRP has been shown to react with the FcR or a closely related receptor of monocytes and lead to phagocytosis, to react with certain FcR-bearing lymphocytes, and to activate the platelet. Thus, CRP shares with immunoglobulins the ability to initiate multiple effector functions that have been associated with the inflammatory response, as well as to bring about primary recognition reactions. Obviously CRP-ligand reactions would be favored during intervals of acute inflammation and tissue necrosis, when larger amounts of CRP are available. Therefore, in addition to serving as a diagnostic aid for the presence of inflammatory and necrotic processes, elevated levels of CRP may well provide an important component of the nonspecific host mechanisms, particularly in the early stages following inflammatory stimuli. Inquiries into the structure and function of CRP indicated an unexpected relationship of this molecule to an amyloid-related protein. The amyloid P component shows remarkable structural similarity to CRP and also exhibits calcium-dependent reactivity with widely distributed ligands; those appreciated to date have mainly involved polysaccharides derived from fungi and natural products. While the only relationship of SAP to an immune-related effector system found to date is reactivity with altered C3, it nonetheless seems plausible that SAP, which like CRP recognizes certain microbial and altered host molecules and has the potential of activating a host effector system at the recognition site. Further inquiry into the structure and functional relationships of these molecules, which are broadly distributed through the vertebrates, should help to reveal the role that CRP and other acute phase proteins have in the body economy and provide additional insights to the understanding of body defense mechanisms in inflammatory, repair, and defense processes generally.

Irving Kushner

Papers

Acute-Phase Proteins and Other Systemic Responses to Inflammation

C-reactive Protein

The phenomenon of the acute phase response

Serum c‐reactive protein levels in disease*

C-reactive protein and the acute phase response.