|Year : 2016 | Volume
| Issue : 1 | Page : 32-35
Harpreet Singh Grover, Rohit Saini, Pearl Bhardwaj, Amit Bhardwaj
Department of Periodontology, Faculty of Dental Sciences, SGT University, Gurgaon, Haryana, India
|Date of Web Publication||16-May-2016|
Department of Periodontology, Faculty of Dental Sciences, SGT University, Gurgaon, Haryana
Source of Support: None, Conflict of Interest: None
The acute-phase response (APR) is a prominent systemic reaction of the organism to local or systemic disturbances in its homeostasis caused by infection, tissue injury, trauma or surgery, or immunological disorders. The tissue macrophage is most commonly regarded as initiating the APR through direct stimulation and secretion of various cell communicating factors. Proinflammatory cytokines and mediators are significantly elevated with gingival inflammation and during the destructive phase of periodontitis. Cytokines appear to play a major role in the clinical symptoms and tissue destruction associated with progressing periodontitis. Many of these cytokines are derived from activated macrophages and can act both locally and distally to amplify cytokine production from other cell types. The host responses to periodontal disease and cardiovascular diseases were reflected by an increase in the acute-phase proteins (serum amyloid A and C-reactive protein).
Keywords: Acute-phase proteins, acute-phase response, C-reactive protein, cytokines, haptoglobins, pentraxins, serum amyloid A
|How to cite this article:|
Grover HS, Saini R, Bhardwaj P, Bhardwaj A. Acute-phase reactants. J Oral Res Rev 2016;8:32-5
| Introduction|| |
The first reaction of the body to immunological stress is the innate, nonspecific response preceding specific immune reactions. The acute-phase response (APR) is a prominent systemic reaction of the organism to local or systemic disturbances in its homeostasis caused by infection, tissue injury, trauma or surgery, or immunological disorders. The purpose of these responses is to restore homeostasis and to remove the cause of the disturbance. The tissue macrophage is the most commonly regarded as initiating the APR through direct stimulation and secretion of various cell communicating factors.
An additional APR during these processes leads to the release of proinflammatory cytokines. These cytokines, nitric oxide, and glucocorticoids trigger and modulate the systemic acute-phase reaction and the hepatic acute-phase protein (APP) response. During the APR, plasma viscosity increases as a result of the changes in total blood protein concentration, among which, is an increase of fibrinogen that influences the erythrocyte sedimentation rate (ESR) used in many Western hospitals as a nonspecific marker for disease activity. Because fibrinogen is a slow reacting positive acute-phase reactant with a possible delay of some days after infection, the ESR increases and then reflects the activity of the APR. The APR is stimulated by the release of cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-α) from macrophages and monocytes at the site of inflammatory lesions or infections.
| Classification of Acute-Phase Proteins|| |
On the basis of protein concentrations
Negative acute-phase proteins
The liver responds by producing a large number of APRs. At the same time, the production of a number of other proteins is reduced; these are therefore referred to as “negative” APPs. Negative APPs are albumin, transferring, transthyretin, transcortin, and retinol-binding protein.
Positive acute-phase proteins
Positive APPs are C-reactive protein (CRP), D-dimer protein, mannose-binding protein (MBP), alpha 1 antitrypsin, alpha 1 antichymotrypsin, alpha 2 macroglobulin, fibrinogen, prothrombin, factor VIII, von-Willebrand factor, plasminogen, complement factors, ferritin, serum amyloid P component (SAP) complement, serum amyloid A (SAA), ceruloplasmin (Cp), and haptoglobin (Hp).
On the basis of their mode of action
- Protease inhibitors, e.g., alpha 1 antitrypsin, alpha 1 antichymotrypsin.
- Coagulation proteins, e.g., fibrinogen, prothrombin.
- Complement proteins, e.g., C2, C3, C4, C5, factor B.
- Transport proteins, e.g., Hp, Cp, hemopexin.
- Other proteins, e.g., CRP, SAA, SAP, acid glycoprotein (AGP).
| Functions of Acute-Phase Proteins|| |
The function of positive APPs is regarded as important in optimization and trapping of microorganism and their products, in activating the complement system, in Binding cellular remnants such as nuclear fractions, in neutralizing enzymes, scavenging free hemoglobin and radicals, and modulating the host's immune response. CRP is the first described APP in 1930. It binds directly to several microorganisms, and activates the complement system by the classical C1q pathway, and acts as opsonins. The strong APPs include CRP, α2 macroglobulin, SAA, which respond rapidly to inflammatory stimuli and serum level. Moderate APP includes Hp, fibrinogen, α1 antitrypsin which can increase 2-10 fold. Complement component C3 and Cp are considered weak APPs that may increase up to 2 fold.
| Regulation of Acute-Phase Protein Production|| |
The APR is elicited by cytokines. The three main groups of cytokines that govern the production of APPs as described by Van Miert are as follows:
- Cytokines which act as positive or negative growth factors include IL-2, IL-3, IL-4, IL-7, IL-10, IL-11, IL-12, granulocyte-macrophage colony stimulating factor.
- Cytokines having proinflammatory properties are TNF-α/β, IL-1α/β, IL-6, IFN-α/γ, IL-8, macrophage inhibitory protein-1.
- Factors with anti-inflammatory activity-IL-1 receptor antagonists, soluble IL-1 receptors, IL-1 binding protein, TNF-α binding protein.
IL-1 is present at sites of inflammation, and it also exhibits an ability to induce an inflammatory response, it is therefore considered to be an important mediator of inflammation. IL-1 increases the transcription of some APPs and decrease the transcription of other hepatic proteins. IL-1 also induces the production of IL-6, playing another role in APP production.
IL-6 is a pleiotropic cytokine involved in the regulation of APR, immune response, and hematopoiesis. In several inflammatory conditions and during an APR induced by the administration of endotoxins or septic shock, increased leukemia inhibitory factors levels in plasma, and inflammatory body fluids results in the induction of Type 2 APP.
TNF is considered a major inflammatory mediator. The effects of TNF on acute-phase induction include increased biosynthesis of complement proteins factor B and C3 and α1 antichymotrypsin. TNF also decreases the biosynthesis of albumin and transferrin. All three cytokines (IL-1, IL-6, and TNF) can also be carried via the blood to distant sites, inducing an acute-phase reaction.
Glucocorticosteroids decrease the level of IL-1, TNF, and IL-6 in the peripheral blood via transcriptional and posttranscriptional routes and prolong their impact on the target cells through the elevation of the expression of their receptors. Prostaglandins also inhibit the release of IL-1 from macrophages. There exist apparent feedback mechanisms involving both liver synthesized APP and neuroendocrine factors from the central nervous system, which contribute to regulation of the APR to inflammation.
| Pentraxins and C-Reactive Proteins|| |
Pentraxins are superfamily of proteins, phylogenetically conserved from arachnids to mammals and characterized by the presence of their carboxyl and terminal of a 200 amino acid pentraxin domain. The pentraxin was first assigned to CRP for its ultrastructural appearance of five subunits. CRP gene and its polymorphisms are found to be associated with marked increase in CRP levels thus increasing the risk of cardiovascular diseases. CRP was originally discovered by Tillett and Francis in 1930 as a substance in the serum of patients with acute inflammation that reacted with the C-polysaccharide by the liver and by adipocytes.
Human CRP is composed of five identical polypeptide units noncovalently arranged as a cyclic pentamer around a Ca-binding cavity. Based on the primary structure of the subunits, the pentraxin is divided into short and long pentraxins. The short pentraxins reactive proteins and serum amyloid pentraxins component are produced by the liver and represent the main APPs in human and mouse, respectively. The long pentraxins, i.e., PTX3, are produced by innate immunity cells (e.g., polymorphic mononuclear cells [PMN], macrophages, and dendritic cells), interact with several ligands, and play an essential role in innate immunity.
CRP levels rise dramatically during inflammatory processes occurring in the body. CRP rises up to 50,000 fold in acute inflammation, such as infection. It rises above normal limits within 6 h, and peaks at 48 h. CRP binds to phosphorylcholine on microbes. It is thought to assist incomplete binding to foreign and damaged cells, and a cell enhances phagocytosis by macrophages, which express a receptor for CRP. It is also believed to play an important role in innate immunity, as an early defense system against infections.
| Serum Amyloid A|| |
SAA proteins are a family of apolipoproteins and produced by the liver. They were originally described as an APP with a precursor relationship to the major constituents of amyloid A fibriles in reactive amyloidosis. These proteins have several roles, including the transport of cholesterol to the liver for secretion into the biles, recruitment of immune cells to inflammatory sites, and Induction of enzymes that degrade, such as amyloidosis, atherosclerosis, and rheumatoid arthritis. Several isotypes of SAA are found; Types 1 and 2 represent positive APPs.
| Haptoglobin|| |
Hp is a protein in the blood plasma that binds free hemoglobin released from erythrocytes with affinity and thereby inhibits its oxidative activity. Infection or inflammation may lead to 2-10 fold increase in haptoglobulin and biologic significance of the elevation in haptoglobulin level should be interpreted with respect to other APP (CRP).
| Mannose Binding Protein|| |
The most important acute-phase opsonin is the Ca-dependent MBP, which can react not only with mannose but several other sugars, so enabling it to bind with an exceptionally wide variety of Gram-negative and -positive bacteria, yeasts, viruses, and parasites; its subsequent ability to trigger the classical C3 convertase through two novel mannose-associated serine proteases (MASP-1 and MASP-2) qualifies it as opsonins. MBP is a multiple of trimeric complexes, each unit of which contains a collagen-like region joined to a globular lectin-binding domain. This structure places it in the family of collectins (collagen + lectin) which have the ability to recognize “foreign” carbohydrate patterns differing from “self” surface polysaccharides normally decorated by terminal galactose and sialic acid groups while the collagen region can bind to and activate phagocytic cells through complementary receptors on their surface.
| Transferrin|| |
Transferrin is a blood plasma protein for iron ion delivery. Transferring is a glycoprotein, which binds iron very tightly but reversibly. Transferrin is found in the mucosa and binds iron, thus creating an environment low in free iron, where few bacteria are able to survive. The levels of transferrin decrease in inflammation, seeming contradictory to its function. A decrease in the amount of transferrin would result in hemosiderin in the liver. Transferring has a bactericidal effect on bacteria, in that it makes Fe 3+ unavailable to the bacteria.
| α 2-Macroglobulin|| |
It is one of two principal protease inhibitor in human plasma, other being α1-antitrypsin macrophages and fibroblast rapidly phagocytose the complexes of protease and α2 macroglobulin. This molecule function in homeostasis, coagulation, and complement pathway. It can also be carrier protein for IL-6 and may modulate the IL-6 activity as part of APR.
| Ykl-40|| |
YKL-40 is a chitin-binding glycoprotein. YKL-40, a new APP, is shown to be elevated in inflammatory diseases, such as rheumatoid arthritis, Type 2 diabetes mellitus, and coronary artery diseases. YKL-40 levels in gingival crevicular fluid (GCF) as well as serum have been shown to be increased from a state of gingival health to gingivitis and further in periodontitis.
| Fibrinogen|| |
It accumulates at the site of injury and in the presence of enzymes released from PMN and platelets, fibrin is formed. It increases the tensile strength of the wound and stimulates fibroblast proliferation and growth.
| Acute-Phase Reactants in Periodontics|| |
Pro-inflammatory cytokines and mediators are significantly elevated with gingival inflammation and during the destructive phase of periodontitis. One consequence of these localized gingival inflammatory reactions has been the identification of elevated levels of various APPs in the GCF. These have included α2-macroglobulin, α1-antitrypsin, and CRP, which are altered in the crevicular environment, presumably as a result of numerous host-bacterial interactions in the sulcus, and may contribute to the defense of the host in this millieu.
Cytokines appear to play a major role in the clinical symptoms and tissue destruction associated with progressing periodontitis. Many of these cytokines are derived from activated macrophages and can act both locally and distally to amplify cytokine production from other cell types (such as fibroblasts and endothelial cells), which then emerge from the local tissues and can initiate systemic APRs. Since multiple cytokines have been detected in both gingival tissues and GCF, changes in local acute-phase reactants might be expected. The total amount of IL-1a and IL-1b, but not total IL-1Ra were found to be correlated with alveolar bone loss score.
Direct and indirect immunodot techniques are evaluated for quantifying APPs within GCF from diseased and healthy sites. The periodontitis subjects were found to have a reduced level of total salivary antioxidants compared with the healthy subjects, possibly exposing them to the damaging effects of free radical species in the oral and periodontal environment. Therefore, alterations in the local environment may be essential to periodontal disease activity and may reflect increased levels of local radical production by local polymorphonuclear leukocytes and macrophages during disease progression. Interference with the formation of these soluble mediators results in the impairment of the APR to the infecting bacterial species.
| Acute-Phase Reactants and Its Correlation to Systemic Disease|| |
Some disease states are related to APPs like the pathogenic role of fibrin in thrombosis. Similarly, CRP-mediated complement activation has a key role in some forms of tissue alteration such as cardiac infarction. Fever and sustained elevation of levels of CRP, ESR, and other inflammatory markers are common problems during treatment of infective endocarditis. Elevated serum values are known to be associated with increased risk of human atherosclerosis. CRP binds to low- and very low-density lipoproteins and SAA protein is associated with high-density lipoproteins. This suggests that these APPs may interfere with the metabolism of serum lipoproteins during the acute phase of infection.
The causal relationship between the APP, SAA, and the extracellular deposition of amyloid fibrils has been proven. CRP levels provide a sensitive and objective indicator of disease activity and clearly reflect the response to therapy of rheumatoid arthritis. In rheumatoid arthritis patients plasma, IL-10 increased, and IL-6 and CRP are significantly elevated versus controls. Low levels of acute-phase SAA are noted in inflamed joint fluid. Studies of neonates with streptococcal infections and bacteremia suggested that CRP is a marker for the acute period of infection and α1-AGP is a marker of recovery.
Of the numerous periodontal variables analyzed in this retrospective analysis, bone loss appeared to be the most consistent variable associated with coronary heart disease and thus, the periodontal disease appeared to be associated with excess risk of cardiovascular disease and stroke. Moreover, periodontitis patients presented with increased levels of serum fibrinogen (an APP) and elevated white blood cells, significant risk factors for coronary heart disease. Recently provided preliminary data associating specific periodontal pathogens, immune responses, and inflammation with the formation of atheromatous plaques and associated with cardiovascular disease. The host responses to periodontal disease and cardiovascular diseases were reflected by an increase in the APPs (SAA and CRP).
| Conclusion|| |
The acute-phase reaction can be applied not only to the assessment of general health but is also valuable for the estimation of periodontal health. These acute-phase reactants are superior to cytokines for monitoring periodontal health because cytokines are cleared from the circulation within a few hours whereas APP levels remain unaltered for up to 48 h or sometimes longer. The acute-phase reaction offers a biological effect mechanism which is appropriate to include in future systems for inspecting periodontal health and disease activity prior to and following treatment.
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Conflicts of interest
There are no conflicts of interest.
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