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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 2  |  Issue : 2  |  Page : 25-39

Host response in periodontology: The defensive shield of the supporting structures of teeth


1 Department of Periodontics and Oral Implantology, Kalinga Institute Dental Sciences, KIIT Deemed to be University, Bhubaneswar, Odisha, India
2 Department of Oral and Maxillofacial Surgery, Kalinga Institute Dental Sciences, KIIT Deemed to be University, Bhubaneswar, Odisha, India

Date of Submission11-Dec-2020
Date of Decision12-Dec-2020
Date of Acceptance21-May-2021
Date of Web Publication24-Jun-2021

Correspondence Address:
Dhirendra Kumar Singh
Department of Periodontics and Oral Implantology, Kalinga Institute Dental Sciences, KIIT Deemed to be University, Bhubaneswar, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcdoh.jpcdoh_6_20

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  Abstract 


Oral microbial infections produce a significant rise in systemic inflammatory responses, manifested by acute-phase cytokines and acute-phase inflammatory reactants. Therapeutic oral manipulations or the inappropriate or absence of intervention of progression periodontal disease could have a significant influence on these systemic diseases. Periodontal pathologies usually refer to common inflammatory disorders known as gingivitis and periodontitis, which are caused by pathogenic microorganisms present in the subgingival dental plaque, and cause an inflammatory response. These Inflammatory response process results in the destruction of periodontium, and eventually in tissue, which further leads to tooth loss. The present article explains the role and significance of the host response in periodontal diseases.

Keywords: Host response, inflammation, periodontal diseases, periodontal pathogens, periodontitis


How to cite this article:
Singh DK, Pathi J. Host response in periodontology: The defensive shield of the supporting structures of teeth. J Prim Care Dent Oral Health 2021;2:25-39

How to cite this URL:
Singh DK, Pathi J. Host response in periodontology: The defensive shield of the supporting structures of teeth. J Prim Care Dent Oral Health [serial online] 2021 [cited 2021 Oct 24];2:25-39. Available from: http://www.jpcdoh.org/text.asp?2021/2/2/25/319195




  Introduction Top


To counter the threat, i.e. because of the invasion of the body by living organisms, including viruses, bacteria, and protozoan parasites, certain general defense mechanisms have evolved, i.e. – a relatively impermeable epidermis, methods and ridding the body from noxious maternal such as vomiting, diarrhea, and coughing, the dilution of irritants by increased flow of interstitial fluid in inflammatory edema, and the destruction of particulate matter by phagocytic cells.

In addition, there exists in vertebrates a special mechanism of immense potential which is mobilized when the body is expressly and specifically adapted to overcome the effects of the particular invades in question.

The specific reactive process induced in a host by an antigenic stimulus is known as immune response. The immune system responds to the introduction of foreign molecules by the induction of two main protective mechanisms.

Humoral immunity is mediated by Ab molecules and cell-mediated immunity and involves the direct action of immune cells.


  Components in Host Response Top


The components participate in host response can broadly classified as follows:

Cells

  • Acute inflammatory cells – Polymorphonuclear neutrophils (PMNs), mast cells basophils, eosinophils
  • Chronic inflammatory cells – macrophages, lymphocyte, plasma cells
  • Epithelial cells
  • Fibroblast.


Antibodies and complement system

  • Cytokines Immune mechanisms


  • Mediator – Prostaglandins.

    Effectors – Matrix metalloproteinases (MMPs)

  • It is recognized that host responses play a very important role in most forms of gingival and periodontal disease.
  • Development of gingivitis and periodontitis depends on the interaction between the resident microbiota and the host response.[1]
  • Desquamative gingivitis-like lesions frequently result from a host response.


Inflammatory cells

In response to specific stimuli, inflammatory cells chemotactically migrate and concentrate in localized areas where they phagocytize bacteria and bacterial components or remove damaged tissue.

Some of these, such as T and B lymphocytes, divide and increase in number by blastogenesis. Others release vasoactive products, and still, others produce substances such as plasma cells and macrophages that cause or assist in the lysis of other host cells or the destruction of alveolar bone.

Mast cells

These are from mesenchymal origin and connective tissue equivalents of circulating basophils. They are located in connective tissue specifically around the blood vessels.

Mast cells are important because of their cytoplasmic granules, which contain histamine, slow-reacting substance of anaphylaxis, heparin, eosinophil chemotactic factor of anaphylaxis, and bradykinin, all of which are released into the gingival tissues.

Degranulation of mast cells occurs during nonimmunologic and immunologic immediate hypersensitivity reactions of the anaphylactic type, when antigen reacts with surface-bound IgE Ab mast cell interleukin has been shown to enhance collagenase activity and heparin may augment bone resorption by potentiating the effect of parathyroid hormone.

They are present in normal gingival connective tissue and in junctional epithelia.

Basophils

It appears to be to amplify the reaction that starts with the mast cells at the site of initial tissue disruption.

Eosinophils

  • Function of eosinophils to regulate regulate mast cell activities; they release large quantities of prostaglandin, and PGS appears to inhibit the release of histamine by neighboring mast cells
  • The granules of eosinophils are rich in acid phosphatase and peroxidase activity
  • The exact functions of eosinophils are not known. Two roles have been postulated, ingesting immune complexes and limiting inflammatory reactions by antagonizing the effects of mediators
  • In the site of allergic response, eosinophils are triggered to release histaminase and aryl sulfatase which inactivate the allergic mediators.


Neutrophils (polymorph nuclear neutrophilic granulocytes)

PMNs are thought to play a significant role in gingival and periodontal disease. These cells are found in all inflammatory lesions, particularly in the more acute lesions, where they concentrate at sites of injury, chemically attracted to the area through the process of chemotaxis. The neutrophils then engulf (phagocytosis) and subsequently kill and most microorganisms and neutralized other noxious substances.

Neutrophils may also cause tissue destruction.[2]

Neutrophils are the initial leukocytes recruited into the gingiva. Neutrophils exist in the circulation and migrate into the junctional epithelium and gingival crevice, where they provide the first cellular host mechanism to contact and control periodontal pathogens [Table 1].
Table 1: Chemo attractants for neutrophils

Click here to view


Neutrophils are well adapted to function in hypoxic environment, because virtually all of their energy is derived from fermentation of stored glycogen rather than oxidative phosphorylation. They possess a large number of antimicrobial compounds, most of which do not depend on oxygen. Evidence suggests that neutrophils, in addition to their well-known antimicrobial roles, moderate the inflammatory activities of the chronic immune system.

Neutrophils can crawl at a rate of about 400 μm/h. Hence, the neutrophil uses the circulatory system to travel rapidly about the body. Still, the primary role of the neutrophils is the destruction of pathogens that threaten tissues outside of the blood including periodontium. For this reason, leaving the blood, finding targets, and killing targets are important phagocyte functions in defense of periodontium.

Neutrophils

Neutrophils are the primary phagocytic cells in the acute response. The normal function of neutrophils can be broken down into a defined series of molecular events useful in describing how neutrophils respond to bacterial invasion.[3]

Normal neutrophil function can be discussed as quantifiable events.

  • Stimulation of the acute phase (generation of the signal)
  • Recognition of the signal
  • Migration to the source of the signal – diapedesis (emigration)
  • Recognition of the invader (opsonization)
  • Phagocytosis
  • Microbicidal activity.


Margination and diapedesis (emigration)

Neutrophils adhere to the luminal surface of the vascular endothelium (rolling, margination) and migrate across the endothelium (diapedesis, interendothelial transmigration).

There are two phases of leukocyte–endothelium adherence.

  1. The selectin-dependent phase (primarily involved in rolling)
  2. The integrin-dependent phase (primarily involved in diapedesis).


Selectins

Selectins are closely related to the regulators of complement activation (RCA) gene region products (such as complement regulatory [CR] 1 and factor 4). Like the regulators, they are encoded on chromosome 1 and possess CR motifs referred to as short consensus repeats that may be important in binding C3, C4, and C5 metabolites. The selectins possess lectin and epidermal growth factor-like domains[4] Lectin activity is important in the adhesion of phagocytes to the endothelium. Some of the initial, reversible rolling contact between the leukocyte and uninflamed endothelium is mediated by L-selectin, which is constitutively expressed on the surface of the leukocyte [Table 2].
Table 2: Selectins

Click here to view


  • Inflammation causes endothelium to immediately express P-selectin, which it stores in granules (Weibel–Palade bodies) and also induces the biosynthesis of E-selectin. Both P- and E-selectin strengthen the binding between the leukocyte and the endothelial cell and increase the number of leukocytes “rolling” in the inflamed postcapillary venule, the first manifestation of margination.


P-selectin binds to the ligand gp 150 – Lewis X, and E-selectin binds to Sialyl-Lewis X, carbohydrate-bearing moieties found on the leukocyte surfaces.

Leukocyte β1 integrins

Interleukin (IL)-8 causes the leukocyte to shed L-selectin and to express the β2 integrins, which are sequestered in the specific granules. The leukocyte β2 integrins include three related transmembranes glycoproteins consisting of a noncovalently associated heteroduplex structure. They share a common β2 subunit and differ in the α subunit.[5]

The three leukocyte integrins are leukocyte function – ass–antigen-1 (LFA-1; CD1 1a/CD18), Mac11 (CD11b/CD18) complement receptors, and p150, 95 (CD11c/CD18 complement receptor 4) [Table 3].
Table 3: Integrins

Click here to view


The distribution of LFA-1 is greater than that of the other two β2 integrins; both LFA-1 and Mac-1 are important in diapedeses.

The leukocyte β2 integrins are particularly appealing as the molecular mediators of binding to endothelial cells.

At the beginning of transendothelial migration, neutrophils show distinct polarization, extending pseudopodia between the endothelial cells while maintaining the nuclei and granules on the luminal side.

Chemotaxis

Chemotaxis is the directed movement of a cell along a chemical gradient. The neutrophil is attracted by chemical signals (chemotaxins) from multiple sources.[6]

Both C5a and formyl peptides are likely to play a major role in attracting neutrophils into the gingival crevice.

Chemotaxin receptors

Chemotaxis requires that the phagocyte possesses specific chemotaxin receptors for all of the molecular listed above. The most well-studied chemotaxin receptor is the receptor for formyl methionyl peptides, known as the formyl methionyl peptide receptor (FPR). The normal human neutrophil expresses about 50,000 FPRs per cell. The FPR is a transmembrane glycoprotein and binds to formulated hydrophobic peptides derived from bacteria. The affinity of the FPR is modulated by a cytosolic, 40 kD GTP/GDP-binding G protein. The G protein is sensitive to certain microbial toxins, and both cholera and pertussis toxins, which are adenosine diphosphate-ribosylate 6 proteins, inhibit chemotaxis and high affinity binding of formyl methionyl leucyl-phenylalamine (FMLP) by the FPR.[7]

Peripheral blood leukocyte and endothelial cell adhesion molecules

The FPR belongs to a superfamily of 6 protein-coupled receptors, which include light receptors, neuropeptide receptors, and more distantly, the receptors for neurotransmitters. The chemotaxin receptors possess are deeply imbedded within the cell membrane and feature three extracellular loops (designated EL-1, -2, and 3), three cytoplasmic loops (designated CL-1, 2, and 3), and seven transmembrane domains; the G proteins are coupled to CL-3. They are deeply imbedded within the cell membrane and feature three extracellular loops (designated EL-1, -2, and -3), three cytoplasmic loops (designated CL-1, -2, and -3), and seven transmembrane domains; the G proteins are coupled to CL-3.[8]

  1. GP110-membrane glycoprotein in neutrophils are associated with all chemotaxin receptors. Van Dyke et al.[9] have described a 40% deficiency in a 6P110 in Localised juvenile periodontitis (LIP). The exact function of 6P110 is unknown, but antibodies against 6P110 block neutrophil chemotaxis [Table 4].[10]
Table 4: Immunoglobulin superfamily of adhesion molecules

Click here to view


Binding of neutrophils to targets

Opsonization

Opsonization refers to the process of coating a particle with recognizable molecules to enable phagocytic ingestion. Simplistically, there are two types of opsonins that should be considered.

  1. The complement metabolic, i.e. 3b
  2. Immunoglobulin 6 (IgG).


The complement metabolite ic3b

Both alternative and classic pathways of complement activation ultimately produce C3b bound covalently to the target surface. Once C3b is formed, its further metabolism is controlled by the RCA, a group of related proteins encoded in chromosome I.

The phagocyte possesses a regulator, CR1, that serves as a cofactor (to a serum enzyme, factor I) that binds to C3b. In so doing, CRI directs factor I to place a small “nick” in C3b to form ic3b. This abrogates the complement cascade and provides ic3b for endocytosis (amplification and optonization are mutually exclusive).

Immunoglobulin G

Phagocytic adhesion to targets may also be mediated by antibody using surface receptors collectively known as “Fc receptors.” The three main types of Fc receptors for the phagocytes are the IgG receptors FcrRI, FcrRII, and FcrRIII. FCrRI is a high-affinity receptor found mainly on macrophages. The other two are low-affinity receptors found on both macrophages and neutrophils. There are no known Fe receptors – for IgM.

The precise mechanism of phagocyte adhesion to targets may vary with disease states. Both gingivitis and adult periodontitis have been characterized primarily as involving alternative pathway activation, which suggests that the complement activation and opsonization in AP occurs mainly via the alternative pathway. In localized juvenile periodontitis (LJP), probably, in latter stages, C3, B, and C4 cleavage is observed. The complement cleavage patterns observed indicate greater classic pathway activation in LJP, which suggest a higher degree of opsonic antibody interacting with target antigen (Aggregatibacter actinomycetemcomitans).

Binding of Ig by the Fc receptors can activate a number of different biological processes depending on the cell type and receptor type. These processes include phagocytosis, clearance of immune complexes, degranulation and activation of the respiratory burst, and release of inflammatory mediators. Fc receptors specific for IgG, IgE, and IgA have been identified and referred to as FCrR, FC and R, and FCαR, respectively. Different Fc receptors can be found expressed widely on monocytes, neutrophils, platelets, B-cells, eosinophils, basophils, and trophoblasts.

FCrRI (CD64), FCrRII (CD32), and FCrRIII (CD16) can be distinguished from one another on the basis of size, primary structure, monoclonal antibody reactivity, affinity and specificity for ligands, and cellular distribution pattern.

Antimicrobial systems

Neutrophils have oxidative and nonoxidative mechanisms for exerting antimicrobial effects.

Aerobic–respiratory burst

Oxidative mechanisms

They are based on reduction of oxygen with resultant formation of toxic oxygen metabolites. Free radicals and reactive oxygen species (which contain free electrons in their outer orbits) are capable inducing tissue damage.[11]

The oxidative mechanisms include a nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and an enzyme, myeloperoxidase (MPO).

Oxidative antibacterial effects are mediated by two main biochemical entities. The NADPH oxidase system and MPO.

The NADPH oxidase system is required to transport electrons from the cytosolic NADPH to the external surface of the plasma membrane.

The O2 − produced through NADPH is quickly dissimulated to H2O2 in the cellular milieu by 2O2+2H+ → H2O2 + O2, where NADPH oxidase univalently of divalently reduces oxygen to superoxide anion or hydrogen peroxide, respectively.

H2O2 is mildly toxic to a number of oral pathogens. In the presence H2O2, MPO catalyzes the formation of a highly destructive bleach-like substance, hypochlorus acid which is lethal to most microbes.

NADPH + 2O2 = 2O2+ H+ + NADP+ -Superoxide production

The NADPH oxides.

Patients who have chronic granulomatous disease, predisposed to life-threatening infection, cannot mount an efficient respiratory burst during phagocytosis due to defective components of the NADPH complex.

Nitrogen-containing compounds

Nonoxidative mechanisms, in general, appear to be based on membrane disruptive antibiotic activities of peptides or peptide domains within larger proteins.[12]

Antimicrobial components localize to virtually every cellular compartment.

Secondary granules

  1. Specific granules: Which contain lactoferrin, lysozyme, and β12-binding protein (cobalophilin) within their matrices and cytochrome B within their membrane – these may function extracellularly.


Azurophil granule

They contain MPO; defensing; members co-neutral serine protease family including cathepsin G, leukocyte elastase, proteinase 3 and azurocidin, and lysozyme and bactericidal/ permeability-increasing protein (in azurophol granule membrane).

  • The cytosol contains a microbiostatic factor called “calprotectin”
  • The nucleus contains microbicidal histones.


Reactive oxidant production can be stimulated by a number of agonists including N-FMLP, platelet-activating factor, leukotriene B4, and opsonized bacteria–oxidant production also varies between cells obtained from different areas of the body. For example, neutrophils obtained from peripheral blood are poorly responsive, presumably due to the lack of previous exposure to agonist and limited localization of the oxidative burst enzymes to the plasma membrane.

Monocytes and macrophages

  • Unlike neutrophils, which exit the bone marrow as terminally differentiated cells, monocytes exist in the bone marrow in a functionally immature condition[13]
  • As a result, monocytes arrive from blood to the tissues as multipotential cells capable of differentiating in a variety of different ways
  • Once in the tissues, they are referred to as macrophages and differentiate along many different pathways to kill pathogens, regulate clearance of tissue debris, regulate tissue remodeling, and process exogenously derived antigens
  • Macrophages differentiate in response to environmental factors. For example, T cells release interferon-r (IFN-r) and may induce the differentiation of macrophages into antigen-processing and antigen-presenting cells. These antigen-processing and antigen-presenting macrophages have somewhat limited proliferative abilities
  • Bacterial lipopolysaccharide (LPS) induces macrophages to further differentiate into activated macrophages. Fully activated macrophages are capable of adhering to and killing tumors by releasing a cytolytic protease (a 40 kd neutral serine protease secreted only by fully activated macrophages) and tumor necrosis factor-α (TNF-α). Fully activated macrophages are capable of proliferation. Monocytic cells influence both tissue repair and lymphocyte activity by releasing IL-3, IL-6, IL-8, IFN-α, transforming growth factor-β (TGF-β), and TNF-α
  • Macrophages play a direct, important function in cell-mediated immunity. These large highly phagocytic cells are part of scavenger reticuloendothelial system
  • Their phagocytic activity is enhanced by surface receptors in the Fc portion of IgG, which provides increased contact of antigens with the macrophage following antigen–antibody interaction
  • They participate with T lymphocytes in aiding the response of B lymphocytes to many immunogens
  • It is thought that the macrophage “processes” the antigen for the B lymphocyte
  • In inflammatory lesions, macrophages are formed by differentiation of monocytes that are carried to the lesion by blood. These cells act nonspecifically with antigens, which provide them with the capability of destroying a diverse, antigenically unrelated group of bacteria
  • Mononuclear cells are attracted to sites of inflammation by lymphokines (soluble substances released by lymphocytes) such as IFN-r and complement factor (e.g. C5a). They are then retained at these sites by other lymphokines. The ability of the macrophages to ingest, kill, and digest microorganisms is dependent on interaction with other leukocytes, elements of the immune system, in general, and complement. The efficiency of bacterial phagocytosis by the macrophages is enhanced by the reaction of the antibody with the antigen and subsequent complement activation
  • Macrophages are also important because they secrete interleukin (IL-11, IL-6, IL-8, and IL-10), TNF-r, insulin-like growth factors, IFN-r, and other stimulatory, inhibitory, and growth factors. They also produce prostaglandins, cyclic adenosine monophosphate, and collagenase in response to stimulation by bacterial endotoxin, immune complexes, or lymphokines. Macrophage collagenase may play a significant role in collagen destruction in diseased periodontal tissues.


Antigen processing and presentation

Antigen processing is the partial degradation of proteins that results in antigen presentation.[14]

  1. Antigen presentation refers to the expression of peptides (derived by processing) on the cell surface in association with molecules encoded within a gene complex known as the major histocompatibility complex (MHC), located on the short arm of chromosome 6.


  2. MHC Class I molecules are also referred to as human leukocyte antigens A, B, or C (HLA-A, HLA-B, and HLA-C).

    MHC Class II molecules are known as HLA-DR, HLA-DQ, and HLA-DP which include.

    MHC Class III – complaint factors C24.

    • The antigen-presenting MHC-encoded molecular are extremely pleomorphic, and the MHC Class I and Class II molecules are particularly pleomorphic in the area of the specificity pockets. Different allotypes of the MHC molecules bind and present different peptides to T cells and thus dictate which specific T-cell clones respond to a given protein antigen. This is called determinant selection and is the main reason individuals of the same species exhibit diverse immunologic responses to the same antigens. Thus, the alleles of the MHC genes and their allotypic products are largely responsible for immune response pleomorphism.


    Most frequently cells degrade their own proteins and therefore usually express MHC Class I molecules on their surfaces in association with self-peptides. Intracellular infection or neoplastic alteration may lead to the expression of different peptides associated with the MHC Class I molecules on the cell surface.

    MHC Class II molecules may be produced by all cells but are usually limited in distribution to “professional” antigen-presenting cells, including mononuclear phagocytes, Langerhans cells, and B cells.

    A professional antigen-presenting cell is a cell that can process and present antigens derived from the extracellular milieu. Most bacterial infections are extracellular.

    The host uses an endolysosomal pathway to process and present antigens derived from extracellular sources. In this pathway, the host ingests the antigen by phagocytosis or pinocytosis.

    Macrophages ingest antigen by phagocytosis (binding the target particle using the ic3b receptor CR3 [MAC-1]) or the IgG (binding for receptors) and digest it within a phagolysosome. MHC Class II molecules are sequestered within the membrane of storage granules (lysosomes) and become available as a result of fusion between the lysosomal and phagosomal membranes. Peptides are associated with MHC Class II molecules in the phagolysosome, and this complex is expressed (presented) on the phagocyte surface by exocytosis.

    • Processed peptides are bound in two “specificity pockets” within a wide groove of the MHC Class I or Class II molecules. The peptides are bound specifically at two anchor positions: P2-3 and P9 of a nonameric peptite. The intervening 5–7 amino acids float on “bed of water” and maybe in almost any sequence. Thus, the MHC molecules are far less specific than antibodies, which recognize 4–6 contiguous residues.


Major histocompatibility complex Class II molecules

It Includes complement factor C2, C4, and B which are encoded within the MHC.


  Lymphocytes Top


Lymphocytes include three types of cells.[15]

  1. T-lymphocytes or T cells, which are derived from the thymus and play a role in cell-mediated immunity
  2. B-lymphocytes or B cells, which are derived from liver, spleen, and bone marrow, are the precursors for plasma cells, and play a role in humoral immunity
  3. Natural killer (NK) or killer cells (K).


T-cells: THelper → CD4+

60 - 80% of T suppressive cytotonic–CD8+ & circulating lymphocytes are T cells. The T cells are associated with two types of immunological functions, effector and regulatory. The effector functions include activities such as killing of virally infected cells and tumors. The regulatory functions are represented by their ability to amplify or suppress through cytokines or other effector lymphocytes including B and T cells.

Most circulating T-cells express three of the following CD markers.

  1. CD2 receptor for sheep erythrocytes
  2. CD3 T-cell antigen receptor (TCR) complex
  3. CD4 receptor for MHC Class II molecule
  4. CD8 receptor for MHC Class I molecule.


The bone marrow + stem cells contain the enzyme TdT does not express surface CD glycoproteins.

Differentiation in the cortex occurs as the T-cells move through the thymic medulla:

  1. Development of two distinct T-cell populations, helper-inducer T cells (CD4 + ve) and suppressor-cytotoxic T cells (CD8 + ve)
  2. Loss of TdT enzyme.


Approximately 90% of Tcells die intrathymically and never enter the peripheral circulation.

T-helper cells aid in the cellular response of B-cells to differentiate into plasma cells and produce antibodies.

Suppressor-cytotoxic T-cells stimulate cytotoxic and microbiocidal activity of the immune cells.

The TH cells release IL-2 and IFH-4, while the T3 cells release IL-4 and IL-5.

T-cells possess specific antigen receptors referred to as TCRs. TCRs recognize the peptides associated with MHC Class I or Class II molecules.

In contrast to NK cells, T-cells are activated when the TCR recognizes antigen associated with MHC Class I or Class II molecules (The CD4+ coreceptor binds MHC Class II molecules).

The CD8+ coreceptor binds MHC Class I molecules.

Therefore, CD4+ T cells respond to peptide antigens associated with MHC Class II molecules, and CD8+ T cells respond to antigens associated with MHC Class I molecules.

T cells require one additional signal – the costimulatory signal to allow proliferation. Membrane IL-1 is expressed by the antigen-presenting cell only if the environment is appropriate, and this provides the costimulatory signal to T-cells, enabling them to express receptors for growth hormones (e.g. IL-2).

The costimulatory signal that enables the clonal expansion of CD8+ T cells is referred to as B7-2 and interacts with CD28 on the CD8+ T cell.

B-cells

B-cells make up approximately 5%–15% of circulating nucleated cells of normal human blood. They are classically identified by their cell surface 1 g.

Most B-cells express the membrane form of IgM initially. Addition of IgD occurs on most D cells. Thus, the majority of resting B-cells are IgM + and IgD+, whereas IgD tends to be lost soon after activation.

Some B-cells also express IgG, IgA, and IgE. In mucosal-associated lymphoid tissues, the majority of B-cells express IgA as their surface Ig. Other B-cell markers are FC receptor for IgG heavy chain, for complement components (C3b for MHC Class II molecular and for Epstein–Bars virus that identifies the lymphocyte surface CDS). The CD markers that are frequently used to identify B cells are CD19, CD20, and CD21.

Macrophages/the mononuclear phagocyte

The term reticuloendothelial system designates all actively phagocyte cells. The mononuclear phagocytes include tissue macrophages located primarily in the connective tissue matrix of the spleen, liver, and lymphoid tissues and immature circulating blood monocytes[16]

These cells play pivotal roles in both humoral and cell-mediated immune reactions to pathogens; their main features include:

  1. The presence of several cytoplasmic enzymes (nonspecific esterase, lysozyme)
  2. Consistent occurrence of several membrane receptor molecules such as receptors for 1 g molecules (FC receptor) and the complement C3 receptor)
  3. The capability to phagocytize particles, especially those coated with antibody or complement proteins
  4. The ability to directly phagocytize and kill various microorganisms, particularly after activation by lymphokines
  5. Requirement for processing and presenting antigen for subsequent B lymphocyte development and Ag synthesis particularly associated with MHC Class II molecules.


Natural killer cells

  • Approximately 5% of the blood lymphocytes have neither the membrane 1 g characteristic of B-cells not phenotype characteristic of T-cells. Such cells are identified as NK calls and were originally called TPCs or null cells[17]
  • These cells are capable of lysing and variety of tumor cells, without previous sensitization. They are found in the peripheral blood and the lymphoid tissues of human as well as a variety of animal species. They are CD3 but express two markers. CD16 and Leu 19 are useful for their identification. The cells responsible for NK activity are primarily large granular lymphocytes
  • NK cells utilized two distinct mechanisms to lyse their target cells
  • Utilizes NK cell surface FC receptors and antibodies directed against the target cell antigen.


The other involves direct interaction between NK cells and their target cells and utilizes NK cell receptors that have not yet been fully characterized.

  • It is possible to rapidly activate and expand their numbers by culturing with IL-2 in vitro. The resulting population often referred to as lymphokine-activated killer cells is currently being evaluated as an immunotherapeutic tool in the treatment of certain forms of cancer
  • NK cells possess receptors that recognize peptides associated with MHC Class I molecules. Recognition of Ag by the NK cell blocks the activation of the NK cells; almost any NK cell can respond to the loss of a self-molecule on the target surface; therefore, NK cell responses can be rapid. In contrast, only a small proportion of CD8+ T cells can respond
  • To new antigen expressed on the target cell surface, CD8+ T-cell responses are much more sensitive and rapid than NK responses on the second exposure
  • T lymphocytes to B-cell ratio decreases in adult periodontitis because of decreased in T-cell count (1:3).


  • T4: T8 in adult and juvenile periodontitis → 1:1

    (Normal 2:1 – seen in child – gingivitis).

  • The NK cells are recognized by their absence of T-cell receptors (TCRs) and surface immunoglobulin.


Plasma cells

Plasma cells are the terminal cells in the progression from B-cells; they contain abundant cytoplasmic RNA, which is characteristic of a cell actively producing proteins. Plasma cells occur in germinal centers and in tissues, where they produce Ig and antibodies, the effector cells for systemic and local humoral immunity and local humoral immunity, respectively.

Antigen

Antigen is a substance capable of evoking an immune response, which may take three moon forms, i.e. Ab production, cell-mediated immunity, and specific immunological tolerance. When an Ag initiates an immune response, it is known as an immunogen to when it induce tolerance it is a tolerozen.

A complete antigen is able to induce Ab formation and to produce a specific and observable reaction with the Ab which is further required to produce A Hapton– in a low molecular weight substance, hapton is often a simple chemical or drug which is capable of binding to ab or b cell-specific surface but is incapable in initiating an immune response unless it is directly coupled to a carrier molecule.

Proantises – Low molecular weight substance, which do not induce Ab formation but cause delayed hypersensitivity when applied to skin. They appear to act by combining with autologous portions.

Epitope

The portion of an Ag that actually occupy the binding site on B- or T-cell is known as an epitope. Hence, an epitope is the smallest unit of antigenicity.

  • Epitope may be represented by a continuous series of amino acids on a peptide and are then known as linear epitomes. Discontinuous epitope is then known as linear epitope. Discontinuous epitope is residue, not directly in sequence, but is present as apply convolution on the surface of globular proteons. Resulting from secondary and territory protein.


Antibody

A globulin formed in response to an antigen (an immunoglobulin).

Antigen

A macromolecule that will induce the formation of immunoglobulin of sensitize cells that react specifically with antigen.


  Immunoglobulins/Antibodies Top


Antibodies are glycoproteins representative of the adoptive immune system that are present in the serum and fluids of mammals. These bind specifically to foreign antigens such as bacteria, viruses, parasites, and toxins. Antibodies are induced when the lymphoid system interacts with the immunogenic materials on or produced by microorganisms.[18]

Abs (immunoglobulins) are divided into five classes: IgG, IgA, IgH, IgE, and IgD [Table 5].
Table 5: Possible role of Abs in inflammatory disease

Click here to view


All classes and subsets of Ig have similar structural organization, but they differ according to their biologic prepotency carbohydrate content, weight, and amino acid sequence. Every Abs molecule has a valuable region, which, because of its unique amino acid sequence and tertiary structure of its antibody-combining site, allows it to react highly specifically with a particular antigen.

  • Abs are composed of either two or light (small) chain and one of five types heavy (large) polypeptide chain – each class of immunoglobulin has similar sets of light chains but antigenically district sets of heavy chains
  • The base structure appears Y shaped. The tail of the Y contains the ends of two heavy chains and is referred to as Fc fragment– is in this region that complement binding taken place
  • The remaining are the Y-shaped molecule which is composed of the light chains and the reminder of the heavy chains. This is the FAA or antibody-binding site. The number of binding sites is called “Valence” of the molecule: IgG has a valance of two sectors; Ig A – has 4 and Ig M – has 10 (contrary five moreover units).


They can be divided into three antigenic determination or epitopes: Isotypic, allotypic, and idiotypic.

These determinants are located on discrete region of the Ab molecule. The isotypic determinant is at the F or constant region of the heavy and light chain – defines the class and subclass of the Abs, and is common to specify.

The allotypic determinants found on both heavy and light chains at both the FC and Fab region of the Ab molecule may vary from person to person within a species. At present, their chain has been identified to have 25 allotypes called “Con markers.”

The idiotypic determinant is at the Fab or variable region of the antibody molecule. Multiple idiotype may be found on am Ab.

Biologic properties of immunoglobulins

  1. IgG– subclass– 4 G 1 - 64 in the most abundant of all the serum immunoglobulins and is distributed equally between the blood and the extra-vascular fluids.


  2. Its major role is to neutralize bacterial toxins by binding to organism, thereby enhancing their phagocytosis. “Conein secretion, IgG – constitutes 80% total serum Ig, passes the placental battier, and provides newborns with the humoral immunity of the mother.

  3. IgM 1.2 mg/serum five subunits; these Ab are first to be formed after challenge with most antigens, but they are usually present in much long concentration Then IgG.


They have an important role in the early stages of infection and also having the most efficient role in activation of complement system.

Frequently observed in autoimmune disease like rheumatic arthritis, the IgE– IgE (reagenic antibody) is present at 1/125,000 the level of IgG. Despite the low concentration. This class of antibody is responsible for acute allergic reactions.

The cells that produce IgE are abundant in the mucosa of the oral, respiratory, and intestinal (exocrine secretion).

High concentration. IgE is found in patients with asthma, food allergies. There Abs has an affinity for cell surfaces, which is mediated by an attachment site on their FC (fragment crystallizable) fragment.

IgE is homocytotrophic or attaches to most cells and basophilic leukocytes.

Ag reaction with two IgE molecular previously attached to most cells or basophils leads to the release of histamine and other pharmacological active substances.

IgD: Easily degraded by proteolysis energy, it is also found to extents low concentration at 0.03 mg/ml of serum.

IgD binds to a receptor on the surface of B lymphocytes – It may play an important role in triggering B-cell stimulation by antigen, thus initiating the immune response.

Serum IgA – monomer secretory IgA – dimes principal Ig in the exocrine secretions (i.e. saliva, milk respiratory secretions, intestinal mucosa, and tear).

  • 12 mg/ml – serum


Cells produces IgA → subepithelial tissue of the exocrine glands and responds locally occurring Ags.

Secretory IgA contains one secretory piece and a J chain that binds IgA molecules through disulfide bonds.

  • Gingival tissue of crevicular fluid contains serum IgA rather than secretory (IgA)
  • Properties of secretory IgA make them unique and influence their function on mucosal surfaces
  • Secretory IgA is more resistant to digestion by proleolytic enzymes than other Abs. The secretory component of a polypeptide chain attached to the FC portion of IgA stabilizes this portion of the molecule, facilitating its transport across the glandular epithelium
  • The J chain (polypeptide chain) may function in making secretory IgA more resistant to proteolysis
  • IgA activates complement alternative pathways
  • Adhesion of bacteria to tissue surface may be prevented reduced by secretory Abs. This mechanism of protection is thought to be active in bacterial disease (cholera) and dental caries and possibly in the early phase to periodontal disease
  • Bacterial LPS is nitrogenic and causes polyclinical stimulation of β-cells and results in nonspecific and in effective antibodies production
  • Effective Abs are monoclonal, and these are specific and effective.



  The Complement System Top


An important consequence of Ag–Ab interaction is the activation of complement. Complement is the conversion of at least 25 proteins and glycoproteins that make up approximately 10% of the proteins in the normal serum of humans and other vertebrates [Table 6].[19]
Table 6: Biologic effects of complement components

Click here to view


  • These proteins are not Igs and their concentration is not affected by immunization
  • They are synthesized in the liver, the small intestine, the macrophages, and other mononuclear cells
  • The genetic term “complement” refers to a severe of at least 25 proteins that together form an enzyme cascade system which is capable of explosive amplification yet in also under cases and strength homeopathic control.


Complement activation results in three human effector outcomes

  1. Lysis: Of antibody-coated cells, bacteria, or enveloped viruses either directly or following antibody binding
  2. Opsonization: The recognition of Ab and/or complement bound on microorganism b phagocytic cell-bearing specific receptors of complement fragment proteins
  3. Inflammatory: Changes the specific properly of complement splint peptide fragments to induce vasodilation, neutrophils attachments, and endothelial margination results in acute inflammatory.


Pathways of activation

  • There are two major pathways by which complement system may be activated.


    1. The classical pathway
    2. The alternative pathway.


The reaction sequence in the activation of the complement system has a cascading type pathway similar to that of the blood bound by the Fe portion of the Ab in the Ab–Ag complex; the other components of the complement system react in an ordered sequence.

  • In general, each activated complement component cleaves the next reaching member of the series into fragments until the cascade has been completed. Some of the smaller fragments formed during cleavage have phlogistic activity, that is, they cause inflammatory tissue changes. These include vascular permeability.


    1. Classic pathway is activated by a reaction of Ag with IgG or IgM antibodies and by aggregated Igs. The sequence in C1, C4, C2, C3, C5, C6, C7, C8, and C9. C3 is cleaved by the complex C42 into C3b (which binds to the cell membrane) and C3a (which has biologic activity)
    2. An alternative pathway for complement activation also exists. Aggregated Abs of IgG, IgA, and IgE classes, endotoxin, fungi and yeast cell walls, and some viruses, parasites, and other substands can initiate the complement sequence by direct activities of the C3 without triggering the beginning of the cascade starting with C1. The sequence after C3 activation is identical to that of the classic pathway


  • Bacteria Ags such as endotoxin, polysacclaud (dextrin), dental plaque, and pine culture of bacteria can also activate complement by alternative pathway in the absence of Ab
  • Complement activation by these various pathways could result in much that destroys the periodontal tissue (GCF)
  • An important effect of complement occurs when Abs react with invading Ca-positive bacteria, leading to complement activation and lysis of bacteria
  • It appears that positive bacteria are not susceptible to this lyric action of complement but are effective because they are phagocytosed more rapidly after complement activation.



  Immune Mechanisms Top


Immune mechanisms are usually protective responses by the host to the presence of foreign substances such as bacteria and viruses. They may at the same time cause local tissue destruction by triggering several types of overreaction or hypersensitivity. Tissue damage (immunopathologic change) may occur in a sensitized host with subsequent exposure to the sensitizing antigen.

Four types of hypersensitivity reactions have been described:

Type I, II, and III: Reactions are humoral and are termed immediate reactions because they occur in minutes to hours.

Type IV: Reactions are cellular or cell mediated and are termed delayed reactions because they occur within days.

Three of these hypersensitivity reactions are of potential important in periodontal disease. They are anaphylaxis or immediate hypersensitivity.[20]

Anaphylasis (Type 1): (Atopic)

Two variations depend on the route of administration of antigen. Cutaneous anaphylaxis (atopic) if injected locally into the skin, the reaction is so-called systemic or generalized anaphylaxis. If the Ag injected, basic mechanisms for both types of immediate hypersensitivity are the same:

IgE and IgA Abs involved in anaphylaxis.

IgE: plays a directed and sensitize the skin (called a regain) so 1 g Ab act as regain Abs (sensitizing Abs).

IgG: Abs combine with Ag in circulation before it can bind to IgE in the mast cells basophils and prevents sensitization.

Mechanism of anaphylactic hypersensitivity

Anaphylaxis occurs when two IgE Abs that are fixed to a mast cell or basophil react with sensitizing Ag through the Fab portion of the Abs. This Ab–Ag reaction causes the release pharmacologically active substances from the sensitized cells. These substances cause the response and have the potential to induce tissue damage in periodontal disease.[21]

Cytotoxic reactions (Type II): IgG and IgM Abs

In these reactions, Abs react directly with Ags tightly bound to cells. These Ags may be natural surface components of the cell, such as the cell membrane polysaccharide antigens of red blood cells.

  • A cytotoxic reaction involving these cells may result in hemolysis. Cytotoxic antibodies may also react with antigens associated with tissue cells. These cell-associated antigens are associated with tissue cells. These cells associated antigens include normal cell surface antigens or those derived from bacteria drugs or altered tissue components
  • Cytotoxic antibodies IgG and IgM have the ability to fix complements, although complement fixation is not required for all types of cytotoxic reaction
  • In addition to inducing cell lysis, cytotoxic antibodies may cause tissue damage by increasing the synthesis and release of lysosomal enzymes by cells (PMNs) coated with antigen
  • Hemolytic transfusion reactions, hemolytic disease of the newborn, and autoallergic hemolytic anemia are examples of cytotoxic reactions
  • Cytotoxic reactions are seen in autoimmune disease like pemphigus cell membrane
  • To data, no evidence suggests on an important role for cytotoxic reactions in gingivitis periodontitis.


Immune complex (Arthus) reactions (Type III)

  • Local – Arthus reaction
  • System – Serum sickness
  • When high levels of Ag to which the host has been sensitized are present and persist without being eliminated, Ag–Ab (IgG and IgM) complexes precipitate in and around small blood vessels and, with subsequent complement activation, cause tissue damage at the site of the local reaction
  • Inflammation, hemorrhage, and necrosis may occur. Tissue damage appears to be due to the release to lysosomal enzymes from PMNs, mast cell activation, platelet agglutination, microthrombi, formation, and neutrophil chemotoxis– this reaction is referred to as immune complex or Arthus reaction and in usually – mediated by IgM or IgD antibodies.. IgM and IgD have the ability to fix complement, which is partially responsible for the chemotactic alteration of the PMNs crucing to the Arthur reaction.


Cell-mediated immunity of delayed hypersensitivity (Type IV)

  • The phenomenon of delayed hypersensitivity belongs to the class of immune responses known as cell-mediated immunity; these reactions are referred to as Type IV reactions
  • Cellular immunity does not involve circulating Abs but is based on the interaction of Ags with the surface of lymphocytes
  • Some cell bacteria, including actinomyces and some strains of streptococcus, produce extracellular substances that inhibit blast transformation of normal peripheral lymphocytes.


Nonspecific host defense mechanism

Non-specific host defence mechanism is the recognition of the pathogen by lymphocytes. Specific immunity is based upon the antibodies made by b-cells and upon the activities and cytokine secretions of T-cells. B-cells and T-cells have receptors which recognize molecules on the invading organisms. Each B-cell and T-cell has a unique a unique receptor.[22]

  1. Competition for the same nutrients (interactions)
  2. Competition for same specific receptors on host cells
  3. Production of “Bacterious” which are bacterial products toxic to other organisms especially to the same specific
  4. Continual stimulation of immune system to maintain low but constant levels of Class I and Class II histocompatibility and other molecules on macrophages and accessory cells
  5. Stimulation of cross-protective immune factor (natural Abs). The ultimate effect of the first three points mentioned above is to limit the quantity or dominance of any specific spacing of the normal flora.


Natural antibody

They are specific Abs found in healthy persons with no previous history of competent infection. Their production is stimulated by microbial flora that colonies in the oropharynx, gut, etc., which share cross-reactive/cross-protective Ag. They are not always protective, e.g. serum IgA in immune meningitis predisposes to infection by blocking IgG and IgM activity.

Natural Abs usually provide immunization against encapsulated organisms.

Mechanical borrowers

  1. Skin: Relative dryness mild, (pH 5–1)
  2. Mucosal sentence – Antimicrobial
  3. Properties – Lysozymes.



  Mediators Top


Cytokines

  • A series of low molecular weight (30 K DNA) – polypeptides or glycoproteins[23]
  • Act as intercellular mediators (local hormones) among lymphocytic inflammatory cells and other cellular elements in connective tissue
  • Lymphokines – before their production by other cells was recognized
  • Cytokines assist in the regulation and development of immune effector cells, cell-to-cell communication, and direct effector functions
  • Some cytokines exhibit autocrine function-binding to cells. That produced them
  • Paracrine: Binding to nearby cells
  • Endocrine: Binding to distant cells
  • They have multiple target cells and diverse effect (ambiguity)
  • Overlapping spectrum of action (redundamly)
  • Exceptionally with endocrine actions such as TNF,/L
  • Effective in very low concentration.


According to their action

  • Proinflammatory cytokine – ILI and 6, TNF (tumor necrosis)
  • Chemotactic – IL8.


Transforming growth factor

At present, about 20 ILs have been identified and are numbered 1–10.

Classification

Interleukin-1

IL1 (α and β) is pleiotropic cytokine with a variety of activity.

It includes osteoclast-activity factor:

Lymphocyte-activating factor: Because of irritability to stimulate proliferation of phytohemagglutination-treated T-cells.

  • They play a role in T4 cells activation, promotion of β-cell maturation, chemotaxis of neutrophils and macrophages, enhancement of NK cell activity, and other responses
  • It is secreted by monocytes, macrophages, β-cells, fibroblasts, neutrophils, epithelial cells, and many other stimulated cell types. This stimulation results from phagocytosis, complement components (C3a and C5a), and other substances
  • IL1 occurs in the gingival tissues and crevicular fluid and decreases after periodontal treatment. It also increases fibroblast procollagens – formation of PGE2 and bone resorption activity
  • IL – IL2 (α andβ) originally called T-cell growth factor because of its effect on mitogen or antigen-activity T-cells. (TH and Tc) and is known to play a general role in immune responses
  • It also stimulates macrophage functional activity, modulates NK function, and induces NK proliferation
  • It is secreted by T4 cells and NK cells and is increased in periodontal tissues in periodontitis
  • IL3 supports the growth and differentiation of hematopoietic cells including stimulation of most cell growth and histaminic secretion
  • It is secreted by activated T4 cells and NK cells
  • K-4: Originally called T-cell–derived β-cell growth factor (BCGF-1) previously called migration inhibition (M/F) factor
  • It is known to also play a role in the activation, proliferation, and differentiation of β-cells, T-cell growth, macrophage function, and growth of mast cells
  • IgE synthesis by β-cells, is also induced by IL4
  • IL4 is secreted by T4 cells – it is increased in periodontal tissues in periodontitis
  • IL5 is secreted by β-cells, proliferation and enhances IgA production, together with IL4 it also promotes IgE production. It is secreted by T4 cells
  • IL6 stimulates plasma cell production Ig and, with IL1, activates T4 production
  • It is secreted by macrophages, T4 cells monocytes, fibroblasts, and endothelial cells
  • IL6 increases sites of gingival inflammation and plays a role in bone resorption
  • IL7 induces T-cell proliferation by expressing IL2 and IL2 receptors. It is secreted by bone marrow stromal cells
  • IL8 is chemotactic for neutrophils and increases their adherence to endothelial cells. It is secreted by macrophage
  • IL9 is secreted by some T4 cells, induces proliferation of T4 cells in the absence of antigen or antigen-presenting cells, and promotes growth of most cells
  • IL, secreted by TH cells, suppresses by IFN-γ production of Nk cells that are induced by IL-2. IL-10 inhibits the Ag-presenting capacity of monocytes.


Interferons

IFNs (α1, β, and γ) are a family of three glycoproteins produced by leukocytes, fibroblasts, and T lymphocytes, respectively. They provide antiviral activity and enhance macrophage activity (IFN-γ), T-cell activity, Nk-cell activity.

  • IFN-γ also plays a role in bone resorption by inhibiting both the proliferation and differentiation of progenitors of osteoclasts.


Tumor necrosis factors

TNF (α and β), produced by macrophages and TH cells, respectively, cause the necrosis of certain tumors. TNF-α is produced by macrophages after stimulation by Cr-ve bacterial components including LPS, TNFβ, previously known as lymphotonin produced by TH cells.

TNFα and TNFβ play a role in the activation of osteoclasts and stimulate them to cause bone resorption.

TNFα also aids leukocytes in their ability to adhere to endothelial cells and increases their phagocytosis and chemotaxis. These effects, along with the effect on macrophages leading to macrophage-induced angiogenesis, may play a role in the vascular changes seen in periodontal disease.

Assays

Originally, cytokines were identified by their biologic activities, which led to some confusion because of the overlapping activities of some cytokines.

Functional identification

It has been supplemented as a result of cytoline purification and cloning which was allowed production of monoclonal antibodies to the cytokines used in specific radioimmune assays, enzyme-linked immunoabsorbent assays, and enzyme-linked immunospot assays.

The production of appropriate of inappropriate cytokines determines disease expression.

  • Cell-mediated immune response involve the activation of macrophages and induction of different CD4+ and CD8+ T-cells, whereas humoral immunity is characterized by Ab production. These two responses were originally classified in the mouse as being regulated by two distinct subsets of CD4+ helper T cells
  • Th1 and Th2 cells secrete different types of cytokines
  • Th1 cells produce IL-21 IFN-γ and TNF. Th2 cells are defined by the production of IL-4, IL-5, IL-6, IL-10, and IL-13
  • Th1 cytokines are involved in cell-mediated inflammatory reactions. They increased the ability of macrophages to kill intercellular and extracellular pathogens and also mediate delayed type → hypersensitivity reactions
  • Th2 → cytokines are found in associated with strong Ab and allergic responses; these cells stimulate mast cells and eosinophils and FgE Abs
  • The immune response to infection is regulated by the balance between Th1 and Th2 cytokines TNFα-and IL-1 mediate adhesion molecule expression on endothelial cells and hence play a role in the migration of PMNs, lymphocytes, and macrophages into the periodontal tissues.
  • IL-1 produced by macrophages acts as the major mediator of tissue break down in periodontal disease.


Prostaglandin and prostaglandin inhibitors

Cytokines exert their effect by first binding with specific receptor, that in turn bind to second messengers so that a signal is delivered inside the cell in response to the cytokine legend.[24]

  • One group of second messengers is derived from hydrolysis of membrane phospholipids
  • Phospholipase A = C substrate to generate arachidonic acid, which is a precursor of a group of small lipids collectively known as eicosanoids
  • Arachidonic acid is degraded two pathways.


    • Lipoxygenase easya
    • Cyclooxygenase.


  • PGs are composed of 10 classes, of which D9E, F, G1H, and 1 are important.
  • Evidence that PGs could immediate bone resorption was first reported in 1970
  • PGE2 was the potent stimulator of bone resorption and it exhibits a broad range of pro-inflammatory effects
  • IL1 and TNF activate the arachidonic acid pathways and a number of their effects can be attributed to PGE2
  • Cox-2 expression is inducible in response to a number of stimuli including LPS and many cytokines such as IL-1, TNF, and TGF α → At resting condition, Cox-2 is mostly undetectable (Cox 3 – brain)
  • Radicicolous is a fungal antibiotic thought to act as a protein tyrosine kinase inhibitor and has been shown to inhibit the expression of Cox-2 in LPS-stimulated macrophages without effecting enzymatic activity
  • New drugs, cytokine-suppressing anti-inflammatory drugs, such as SKF 86002 thought to act selective inhibitors of Rk and P38 (mitogen-activated protein kinase)
  • Most PGs have been shown to have an overall catabolic effect on gingival fibroblasts
  • Cyclosporine A has a dose-dependent inhibitory effect on PGI2 synthesis in the gingival tissues. As PGI2 normally exerts an antiproliferative effect, it has been suggested that the lack of PGI2 is responsible for the gingival overgrowth associated with cyclosporine A
  • PGE2 and thromboxane A2 were detected only in inflamed tissues, while 6-k-PGE1α was found in all tissues
  • The associated with Pg with increasing inflammation has proved difficult to characterize.



  Effectors Top


Matrix metalloproteinases

Members of the family of metalloproteinases called matrixins – sometimes incorrectly referred to simply as collagenases – are mainly but not exclusively synthesized by connective tissue cell.[25]

  • MMPs can be synthesized by hemopoietic cells, including monocytes and macrophages, keratinocytes, endothelial cells, and many types of tumors
  • They are metal-binding proteinary secreted as proenzyme forms requiring extracellular activation
  • MMPs can synergistically digest all the macromolecules of tissue matrices
  • Although metalloproteinases can be inhibited by the ubiquitous plasma proteinase inhibitor α2-macroglobulin, the major group inhibition of MMPs in tissues is the tissue inhibitors of metalloproteinases (TIMP), and 4 separate gene products in this family have now been identified
  • The expression of metalloproteinases (MMPs) and tissue inhibitors (TIMPs). Of metalloproteinases by connective tissue cells is regulated by complex interactions among a number of cytokines, growth factor, and hormones, some of which are specific to cell type and other that are more ubiquitous. Many factors are the products of monocytes and macrophages and their products in inflammatory situation are key step in initiating metalloproteinase synthesis and tissue degradation. IL1 seems to be particularly important in the upregulation of MMPs, and roles of TNF, PGs, and IL-10 have been documented [Table 7].
Table 7: Classes and properties of human matrix metalloproteinases

Click here to view



  Acute-Phase Reactants in Infection and Inflammatory Diseases Top


  • The acute-phase reaction represents an early and highly complex reaction of the organism to a variety of injuries such as bacterial, viral, or parasitic infection, mechanical or thermal trauma, ischemic necrosis, or malignant growth
  • The acute phase refers to physiological and metabolic alterations that ensue immediately after onset of infection or tissue injury
  • In contrast with the specificity of cellular and humoral immunity, the acute-phase changes are nonspecific and occur in response to many conditions
  • The purpose of these responses is to restore homeostasis and to remove the cause of its disturbance. Characteristic features of the systemic acute-phase response include (i) fever, (ii) neutrophilia, (iii) changes in lipid metabolism, (iv) hypophonic, (v) increased gluconeogenesis, (vi) increased (muscle) protein catabolism and transfer of amino acids from muscle to liver, (vii) activation of the complement and coagulation pathways, (viii) hormonal changes and (ix) induction of acute-phase proteins[26],[27]
  • The tissue macrophage is the cell most commonly regarded as initiating the acute-phase response through direct stimulation and secretion of various cell communication factors.


An additional acute-phase response is an increase in the PMNs and platelet count in theblood. A prominent aspect of the acute-phase response is also the modification of the tune with dilation and leakage of blood vessels, particularly the postcapillary venule. This results in tissue edema, red blood cell extravasation, and associated redness.

These alterations are likely mediated through the release of various inflammatory mediators in the inflamed tissues, including reactive oxygen species, nitrous oxide, and arachidonate metabolites.

The results include activation of macrophages, aggregation of platelets, vessel permeability, and transudation of biological fluids into the tissues and migration of circulating leukocytes.

Acute-phase reaction response molecules

  • Acute-phase proteins serve important functions in restoring homeostasis after infection or inflammation. These include hemostatic functions (such as fibrinogen), microbicidal and phagocytic functions (such as complement components or C-reactive protein), antithrombotic properties, and antiproteolytic properties which are important to contain protease activity at sites of inflammation. Although most acute-phase reactants are synthesized by hepatocytes, some are synthesized by other cell cytes, including monocytes, endothelial cells, fibroblasts, and adipocytes. (Acute-phase protein can be divided into two groups Group I and Group II)[28]
  • The strong acute-phase proteins include C-reactive protein-macroglobulin and serum amyloid A, which responds rapidly to inflammatory stimuli, and serum levels may increase several humdus folds – C-reactive protein.
  • C-reactive protein, when bound to bacteria, promotes the binding of complement, which facilitates their uptake by phagocytes.


(C-reactive protein may be considered a primitive form to antibody specifically interacting with cell membrane components of microorganisms such as bacteria and fungi as well as for damaged mammalian cell membranes). When complexed, C-reactive protein can active complement to enhance opsonization and clearance of the bacteria before the production of specific IgM or IgG. C-reactive protein bound to bacteria or cells can interact with NK cells and with monocytes and may increase the tumoricidal activity of these cells.

C-reactive protein reacts with cell surface receptors resulting in opsonization, enhanced phagocytosis and passive, protection activation of the classical complement pathway; scavenger for chromatin fragments inhibition of growth and/or metastases tumor cells, and modulation of PMN's function.

The synthesis of these acute-phase portions has been shown to be regulated by cytoclones and to a cases extent by glucocorticoid hormones.

Arbitrarily cytoclones related to the acute-phase response can be divided into three groups.

  1. Proinflammatory cytokines initiating or enhancing the cascade of events (TNF and IL 1, IFN-r, and K-8)
  2. IL6 type cytokine (IL6, IL11, leukemia inhibitory factor on costatin M, ciliary nemotrophic factor, and cardiotrophin-1, which are held responsible for the main systemic features of acute-phase response in a variety of tissues)
  3. Anti-inflammatory cytokines downregulating the acute0phase response (IL10, IL4, IL13, and TGF-B).


These individual cytokines induce the full spectrum of acute-phase protein expression. The majority of the acute-phase proteins are glucoproteins, which play a variety of roles in the homeostatic response to injury.

Acute-phase reactants in periodontitis

  • The ability to use acute-phase reactant levers as a measure of infections processes or inflammatory diseases has substantial support[29]
  • Direct and indirect immune to techniques were evaluated for quantifying acute phase proteins within GCF from diseased and healthy sites. Relative amounts of C-reactive protein and L2 macroevolution were determined periodontitis sites exhibiting lower levels of L'2 macroglobulin, and C-reactive protein levels were no different in health and disease.
  • In response to periodontal pathogens, neutrophils release oxidants, proteinases, and other tissue-destructive factors. The balance between these factors, the antioxidants, and endogenously synthesized antiproteinases (such as acute-phase protein) may determine the extent of periodontal damage. Since the acute-phase response plays a central role in promoting healing, periodontitis as a wound-healing problem would be directly affected.



  Conclusion Top


While prevention of periodontal destruction is of primary importance, it is clear that strategies for early intervention, more specific treatment modalities, and more effective assessment of treatment success are high profile areas of interest in periodontology.

  • Recent studies have indicated a closer linkage of periodontitis with systemic manifestations of this chronic infection and inflammation. Thus, the acute-phase response might be useful as biomarkers of periodontitis contribution to systemic diseases, as well as providing a potential mechanistic line between the local and systemic manifestations of periodontitis
  • Specifically, the host responses to periodontal disease and cardiovascular disease were reflected by an increase in the acute-phase proteins (serum amyloid and C-reactive protein)
  • Additional studies have also supported the concept that circulating nonself-materials (such as oral bacterial or these products) may not only contribute to cardiovascular disease but also affect fetal development if they are not successfully removed by the reticuloendothelial septum.[30]


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
Components in Ho...
Lymphocytes
Immunoglobulins/...
The Complement S...
Immune Mechanisms
Mediators
Effectors
Acute-Phase Reac...
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