Year : 2015 | Volume
: 5 | Issue : 2 | Page : 62--67
Immunity and periodontics: Connecting the dots
HS Grover, Rohit Saini, Pearl Bhardwaj, Amit Bhardwaj
Department of Periodontology, Faculty of Dental Sciences, SGT University, Gurgaon, Haryana, India
Department of Periodontology, Faculty of Dental Sciences, SGT University, Gurgaon, Haryana
Immunity is divided into two parts – the innate and adaptive responses. The innate immune system relies upon limited receptors to detect invading pathogens but compensates by targeting conserved microbial components that are shared by the large groups of pathogens. Various cells involved in innate immune responses include neutrophils, macrophages, dendritic cells, mast cell, neutrophils, natural killer cells, and eosinophils. The innate immune responses are the first line of defense against invading pathogens. They are also required to initiate specific adaptive immune responses. The second kind of protection is adaptive immunity which develops throughout our lives. It uses two basic strategies – Humoral immunity which works to eliminate antigens that are extracellular and cellular immunity which deals with antigen residing within a host cell. T- and B-lymphocytes are the main self-defense weapons of the adaptive immune system. Adaptive immunity relies upon a clonal system with each T-cell and B-cell expressing its own unique receptor.
|How to cite this article:|
Grover H S, Saini R, Bhardwaj P, Bhardwaj A. Immunity and periodontics: Connecting the dots.Indian J Multidiscip Dent 2015;5:62-67
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Grover H S, Saini R, Bhardwaj P, Bhardwaj A. Immunity and periodontics: Connecting the dots. Indian J Multidiscip Dent [serial online] 2015 [cited 2021 Aug 2 ];5:62-67
Available from: https://www.ijmdent.com/text.asp?2015/5/2/62/175025
Immunity is divided into two parts that are determined by speed and specificity of the reaction. These are named the innate and adaptive responses. The term innate immunity usually encompasses the elements of the immune system which provide immediate host defense whereas adaptive immunity response consists of antigen-specific reaction through B- and T-lymphocytes.
Innate Immune System
The innate immune system is emerging as a critical regulator of the human inflammatory disease. It is, an evolutionarily ancient component of host defense, is present in all multicellular organisms. Various cells involved in innate immune responses include neutrophils, macrophages, dendritic cells (DCs), mast cell, neutrophils, natural killer (NK) cells, and eosinophils.
Cells in Innate Immunity
It is recognized that periodontal disease and other oral infections are caused by bacteria, but it is patient's own innate immune system which is largely responsible for the destruction of the bone, periodontal ligament, and gingival tissues that support the teeth. Neutrophils, the key white blood cell of the innate immune system, are responsible for detecting and eliminating microbial invaders that make their way into the body. They are the sentinels of the oral immune system and are the predominant leukocyte in blood, accounting for about two thirds of all blood leukocytes (4000–8000 cells/cumm). This high rate of production is essential, as these cells have short circulating half-life of about 10 h and survive up to an additional 48 h once they reach the infected area. When neutrophils leave the blood, they always retain their small size, and hence, were once called microphages.
Neutrophils possess receptors for metabolites of the complement molecule C3, designated complement receptor 1, 3, and 4 (CR1, CR3, CR4), and C5 (C5aR). They also possess receptors for immunoglobulin G (IgG) antibody (FcγR). These receptors enable neutrophils to participate in the inflammatory response and to ingest foreign molecules and cells in the process of phagocytosis.
How neutrophils fight infection
Neutrophils make essentially one-way trips from the bone marrow into the blood and finally into the infected tissue compartment. They are the first line of defense against foreign microbes that make their way past the primary physical barriers that protect the body. They are able to crawl through blood vessel wall at sites expressing key signal protein and vascular cell adhesion molecule (VCAM) on their surface. The expression of a green light protein which signals an infection in the area; is turned on by locally produced inflammatory mediators at the site of infection. Once cells have entered the tissue, there occurs “3 R's” – recruitment, response, and resolution. This leads to the killing of bacteria.
Neutrophils are attracted to the site of microbial infection in response to the specific chemoattractant molecules derived from the microbe or from the responding host, a process known as chemotaxis.
Phagocytosis and intracellular killing
The neutrophil recognizes host-derived molecules that are bound to the bacterial surface (opsonins – IgG, C3b) and engulfs microorganisms via invagination of the plasma membrane, which encloses the microbe in a phagosome.
Oxygen-independent killing relies upon the microbicidal molecules contained in the three sets of neutrophil cytoplasmic granules: Primary (azurophilic granules), secondary (specific), and Gelatinase-containing granules. One, or a combination of means – disrupt the microbial membrane, and enzymes that dissolve the invading pathogen which lead to microbial demise. These enzymes are responsible for oxidative killing inside the phagosome and may be released into the extracellular microenvironment, increasing the oxidative stress in the vicinity.
The same set of tools available to kill microbes intracellularly can be released by neutrophils to the extracellular space in an effort to kill microbes. One-way of extracellular killing that has been of interest in recent years, is called neutrophil extracellular traps.
Successful resolution of inflammation is a prerequisite for the restoration of healthy tissue. Because acute inflammation is characterized by an abundance of infiltrating neutrophils, their elimination, and the restoration of normal numbers of tissue leukocytes, is a critical step in the progression toward tissue repair.
Neutrophil and importance in the periodontal disease
Periodontal disease is one of the most prevalent diseases occurring in man between 70% and 90% of the population experiencing this disease at some point during their lifetime.
Strong evidence demonstrates a significant portion of inflammatory mediated destruction of tooth-supporting tissues. It occurs as a result of collateral damage caused by enzymes released by the hyperactive neutrophils as they attempt to contain the bacterial infection. Neutrophil collagenase (matrix metalloproteinase-8) released during periodontal infections is one of the major enzymes responsible for the degradation of tooth supporting bone and ligament  Low dose of doxycycline inhibits neutrophil collagenase and periodontal destruction in patients with periodontal disease which is resistant to conventional periodontal therapy  Chediak–Higashi syndrome and leukocyte adhesion deficiency syndrome have an increased susceptibility to the periodontal destruction , Neutrophils can minimize the destructive effects of plaque and bacteremia.
Monocytes which constitute 3–7% of leukocytes are usually the second cell type to move to the site of injury. Monocytes exit the bone marrow after 2 days in a relatively immature state and may differentiate in the tissues. Monocytes are referred to as macrophages when they leave the blood.
Macrophages are the key cells for the inflammatory processes as regulators directing inflammation to chronic pathological changes or resolution with no damage. They are involved in a remarkably diverse array of homeostatic processes of vital importance to the host.
Functions of macrophages include
Elimination of the invading bacteria Recruitment of other cells to the site of infection Clearance of the excess neutrophils Production of cytokines and chemokines Activation of the lymphocyte-mediated adaptive immune response.
Macrophage and periodontal disease
Porphyromonas gingivalis has been shown to affect the macrophage migration and activation by inhibiting the production of one of the major macrophage/monocyte. This suggests that macrophages have a protective effect in the stable lesion which are abrogate in the advanced destructive lesion.
Peripheral DCs are leukocytes with cytoplasmic projections, which reside in the suprabasilar portions of squamous epithelium. DCs ingest antigen locally and transport the antigen to the lymph nodes through the afferent lymphatics. They express high levels of MHC class II molecules and CD1 as well as adhesion molecules such as intercellular adhesion molecule-1; leukocyte function associated antigen-3; and costimulatory factors (B7-1, B7-2). DCs are antigen-presenting cells with a unique ability to induce primary immune responses.
Langerhans cells are dendritic bone marrow-derived cells situated suprabasally in the most stratified squamous epithelia. They are thought to act as antigen-presenting cells during induction of immune responses. Besides having functions which are similar to other DCs and macrophages, Langerhans cells are specialized and are able to migrate, playing an important role in antigen presentation to the T-lymphocytes. They may represent a “ first line” of
sensitization of the immune system, leading to clearance of the antigen or to pathological phenomena.
Mast cells originate from pluripotential hematopoietic cells in the bone marrow, undergo part of differentiation in this site, then enter the circulation, and complete their differentiation in peripheral mucosal or connective tissue microenvironments. They are characterized by oval to round nuclei with cytoplasm densely packed with bright red granules. When activated, mast cells may either undergo explosive degranulation and then resynthesize their granules or they may release solitary granules into their environment on an ongoing basis, a process termed as “piecemeal degranulation” that has been observed in both the oral mucosa and skin. Mast cells may subsequently synthesize and secrete additional mediators that are not performed in their granules.
Interaction between mast cells and other immune cell type
They are reciprocal in that certain mediators produced by endothelial cells and resident perivascular macrophages, namely, interleukin-1 (IL-1) and IL-8 can potentiate or inhibit mast cells and histamine release.
An important interaction between mast cell and another cell type is that of antigen presentation to T-lymphocyte. Mast cell express both MHC class I and II molecules as well as CD80, CD86, and CD54 molecules that serve as a second signal for T-lymphocyte activation during antigen presentation. One of the biological and biochemical factors is histamine, which breaks down the tissue barrier, causes edema and helps cellular infiltration.
Correlation of mast cell with periodontal disease
The transition from gingivitis to periodontitis leads to loss of attachment for tooth and loss of alveolar bone. Mediators produced as a part of the host response that contribute to tissue destruction include IL-6 (which are secreted by mast cells). Increased mast cells count in the progressing site of the periodontal disease indicate the importance of the progression of chronic periodontitis.
Natural killer cells
They were 1st discovered in 1975, 20 years after the discovery of T- and B- lymphocytes. NK cells are a distinct subgroup of lymphocytes but do not bear a specific antigen receptor that plays a major role in the ability of the innate immune system to steer immune responses. NK cells are abundant in periodontitis lesions, and NK cell activation has been causally linked to periodontal tissue destruction. The NK-cells possess several classes of antigen receptors, including killer inhibitory receptors and killer activating receptors.
The main physiological role is the protection of the host from parasitic infections. These infections induce antigen-specific immunoglobulin E (IgE) production, the antibodies coating the organisms. They bind to the antibody using the low-affinity receptors (Fcε RIII). They are not phagocytic but have large granules containing major basic proteins, eosinophilic cationic protein, eosinophil peroxidase, and eosinophil-derived neurotoxin which are highly cytotoxic when released onto the surface of organisms.
Basophils resemble the other mature granulocytes but are distinguished by coarse, intensely basophilic granules which usually fill the cytoplasm and often overlie and obscure the nucleus. The granules of basophils contain heparin, histamine, and 5-hydroxytriptamine. In the tissues, these cells become mast cells. Mast cells or basophils on degranulation are associated with histamine release. Basophil participates in the immediate type of hypersensitivity reactions initiated by allergens bound to IgE.
Other cells which contribute to the immune system
The mature erythrocytes of the human peripheral blood are nonnucleated cells and lack the usual cell organelles. The normal human erythrocyte is a biconcave disc, 7.2 μm in diameter, and has a thickness of 2.4 μm at the periphery and 1 μm in the center. The life span of the red cells is 120 days.
Platelets are only apparently very simple cells, being small, nonnucleated, and originated from the cytoplasmic fragmentations of megakaryocytes. Instead, they possess complicated structural features that are related to their functional and biochemical activities. Platelets contain granules which are an important source of inflammatory mediators. They have surface adhesion molecules which enable them to bind to the walls of damaged blood vessels and contribute to the inflammatory response. Activated platelets regulate chemokine release by the monocytes in the inflammatory lesions. These functions make platelets as important components of inflammatory processes. Platelet activating factor is actually a family of structurally related acetylated phospholipids, which possesses potent inflammatory activities.
The endothelial cells form both a barrier and gateway between the blood and tissues. Endothelial cells can be activated by certain cytokines and inflammatory mediators to express adhesion molecules to which leukocytes can bind facilitating their passage through loosened intercellular functions. This occurs at the site of inflammation, but is also a normal process within the postcapillary venules of lymph nodes, thus facilitating the passage of T- and B-cells from the blood into lymphoid tissues during their recirculation around the body.
Adaptive immune system
The second kind of protection is the adaptive immunity which develops throughout our lives. The Adaptive immune responses use two basic strategies:
One response is of humoral immunity which works to eliminate antigens that are extracellular Other is cellular immunity or cell-mediated immunity that deals with the antigen residing within a host cell.
T- and B-lymphocytes are the main self-defense weapons of the adaptive immune system, so-named because this system is shaped by antigen exposure. In contrast to the limited number of pathogen receptors utilized by the innate immune system, the adaptive immune system boasts an extremely diverse, randomly-generated repertoire of receptors.
B-cell-mediated humoral immunity
Humoral Immunity is mediated by B-lymphocytes or B-cells. Their name reflects the fact that their development occurs in the bone marrow. It is now known that the bone marrow stromal cells provide an essential microenvironment for B-lymphocyte development. The earliest B-lymphocyte precursors are bound to the stromal cell surface by adhesive interactions involving several cell-surface molecules, including hyaluronate (HA) and VCAM-1 on the stromal cells and molecules designated CD44, HA receptor, and very late antigen 4 on the B-lymphocyte precursors, respectively. In addition, other molecules provide the adhesive interaction required in the later phases of B-lymphocyte development. Furthermore, it has also been shown that bone marrow stromal cells secrete a variety of cytokines such as IL-4, IL-7, and transforming growth factor (TGF-β) which act on B-lymphocyte progenitors. These findings clearly demonstrate that bone marrow stromal cells provide critical microenvironments for B-lymphopoiesis.
Development of B-cell
The B-cell development can be divided into two stages: Antigen dependent and antigen-independent. B-lymphocytes have been classically defined by the presence or absence of membrane-bound immunoglobulin on the outer surface of their membrane. While mature B-cells predominately express membrane-bound immunoglobulin on their cell membrane, plasma (or memory) cells predominately produce secretory immunoglobulin. One of the most fascinating aspects of B-lymphocytes is their heterogeneity; they differ in terms of the specificity of their antibody combining sites and hence antigenic specificity.
Role in periodontology
In periodontitis lesions, plasma cells are the most common cell type and represent about 50% of all cells, while B-cells comprise about 18%. The proportion of B-cells is larger than T-cells and helper T-cells (Th cells) occur in larger numbers than T cytotoxic cells. Polymorphonuclear cells and macrophages are found in fractions of less than 5% of all cells. Lesions in aggressive and chronic forms of periodontitis exhibit similar cellular composition. Differences in disease severity, however, may reflect increases in plasma cell and B-cell densities.
Cellular immunity is mediated by T-lymphocytes or T-cells. Their name reflects the fact that they mature in the thymus. T-cells involved in eliminating antigen include two subsets and cytotoxic T-cells and Th cell. Both of these have multiple copies of a surface molecule called a T-cell receptor which is functionally analogous to B-cell receptor, it enables the cell to recognize a specific antigen.
Other helper T-cells such as Th17, Th22, and Th9 cells have been identified that are phenotypically distinct from the existing Th cells. Further, it has been shown that Th cells demonstrate plasticity, that is, the ability to transform from one subset to the other.
The T-lymphocyte was associated with two distinct types of immunologic functions: Effector and regulatory. The effector functions included activities such as killing of virally infected cells and tumors. In contrast, the regulatory functions served to amplify or suppress the immune response through cytokines and/or receptor-ligand interactions of costimulatory molecules acting on other effector lymphocytes, including B- and T-cells.
T-cells are subdivided based on whether they possess the co-receptors CD4 or CD8. The CD4 co-receptor reversibly binds (scans for) MHC class II molecules (human leukocyte antigen, [HLA-DR, HLA-DP, and HLA-DQ]) that are found on DCs, macrophages, and B-cells. CD4+ T-cells initiate and help the immune responses by providing proliferative and differentiative signals.
CD8 cytotoxic T-cell-mediated immunity and role in periodontics
The role and contribution of classic cytotoxic CD8+ αβ T-lymphocytes (CTL) in periodontal disease progression are not well-understood. The development of CTL requires the recognition of foreign Ag peptides by MHC class I molecules (or HLA-A, B, and C in humans). The short peptides (i.e. 5–15 amino acids) are generated in the “proteasome” machinery of the infected cells, then transported for Ag processing (7–9 a.a) before being loaded onto the endoplasmic reticulum, where MHC class I molecules pair noncovalently with β2-microglobulin prior to the final expression of these molecules on the cell surfaces of all nucleated cells.
Both Tc1 and Tc2 induce similar inflammatory cell infiltrates; however, perforin-ablated Tc1 and Tc2 cells were still able to induce delayed-type hypersensitivity (DTH; a classic cell-mediated immune response), although at lower levels, suggesting that perforin-mediated cytotoxicity of CD8+ T-cells is not essential for a DTH response. Studies have shown that there is a Tc2-like cytokine expression profile in the gingival tissues of periodontitis subjects. This finding suggests a potential role of CTL in local immune regulation and promotion of humoral immune response during periodontal infections.
CD4 T-cell-mediated immunity
CD4+ Th cells – works to battle microbial infections in the periodontal and oral tissues. Th cells are the pivotal cell type in modulating and regulating the acquired immune system, composed of B-cell-mediated humoral immunity and CD4+ Th and CD8+ CTL-induced cell-mediated immunity. The generation of specific CD4+ Th cells is initiated by the recognition of longer peptides (12–25 a.a. in length) present in the binding grooves of MHC class II molecules (in humans: HLA-DR, DQ, DP) on the surfaces of specialized APC such as macrophages, DCs, and activated B-cells.
CD4+ T-cells mature to form phenotypic subpopulations that are distinguishable on the basis of their cytokine production. In addition to antigen and co-stimulation, professional APCs provide immature Th T-cells with the maturational signal IL-1β, which induces T-cell maturation to a multifaceted Th0 T-cell phenotype. Th0 T-cells produce cytokines, which can stimulate both B-cells and CD8+ T-cells. Other cells in the area, especially macrophages, DCs, other T-cells, and NK-cells provide further differentiation signals. High or low concentrations of IL-12 or cytokines such as interferon-γ (IFN-γ), IL-2, IL-4, IL-10, and (TGF-β) can then induce T-cells to mature to the Thl, Th2, or Th3 phenotypes.
Role in periodontics
A strong innate response leads to a Th1 response under the influence of IL-12, IL-2, and IFN-γ while a weak innate response leads to a Th2 response under the influence of IL-4 cytokines. In a stable lesion, IFN-γ enhances the phagocytic activity of both neutrophils and macrophages and hence contains the infection. In case of a poor innate immune response and minimal IL-12 production, a weak Th1 response may not contain the infection. Mast cell stimulation and the subsequent production of IL-4 would encourage a Th2 response, B-cell activation, and antibody production. If these antibodies are protective and clear infections, the disease will not progress but if they are not protective, as in the case of IgG2, the lesion will persist. Continued B-cell activation may result in large amounts of IL-1 and hence tissue destruction.
Innate and adaptive immune responses are important responses that are elicited in response to Gram-negative anaerobes causing the periodontal infection. This response actually protects the individual from the harmful effects of bacteria by causing the lysis of various bacterial species but at the same time also cause damage to host tissues in the form of loss of periodontium, alveolar bone loss, etc.
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Conflicts of interest
There are no conflicts of interest.
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