Host Response to periodontal disease

host response to periodontal disease
the tissue of periodontium are exposed to various environmental factors in the oral cavity. over 300 species of bacteria have been isolated in the oral cavity. the periodontal tissue remain in a state of partnership (symbiosis) with most of the bacteria and only under certain circumstances do we suffer from their attack because, host defense system strikes the balance in host defense mechanisms.
role of saliva in host defense
1- a vehicle for swallowing bacteria.
2- inhibition of attachment of bacteria.
3-bacteriocidal action by the peroxidase system.
4-bacteriocidal action by lysozyme, lactoferrin and other factors. non specific salivary factors include peroxidase
scn ? + h2o2 ? hoscn hypothiocyanous kill bacteria thiocyanate from
salivary gland generated by salivary glands, bacteria, neutrophils
the non specific components in saliva is peroxidase is synthesized by salivary gland acini and secreted in to saliva, where it becomes bound to bacteria and thiocyanate is secreted into saliva by the ductal cells.
lactoferrin: it secreted by salivary gland, which bind iron, an important growth factor for microorganisms.
lysozyme: it is antimicrobial enzyme in the saliva it degrade mucopeptides in the cell wall of gram negative bacteria causing lyses. while specific components in saliva is secretory iga, the most important ig present in saliva, it resistant to microbial and suited for saliva, mainly derived locally from plasma cells. it inhibit microbial adherence to the oral surface.
gingival epithelium: has three functions:
epthelial cells are tightly attached to each other.2. keratinization to resist trauma. 3. presence of permeability barriers.
gingival cervicular fluid: gingival cervicular function are : washing non adherent bacteria and their products out of the crevice, reducing the diffusion of plaque products in to the tissues. 3- it also carries a steady supply of inflammatory mediators, protease inhibitors and host defence agent such as complement and antibody into the crevice.
complement
complement is considered as part of the innate immunity because of its role in inflammation, phagocytosis and bacterial killing. complement may be activated by bacterial invasion, but also by reactions between antigens and antibodies, and therefore, it may play a role in adaptive immunity, as well. complement is an enzymatic system of serum proteins made up of nine major components (c1 - c9) that are sequentially activated during two pathways, the classical pathway (the sequence is c1,c2,c3,c4,c5,c6,c7,c8,c9) and the alternative pathway(the sequence is c3,c4,c5,c6,c7,c8,c9), resulting in a variety of antibacterial defenses. complement components play a part in phagocytic, chemotaxis, opsonization and the inflammatory response, and may be involved in the lysis of certain bacteria, some viruses, and other microorganisms. complement is activated in the classical pathway by reactions between antibodies and antigens on the surface of a microbe. some immunoglobulins (i.e., igg and igm) can "fix complement" because they have a complement binding site on the fc portion of the molecule. the reaction between igg and ag activates the complement and initiates a "cascade reaction" on the surface of the microbe that results in the principal effects of complement which are:
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1. generation of inflammatory factors, c3a and c5a, which focus antimicrobial serum factors and leukocytes into the site of infection.
2. attraction of phagocytes. chemotactic factors c3a and c5a attract phagocytes to the site.
3. enhancement of phagocytic engulfment. c3b component on ag - ab complex attaches to c3b receptors on phagocytes and promotes opsonization of ab-coated cells. c3b-opsonization is important when ab is igm because phagocytes have receptors for fc of igm only when it is associated with c3b.
4. lysis of bacterial cells (lysozyme-mediated) or virus-infected cells. when c8 and c9 are bound to the complex, a phospholipase is formed that destroys the membrane of ag-bearing host cells (e.g. virus-infected cells) or the outer membrane of gram-negative bacteria. lysozyme gains access to peptidoglycan and completes destruction of the bacterial cell.
in addition to the classical pathway of complement activation, an alternative pathway (sometimes called the "properdin pathway") of complement activation exists, which is independent of immunoglobulins. insoluble polysaccharides (including bacterial lps, peptidoglycan and teichoic acids) can activate complement. this allows antibody-independent activation of the complement cascade that is thought to be important in initial (pre-antibody) defense against various types of infections caused by bacteria.
figure 1. the complement cascade, precipitated by certain antigen-antibody reactions (classical pathway) or by bacterial polysaccharides (alternative pathway), leads to four principal antimicrobial effects: 1. phagocytes are attracted to the site (polymorph accumulation) 2. inflammatory agents re produced and/or released from cells (inflammation) 3. microbes are opsonized to enhance uptake by phagocytic cells (phagocytosis) 4. gram-negetive bacteria are lysed in the presence of lysozyme (lysis of microbe).
figure 2-19
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figure 2-35
the inflammatory cell response
phagocytic defenses
when invading an pathogen penetrates the tissues, the inflammatory response is immediately brought into play. part of this response leads to the recruitment of phagocytes at the site of inflammation. phagocytes are a class of cells which are capable of ingestion (engulfment) and destruction of microorganisms and viruses that are responsible for inciting the inflammatory response. first to accumulate around the invaders and initiate the phagocytic process are neutrophils. later, local and blood-borne macrophages also migrate to the tissue site and initiate phagocytosis. neutrophils (also known as polymorphonuclear leucocytes or pmns) and macrophages are sometimes referred to as professional phagocytes for their roles in this process.
properties of neutrophils
neutrophils have their origin in multi-potential stem cells in the bone marrow. they differentiate in the marrow and are released in a mature form, containing a full complement of bactericidal agents. they are short-lived cells which constitute 30-70% of the circulating white blood cells (leukocytes). during differentiation in the marrow (2-3 days) the nucleus of the cell becomes multilobed (hence the name polymorphonuclear leukocyte), cell division ceases, and mitochondria and endoplasmic reticulum disappear from the cytoplasm. at the same time the cell becomes motile and actively phagocytic. cytoplasmic granules are formed from the golgi apparatus. these membranous granules are called lysosomes and contain the various bactericidal and digestive enzymes which can destroy bacterial cells after engulfment. the contents of lysosomes include lysozyme, cationic proteins, acid hydrolases, proteases, peroxidase and lactoferrin. neutrophils also contain large store of glycogen since they derive most of their metabolic energy from glycolysis, they can function efficiently in anaerobic environments. once a neutrophil enters the tissues, it never returns to the circulation.
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when the neutrophils migrate across the endothelium it is called rolling and margination. when the neutrophils migrate across the endothelium it is called diapedesis and interendothelial transmigration. hense there are two phases of leukocyte endothelial adherence.
a. the selectin-dependent phase primary in rolling and margination. b. the integrin-dependent phase (primarily in diapedesis).
the selectin-dependent phase: the various selectins are:
1- l-selectin-express on the surface of leukocyte.
2- p-selectin-stored in the granules of endothelial cells(weibel-palade bodies).
3- e-selectin-expressed by endothelial cells.
p-selectin and e-selectin:they both strengthen the binding between the leukocyte and the endothelial cell and increase the number of leukocyte rolling.the integrin-dependent phase: (leukocyte b2-integrins): the three leukocyte integrines are sequestered in the specific granules of leukocytes.
lfa-1-leukocyte function-associated antigen-1. cd11a\cd18 or mac-1 /cd11b/cd 18.
cd11c/cd18
these leukocyte b2-integrins act as the molecular mediators of binding to the endothelial cells and their binding affinity can be increased or decreased as the leukocyte traverses the postcapillary venule.
properties of macrophages
macrophages (also called mononuclear phagocytes) also arise from bone marrow stem cells which give rise to promonocytes which develop into monocytes that are released into the blood stream. monocytes make up 3-7% of the circulating white blood cells. the monocyte is actively phagocytic and and bactericidal. within 2 days or so, the blood stream monocytes (sometimes called wondering macrophages) emigrate into the tissues where they settle down, enlarge and become fixed macrophages (tissue histiocytes), which also have phagocytic potential. macrophages are more active in phagocytosis than monocytes and develop many more granules containing hydrolytic enzymes. new macrophages can develop by cell division under inflammatory stimuli, but most macrophages are matured blood monocytes.
the total pool of macrophages is referred to as the system of mononuclear phagocytes. the system is scattered throughout connective tissue, basement membranes of small blood vessels, liver sinusoids, the spleen, lung, bone marrow and lymph nodes. monocytes from the blood migrate into virtually every organ in the body where they mature into fixed macrophages. in the lymph nodes, they function as scavengers to remove foreign material from the circulation.
compared to neutrophils, macrophages are long-lived cells. as phagocytes, neutrophils play a more important role in the acute stages of an infection, while macrophages are principally involved in chronic types of infections. neutrophils circulate in the blood stream, and during an
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acute inflammatory response they migrate through the endothelial cell junctions as part of the inflammatory exudate. they migrate to the focus of the infection and ingest or "phagocytose" the foreign agents. neutrophils which have become engorged with bacteria usually die and largely make up the material of pus.
macrophage functions in the gingival, crevice and pocket.
macrophages attracted to the area during an inflammatory response, are slower to arrive and become increasingly involved in chronic infections. they, too, are actively phagocytic and will engulf and destroy foreign particles such as bacteria. however, macrophages have another indispensable function in host defense: they "process" the antigenic components of infective agents and present them to lymphocytes, a process that is usually required for the initiation of the adaptive immune responses of the host. for this activity, macrophages are known as antigen-presenting cells or apc s and they are an important bridge between the innate defenses and the adaptive immune response. macrophage secrete cytokines, most significant cytokine is il-1 which is a key mediator both in inflammation and immunity induced by bacteria. tnf (tumor necrosis factor) is also produced by macrophage. both il-1 and tnf have similar functions. they increase inflammation by releasing histamine from mast cells, attracting neutrophils and more macrophage into the tissue and by causing many other cell to release prostaglandins. macrophage can mediate a small amount of bystander damage. the damage could be caused by direct effect that is by secreting enzymes and toxins (similar to neutrophils) and indirectly by secretion of cytokines. in excess amount il-1 and tnf can have several damaging effects such as stimulation of bone resorption and tissue fibrosis. other cells such as mast cells, fibroblast, endothelial cells, plasma cells and epithelial cells are also seen in the gingival connective tissue during inflammatory response.
the phagocytic process
phagocytosis and destruction of engulfed bacteria involves the following sequence of events: 1. delivery of phagocytic cells to the site of infection
2. phagocytic adherence to the target
3. ingestion or engulfment of the target particle
4. phagolysosome formation
5. intracellular killing
6. intracellular digestion (and diegestion, in the case of macrophages)
these steps involved in the phagocytic process in macrophages are illustrated below.
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figure 1. phagocytosis by a macrophage. a bacterium, which may or may not be opsonized, is engulfed by the process of endocytosis. the bacterium is ingested in a membranous vesicle called the phagosome. digestive granules (lysosomes) merge with phagosome, release their contents, and form a structure called the phagolysosome. the killing and digestion of the bacterial cell takes place in the phagolysosome. the macrophage egests debris while processing the antigenic components of the bacterium, which it returns to its surface in association with mhc ii for antigen presentation to t cells.
delivery of phagocytic cells to the site of infection
the delivery of phagocytic cells, monocytes or neutrophils, to the site of microbial infection
involves two processes:
diapedisis: the migration of cells across vascular walls which is initiated by the mediators of inflammation (kinins, histamine, prostaglandins, etc.)
chemotaxis. phagocytes are motile by ameboid action. chemotaxis is movement of the cells in response to a chemical stimulus. the eventual concentration of phagocytes at a site of injury results from chemotactic response by the phagocytes which is analogous to bacterial chemotaxis. a number of chemotactic factors (attractants) have been identified, both for neutrophils and monocytes. these include bacterial products, cell and tissue debris, and components of the inflammatory exudate such as peptides derived from complement.
phagocytic adherence
phagocytosis is initiated by adherence of a particle to the surface of the plasma membrane of a phagocyte. this step usually involves several types of surface receptors on the phagocyte membrane. three major receptors on phagocytes recognize the fc portion of igg antibody molecules: one is for monomeric igg and the others are for antigen-crosslinked iggs. another receptor binds a complement factor, c3b. other phagocyte receptors bind fibronectin and mannose-terminated oligosaccharides. under certain circumstances of infection, bacteria or viruses may become coated or otherwise display on their surfaces one or another of these substances (i.e., igg, c3b, fibronectin or mannose). such microbes are said to be opsonized and such substances as igg or complement c3b bound to the surface of microbes are called opsonins. (opsonin comes from a greek word meaning "sauce" or "seasoning": they make the bacterium or virus more palatable and more easily ingested by the phagocyte.) opsonins provide extrinsic ligands for specific receptors on the phagocyte membrane, which dramatically increases the rate of adherence and ingestion of the pathogen. opsonized bacteria can be cleared from the blood by phagocytes many types of non opsonized bacteria cannot be cleared.
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less firm attachments of a phagocyte to a particle can take place in the absence of opsonization. this can be thought of as nonspecific attachment which might be due to net surface charge on the phagocyte or particle and/or hydropinghobicity of the particle.
ingestion
after attachment of the phagocyte to its target, some sort of signal generation, which is poorly understood, results in physical or chemical changes in the cell that triggers ingestion. ingestion is an engulfment process that involves infolding or invagination of the cell membrane enclosing the particle and ultimately releasing it into the cytoplasm of the cell within a membrane vesicle. the end result of ingestion is entry of the particle enclosed in a vesicle derived from the plasma membrane of the cell. this structure is called the phagosome.
formation of the phagolysosome
the phagosome migrates into the cytoplasm and collides with lysosomal granules which explosively discharge their contents into the membrane-enclosed vesicle (phagosome). membranes of the phagosome and lysosome actually fuse resulting in a digestive vacuole called the phagolysosome. other lysosomes will fuse with the phagolysosome. it is within the phagolysosome that killing and digestion of the engulfed microbe takes place. some of the microbicidal constituents of the lysosomes of neutrophils and macrophages include lysozyme, cationic proteins, various proteases and hydrolyases and peroxidases. the killing processes are confined to the membranous organelles of the phagocytes (the phagolysosome) such that none of the toxic substances and lethal activities of the phagocytes are turned against themselves.
intracellular killing of organisms
after phagolysosome formation the first detectable effect on bacterial physiology, occurring within a few minutes after engulfment, is loss of viability (ability to reproduce). inhibition of macromolecular synthesis occurs later. by 10 to 30 minutes after ingestion many pathogenic and nonpathogenic bacteria are killed followed by lysis and digestion of the bacteria by lysosomal enzymes. the microbicidal activities of phagocytes are complex and multifarious. metabolic products, as well as lysosomal constituents, are responsible. these activities differ to some extent in neutrophils, monocytes and macrophages.
the microbicidal activities of phagocytes are usually divided into oxygen-dependent and oxygen-independent events
oxygen-independent activity
lysosomal granules contain a variety of extremely basic proteins that strongly inhibit bacteria, yeasts and even some viruses. a few molecules of any one of these cationic proteins appear able to inactivate a bacterial cell by damage to their permeability barriers, but their exact modes of action are not known. the lysosomal granules of neutrophils contain lactoferrin, an extremely powerful iron-chelating agent, which withholds potential iron needed for bacterial growth. the ph of the phagolysosome may be as low as 4.0 due to accumulation of lactic acid, which is sufficiently acidic to prevent the growth of most pathogens. this acidic environment apparently optimizes the activity of many degradative lysosomal enzymes including lysozyme, glycosylases, phospholipases, and nucleases.
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oxygen-dependent activity
liganding of fc receptors (on neutrophils, monocytes or macrophages) and mannose receptors (on macrophages) increases their o2 uptake, called the respiratory burst or "oxygen burst". these receptors activate a membrane-bound nadph oxidase that reduces o2 to o2- (superoxide). superoxide can be reduced to oh. (hydroxyl radical) or dismutated to h2o2 (hydrogen peroxide) by superoxide dismutase. o2-, oh., and h2o2 are activated oxygen species that are potent oxidizing agents in biological systems which adversely affect a number of cellular structures including membranes and nucleic acids. furthermore, at least in the case of neutrophils, these reactive oxygen intermediates can act in concert with a lysosomal enzyme called myeloperoxidase to function as the myeloperoxidase system, or mpo.
myeloperoxidase is one of the lysosomal enzymes of neutrophils which is released into the phagocytic vacuole during fusion to form the phagolysosome. myeloperoxidase uses h2o2 generated during the respiratory burst to catalyze halogenation (mainly chlorination) of microbes contained within the phagolysosome. such halogenations are a potent mechanism for killing cells.
when the nadph oxidase and myeloperoxidase systems are operating in concert, a series of reactions leading to lethal oxygenation and halogenation of engulfed microbes occurs.
intracellular digestion
dead microbes are rapidly degraded in phagolysosomes to low molecular-weight components. various hydrolytic enzymes are involved including lysozyme, proteases, lipases, nucleases, and glycosylases. neutrophils die and lyse after extended phagocytosis, killing, and digestion of bacterial cells. this makes up the characteristic properties of pus.
macrophages egest digested debris and allow insertion of microbial antigenic components into the plasma membrane for presentation to lymphocytes in the immunological response.
neutrophil disorders associated with periodontal diseases
1-diabetes mellitus.
2-papillon lefever syndrome.
3-downs-syndrome.
4.chediak-higashi syndrome.
5.drug-induced agranulocytosis.
6.cyclic neutropenia.
periodontal disease associated with neutrophil disorders acute necrotizing ulcerative gingivitis (anug).
localized juvenile periodontitis (ljp).
prepubertal periodontitis (ppp).
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rapidly progressive periodontitis (rpp). refractory periodontitis (rp).
lymphocytes: three types of cells included,
t-lymphocytes or t-cells: derived from the thymus and play a role in cell mediated immunity. b-lymphocytes or b-cells: derived from liver, spleen and bone marrow. they are precursors for plasma cells and play a role in humoral immunity.
3. natural killer (nk) cells.
t-cells t lymphocytes are usually divided into two major subsets that are functionally and phenotypically different. t helper (th) cells, also called cd4+ t cells, are involved in coordination and regulation of immunological responses. they function to mediate responses by the secretion of lymphokines that stimulate or otherwise affect other cells involved in the immune responses.
the second subset type of t lymphocytes are cytotoxic t lymphocytes ( tc cells or ctls) or cd8+ t cells. these cells are involved in directly killing certain tumor cells, virus-infected cells, transplant cells, and sometimes eucaryotic parasites. cd8+ t cells are also important in down-regulation of immune responses.
the immunological response
immunological responses are associated with macrophages or dendritic cells and two
subpopulations of lymphocytes, b-cells and t-cells.
under antigenic stimulus, b-lymphocytes become transformed into antibody-secreting plasma cells. the plasma cells synthesize large amounts of immunoglobulins (antibodies) under the control of helper and suppressor t- lymphocytes which will react stereochemically with the stimulating antigen.the antibody predominantly is igg, which can opsonize and activate complement. small amount of igm is also seen which is more an activator of the complement and less of an effective opsonin. theses antibodies pass into the gingival inflammatory exudates and then out into the gingival crevice in the cervicular fluid. possible mechanisim of action of antibodies in the periodentitis: 1:binding to bacteria, thus: a-opsonizing for phagocytosis b: activationg neutrophile enzyme secretion c: coating bacteria and inhibiting attachment d: activating complement and thus enhancing opsonization. e: directly inhibiting bacterial metabolisim.2: binding to soluble factors thus:a: nurtalizing toxins b: inhibiting enzymes.
under antigenic stimulus, pre t-lymphocytes differentiate into several classes of effector t cells which are committed to various activities upon recognition of the specific antigen that induced their formation. t cells have many activities relevant to immunity including (1) mediation of the b-cell response to antigen (2) ability to recognize and destroy cells bearing foreign ag on their surface and (3) production of a variety of diffusible compounds called cytokines and/or lymphokines, which include substances that are activators of macrophages, mediators of inflammation, chemotactic attractants, lymphocyte mitogens, and interferon. cytokines and lymphokines are molecules (peptides, proteins) produced by cells as a means of intercellular communication. generally, they are secreted by a cell to stimulate the activity of another cell. cell mediated immune responses in periodontal diseases: it is so called because it involves contact between cytotoxic t-cell and the target to be destroyed. these reactions are
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effective against persistent antigens, which are resistant to degradation, and the cells infected with viruses and tumor cells.
the overall aspects of the induction of an immunological response (ami and cmi) are shown in the following schematic diagram.
figure 3. schematic diagram of the development of the immune responses
immunological mechanisms
micro-organisms and their products are recognized as being different from the host because they contain structures, which are not found in the human body. these called antigens (antibody-generating) are first recognized by lymphocytes and each lymphocyte are capable of recognizing only one foreign antigen and when contact with antigen is triggered to divide several times and therefore with in few days there are many more cells with the same specificity. this amplification process is known as clonal expansion. this will result the production of larger pool of cells, which are differentiated to protect the host either by humoral or cell-mediated mechanisms. humoral responses are carried out by lymphocytes, which differentiate into plasma cells secrete antibody and cmi do not require antibody but depend on clonal expansion to provide large number of lymphocytes, which destroy targets directly. this direct effect of an immune reaction against a foreign antigen results in significant tissue damage is referred to as hypersensitivity reaction.
anaphylaxis is a severe, whole-body allergic reaction to a chemical that has become an allergen substance that can cause an allergic reaction).
type-1 or anaphylactic reactions: it is also called regain-dependent reactions: two variations of the anaphylactic hypersensitivity depending on the route of antigen administration, if injected locally into skin, the reaction is called cutaneous anaphylaxis. if ag injected intravenously it is called systemic or generalized anaphylaxis.
mechanisms of anaphylactic hypersensitivity: anaphylaxis occurs when two ige antibodies that are fixed to a mast cell or basophile react with the antigen through the fab portion of the antibody-antigen reaction causes the release of pharmacologically-active substances from sensitized cells. these mediators released by the human mast cells include: a: histamine- increased capillary permeability. b: alpha 2-macroglobulins-collagenase activation: srs-a- smooth muscle contraction.
type-ii: cytotoxic reactions in cytotoxic type, antibodies react directly with antigens tightly bound to cells. a cytotoxic reaction involving these cells will result in hemolysis. cytotoxic antibodies are of igg or igm class. in addition to inducing cell lysis, cytotoxic abs may cause tissue damage by increasing syntheses of lysozymal enzyme by cells(pmn). the tissue in the vicinity of these enzymes will be then damaged. cytotoxic reaction is seen in autoimmune
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diseases when antibody react with own tissue components. for example, this occurs in pemphigus where antibodies react with cell membranes and epithelial basement membrane. to date evidence suggest an important role for the cytotoxic reaction in the gingivitis and periodontitis.
type iii: immune complex or arthus reactions: when high level of ags are present, antigen-antibody complexes precipitate in and around small blood vessels and with subsequent complement activation cause tissue damage at the site of local reaction.
type iv: cell mediated or delayed hypersensitivity: cellular immunity dose not include circulating antibodies but it based on the interaction of the antigens with the surface of t- lymphocytes.
prepared by
prof. dr. raad ali
a. prof. dr. zainab almahdi
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