Acace my - eports
`
`Informational Paper
`The Pathogenesis of Periodontal Diseases
`
`This informational paper was prepared by the Research, Science, and Therapy Committee of The
`American Academy of Periodontology, and is intended for the information of the dental profession. The
`purpose of the paper is to provide an overview of current knowledge relating to the pathogenesis of
`periodontal diseases. The paper will review biological processes thought to provide protection against
`periodontal infections. It will further discuss the mechanisms thought to be responsible for both over-
`coming and subverting such protective mechanisms and those that lead to destruction of periodontal
`tissues. Since an understanding of pathogenic mechanisms of disease is one foundation upon which
`new diagnostic and therapeutic modalities are based, the practitioner can use this information to help
`make decisions regarding the appropriate application of such new modalities in patient care settings. J
`Periodontol 1999;70:457470.
`
`p athogenesis deals with the mode of origin
`
`or development of disease. In this paper,
`currently accepted concepts of the origin
`and progression of gingivitis and periodontitis are
`discussed. Since nearly all of the periodontal dis-
`eases are associated with and thought to be
`caused by microorganisms, some references to
`etiologic agents are of necessity utilized, particu-
`larly when certain disease processes are clarified
`by example.
`Periodontal diseases comprise a variety of
`conditions affecting the health of the periodon-
`tium. Although the classification scheme defined
`at the 1989 World Workshop in Clinical
`Periodontics subdivided these diseases into a
`number of clinically defined subforms, 1 subse-
`quent attempts to categorize patients according
`to the defined criteria have demonstrated the
`considerable problem of overlap in the disease
`definitions. 2 Furthermore, many of the microbio-
`logical and host response features of these dis-
`eases are common to several of the subforms of
`periodontitis. It has been the consensus of sev-
`eral groups, including the 1996 World Workshop
`in Periodontics,3 that the current classification
`scheme requires revision. Such a revision could
`lead to considerably improved diagnostic cate-
`gories if the disease definitions were dependent
`upon knowledge of the etiology and pathogene-
`sis of the various disease subforms as well as
`
`* This paper was developed under the direction of the Committee
`on Research, Science and Therapy and approved by the Board
`of Trustees of The American Academy of Periodontology in
`January 1999.
`
`upon more traditional parameters such as signs
`of inflammation, probing depths, clinical attach-
`ment loss, and age of onset.
`Thus, although considerable progress has
`been made in defining both etiologic agents and
`pathways of pathogenesis in various forms of
`periodontal diseases, insufficient information
`exists to definitively recategorize these diseases.
`The approach to describing pathogenic mecha-
`nisms in this paper will, therefore, be in part
`generic and thus refer to "gingivitis" and "peri-
`odontitis" rather than to specific disease sub-
`forms. Where appropriate, descriptions of evi-
`dence for specific or unique pathways associated
`with specific forms of disease (as defined at the
`1989 World Workshop in Clinical Periodontics)
`will be presented.
`PATHOGENESIc (cid:9)
`INGIVITIc
`Chronic marginal gingivitis is characterized clini-
`cally by gingival redness, edema, bleeding,
`changes in contour, loss of tissue adaptation to
`the teeth, and increased flow of gingival crevicu-
`lar fluid (GCF). 4,5 Development of gingivitis
`requires the presence of plaque bacteria 8,7 which
`are thought to induce pathological changes in
`the tissues by both direct and indirect means. 8
`Ilistopathologic observations have led to the
`subdivision of gingivitis into 3 stages. 8-10 The ini-
`tial lesion appears as an acute inflammatory
`response with characteristic infiltration with neu-
`trophils. Vascular changes, epithelial cell
`changes, and collagen degradation are apparent.
`These initial changes are likely due to chemotac-
`
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`tic attraction of neutrophils by bacterial con-
`stituents and direct vasodilatory effects of bacter-
`ial products, as well as activation of host systems
`such as the complement and kinin systems and
`arachidonic acid pathways) 1,12
`The early lesion is characterized by a lym-
`phoid cell infiltrate dominated by T lymphocytes,
`with extension of collagen loss, while the estab-
`lished lesion is dominated by B lymphocytes and
`plasma cells. Although direct evidence for spe-
`cific mechanisms explaining the appearance and
`progression of gingivitis lesions is not available,
`the chronic inflammatory infiltrate characteristic
`of the early and established lesions, as well as
`the proliferation of the junctional epithelium and
`destruction of collagen, are consistent with the
`activation of mononuclear phagocytes and
`fibroblasts by bacterial products with the recruit-
`ment and activation of the local immune system
`and cytokine pathways. The progression of the
`lesion from acute inflammation through T cell
`and then B cell predominance is likely orches-
`trated by a progression of cytokines (dealt with in
`more detail below) which are responsible for
`recruitment, differentiation, and growth of the
`characteristic cell types with progressive chronic-
`ity of the lesion. Importantly, meticulous removal
`of plaque will usually result in resolution of the
`chronic gingivitis lesion without residual tissue
`destruction.
`Acute necrotizing ulcerative gingivitis
`(ANUG), an acute infection of the gingiva char-
`acterized by interdental soft tissue necrosis and
`ulceration, pain, and bleeding, 13 is characterized
`histologically by frank invasion of the gingival
`connective tissues by spirochetes and a predom-
`inance of Preuotella intermedia and Fusobac-
`terium nucleatum in the non-spirochetal flora. 13
`The association of ANUG with recent episodes of
`stress, or with other conditions of impaired host
`defense such as malnutrition, immunosuppres-
`sion, and systemic diseases, implicates any of a
`number of possible environmental and systemic
`stressors as pathogenic factors leading to the
`expression of the same syndrome. 14-2° A com-
`mon feature of nearly all cases is very poor oral
`hygiene, and nearly all cases can be managed
`with local debridement, improved plaque control,
`and judicious use of antibiotics.
`Pathologic changes in the gingival tissues con-
`sistent with clinically chronic or acute gingivitis
`have been noted in a number of systemic condi-
`
`tions.21-23 Some of these conditions may mimic
`the vascular alterations seen in plaque-induced
`gingivitis or result in cellular infiltration by aber-
`rant leukocytes or other vascular elements.
`These include acute leukemia, hemophilia,
`Sturge-Weber syndrome, and Wegener's granulo-
`matosis. In other cases a defective host response
`to bacterial infection may be manifested as an
`overexpression of gingival inflammation or
`caused by an alteration in the usual bacterial
`microflora. Such conditions include Addison's
`disease, diabetes mellitus, thrombocytopenia,
`combined immunodeficiency diseases, and HIV
`infection. A third group of these conditions is
`related to hormonal changes manifested as an
`exaggerated inflammatory response to plaque as
`well as an alteration in the subgingival
`microflora. These include changes associated
`with pregnancy, puberty, steroid therapy, and use
`of birth control medications. 24-27 Finally, a large
`number of drugs, many of which are associated
`with therapy for seizure disorders, hypertension,
`or transplant rejection, cause gingival enlarge-
`ment in the presence of bacterial plaque. 28-33
`
`PATHOGENESIS OF PERIODONTITIS
`Periodontitis is clinically differentiated from gin-
`givitis by the loss of the connective tissue attach-
`ment to the teeth in the presence of concurrent
`gingival inflammation.34 Loss of the periodontal
`ligament and disruption of its attachment to
`cementum, as well as resorption of alveolar bone
`occurs. Together with loss of attachment, there is
`migration of the epithelial attachment along the
`root surface and resorption of bone. 9 The
`histopathology of the periodontitis lesion is in
`many ways similar to that of the established
`lesion of gingivitis, with a predominance of
`plasma cells, loss of soft connective tissue ele-
`ments, and, in addition, bone resorption.
`Despite the histopathologic similarities
`between gingivitis and periodontitis, evidence is
`lacking that would indicate that periodontitis is
`an inevitable consequence of gingivitis.
`Furthermore, the pathogenic mechanisms
`explaining the progression of gingivitis lesions to
`periodontitis lesions are not clear, and the factors
`that lead to the initiation of periodontitis lesions
`are unknown. Clinical models of disease activity
`in periodontitis range from a continuous progres-
`sion of disease during which loss of attachment
`occurs at a slow rate over long periods of time to
`
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`an episodic burst model in which loss of attach-
`ment occurs relatively rapidly during short peri-
`ods of disease activity. 35-37 Clinical data indicate
`that either mechanism could be operant in differ-
`ent patients or at different sites or at different
`times within the same patient, implying that the
`pathogenesis of periodontal attachment loss
`could differ between patients and sites and times.
`Understanding the pathologic mechanisms
`involved still awaits measurement methods that
`clearly differentiate between active and quiescent
`disease.
`Bacterial Virulence
`It is widely accepted that the initiation and pro-
`gression of periodontitis are dependent upon the
`presence of microorganisms capable of causing
`disease. Although more than 300 species of
`microorganisms have been isolated from peri-
`odontal pockets, it is likely that only a small per-
`centage of these are etiologic agents. 38 Among
`the characteristics that implicate an organism or
`group of organisms as etiologic agents are bacte-
`rial virulence factors. These are bacterial con-
`stituents or metabolites capable of either causing
`disruption of homeostatic or protective host
`mechanisms or causing the progression or initia-
`tion of the disease. If such bacterial virulence
`characteristics are truly contributing to disease
`pathogenesis, modification of such virulence fac-
`tors should result in an improvement in clinical
`condition. Thus, the pathogenesis of periodontal
`disease lesions is in part dependent upon the vir-
`ulence as well as the presence and concentra-
`tions of microorganisms capable of producing
`disease.
`At least 3 characteristics of periodontal micro-
`organisms have been identified that can con-
`tribute to their ability to act as pathogens: the
`capacity to colonize, the ability to evade anti-
`bacterial host defense mechanisms, and the abil-
`ity to produce substances that can directly initi-
`ate tissue destruction. It is now apparent that
`within a given pathogenic species, such as
`Actinobacilius actinomycetemcomitans or
`Porphyromonas gingivalis, only a subset of bac-
`terial types or clonal or genetic subtypes may be
`pathogenic. 39'4° Thus the presence of a patho-
`genic bacterial species in the subgingival plaque
`may not by itself imply that a pathogen is pre-
`sent with virulence characteristics necessary to
`initiate or propagate periodontitis lesions. For
`example, recent data indicate that strains of A.
`
`actinomycetemcomitans in young patients with
`localized juvenile periodontitis differ from those in
`older patients with previously active disease in
`their ability to produce a leukotoxin that is
`thought to be an important virulence characteris-
`tic of this species. 39
`Bacteria need to possess the ability to survive
`and propagate in periodontal pockets in the
`complex ecosystem of the biofilm. Some exam-
`ples of factors that have been identified as pro-
`moting virulence of important periodontal
`pathogens follow. Virulent organisms can express
`appendages such as fimbriae or molecules such
`as adhesins which promote association with tis-
`sues or other bacteria. 41,42 Furthermore, viru-
`lence can be enhanced via the presence of a
`capsular polysaccharide (as in the case of P gin-
`givalis) which provides resistance to host
`defenses such as antibody and complement.
`Some organisms are able to invade into or
`through host tissues, thereby creating a
`sequestered environment for their protection and
`gaining more direct access to susceptible host
`tissues. Two major periodontal disease patho-
`gens, A. actinomycetemcomitans and P gingi-
`ualis, are able to invade into the tissues. A. actin-
`omycetemcomitans can pass through epithelial
`cells into the underlying connective tissues, 43
`while P gingivalis can invade and persist in
`epithelial cells. 44,45 It is likely that tissue inva-
`siveness of these organisms may explain the dif-
`ficulty in eradicating A. actinomycetemcomitans
`by mechanical root debridement, and could also
`explain the relatively high concentrations of
`serum antibody reactive with these two species
`in comparison with other bacteria in dental
`plaque.
`An important feature of nearly all pathogenic
`microorganisms is the ability to evade the host
`defense mechanisms that would ordinarily con-
`trol such infections and prevent disease.
`Foremost among these defense mechanisms in
`the periodontium is clearance of bacteria by neu-
`trophils with the assistance of antibodies and
`complement proteins. 48,47 In health, neutrophils
`appear to form a barrier at the plaque-tissue
`interface, controlling bacterial numbers and pre-
`venting ingress of bacteria or their products to
`the tissue surface. The immune system typically
`assists the neutrophil by producing antibody
`molecules that opsonize bacteria; such opsonic
`antibodies, alone or in concert with the comple-
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`ment system, allow the neutrophil to recognize,
`ingest, and degrade bacteria. The local reposi-
`tory of such antibody molecules is the gingival
`crevicular fluid (GCF), a modified inflammatory
`exudate which flows through the junctional and
`sulcular epithelium into the gingival crevice or
`pocket. Amongst a large variety of other mole-
`cules, the GCF contains serum components such
`as antibody molecules, 48 locally produced anti-
`body molecules49 and other substances, such as
`neutrophil granule constituents, 50,51 that can be
`reflective of local immunology and inflammatory
`processes. Antibacterial antibodies can provide
`many protective functions. Opsonic antibodies
`promote phagocytosis via interactions with
`phagocyte Fc receptors. 52-54 In some cases, anti-
`bodies can activate the complement system, an
`antibacterial cascade of naturally occurring pro-
`teins, which can deposit additional opsonins on
`the bacterial surface, release chemical mediators
`that recruit additional neutrophils, and deposit
`macromolecular complexes into the bacterial sur-
`face that will lyse and kill certain bacteria.
`Antibodies may also be produced that will specifi-
`cally neutralize bacterial toxins and enzymes, 48,55
`or that will disrupt bacterial colonization by pre-
`venting adherence to the tooth or epithelial sur-
`face or to other bacteria. 56
`Little is known about the sequence of events
`leading to the initial breakdown of this barrier
`and subsequent initiation of periodontitis. A great
`deal is known, however, about the mechanisms
`evolved by some periodontal bacteria to over-
`come this protective mechanism, and some
`examples of this are given below. Some organ-
`isms, such as strains of A. actinomycetemcomi-
`tans 57 or Campy tobacter rectus,58 produce
`leukotoxins that can kill neutrophils directly, thus
`disrupting the primary antibacterial defense
`mechanism in the gingival crevice. Secondly,
`some bacteria, such as P gingivalis, produce
`proteolytic enzymes that either directly degrade
`antibody and complement proteins in the sur-
`rounding serum or GCF or prevent the accumu-
`lation of these molecules on the bacterial
`surface. 55,59 This activity would prevent accumu-
`lation of complement-derived chemotactic fac-
`tors which would ordinarily recruit many addi-
`tional neutrophils to the site of infection, as well
`as retard the phagocytosis of both the proteolytic
`bacteria themselves and other bacteria that are in
`close proximity. Third, some bacteria such as A.
`
`actinomycetemcomitans produce factors that
`suppress the immune response to itself and other
`bacteria, 60, 61 thereby diminishing the production
`of otherwise protective antibodies. Finally, as
`mentioned above, some bacteria can invade tis-
`sue cells and avoid contact with neutrophils and
`molecules of the immune system. Thus, patho-
`genic bacteria appear to have devised a number
`of means by which they can evade control by
`neutrophils, either by directly decreasing their
`numbers or by destroying host mechanisms
`meant to promote opsonization, phagocytosis,
`and bacterial killing.
`The interaction between neutrophils, antibody,
`and complement provides primary protection
`against the deleterious effects of periodontal
`pathogens. In general, high levels of antibody do
`not appear in a patient's serum or GCF until
`some time after the disease process has initiated.
`High levels of antibodies reactive with bacterial
`virulence factors such as A. actinomycetemcomi-
`tans leukotoxin or P gingivalis proteases, or with
`whole bacterial antigen preparations, do not
`occur until relatively late in the disease process
`and probably do not play an important role in
`prevention of disease initiation. 48,62 However, it
`appears that in the case of the antibody response
`to A. actinomycetemcomitan.s and P gingivalis in
`early-onset periodontitis patients the extent and
`severity of disease is the least in patients with the
`highest titers; thus, some antibody responses to
`periodontal disease pathogens may ultimately
`prevent or delay progression of existing dis-
`ease.63,64
`
`Destruction of Periodontal Tissues
`The protective responses to periodontal
`pathogens may be overcome in a number of
`ways as outlined above, and the concentration of
`pathogens in subgingival plaque may reach a
`critical level required for initiation or progression
`of tissue destruction. Although at least two path-
`ogenic bacteria have been shown to invade the
`superficial layers of the periodontal tissues, it is
`readily apparent from histologic observation that
`pathologic effects on connective tissue and alve-
`olar bone occur at sites deep to the subgingival
`plaque and invading microorganisms. For this
`reason, in addition to the possible direct patho-
`logic effects of bacteria on the periodontal tis-
`sues, it is clear that damage to the periodontium
`must also occur by indirect means. Bacterial
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`products must gain access to the cellular con-
`stituents of the gingival tissues and activate
`cellular processes that are destructive to
`collagenous connective tissue and bone.
`Direct effects of bacteria. It is likely that direct
`pathological effects of bacteria and their products
`on the periodontium are significant during early
`stages of disease. Analysis of plaque samples
`from patients with increasingly severe levels of
`gingival inflammation reveals a succession of
`bacterial species with increased capacity to
`directly induce an inflammatory response. For
`example, increased and persistent levels of
`Fusobacterium nucleatum in sites of mild gingivi-
`tis and the consequent production of its metabolic
`by-products may directly affect the gingival vas-
`culature. The resulting edema and increase in
`production of GCF may provide the environment
`and nutrients that allow putative pathogens to
`flourish.38 Although it is unknown whether or not
`gingivitis is a prerequisite to development of a
`periodontitis lesion, it is reasonable that the alter-
`ation of the gingival environment by toxic or pro-
`inflammatory by-products of the gingivitis flora can
`set the stage for increased concentrations of more
`virulent microorganisms within the plaque mass.
`It is also likely that bacteria can contribute to
`the pathogenesis of periodontal diseases directly
`by many other means. P gingivalis, for example,
`is known to produce enzymes (proteases, colla-
`genase, fibrinolysin, phospholipase A) that could
`directly degrade surrounding tissues in the super-
`ficial layers of the periodontium. In addition it
`produces metabolic by-products such as H 2S,
`NH3, and fatty acids that are toxic to surrounding
`Cells.45,65-67 Furthermore, bacterial constituents
`such as lipopolysaccharide (LPS) are capable of
`inducing bone resorption in vitro. 68
`Indirect effects of bacteria. Once the major
`protective elements in the periodontium have
`been overwhelmed by bacterial virulence mecha-
`nisms, a number of host-mediated destructive
`processes are initiated. Polymorphonuclear
`leukocytes (PMNs), which normally provide pro-
`tection, can themselves contribute to tissue
`pathology. During the process of phagocytosis,
`these cells typically "spill" some of their enzyme
`content extracellularly during a process known
`as degranulation; some of these enzymes are
`capable of degrading the surrounding host tis-
`sues, namely collagen and basement membrane
`constituents, contributing to tissue damage.
`
`There is increasing evidence that the bulk of
`tissue destruction in established periodontitis
`lesions is a result of the mobilization of the host
`tissues via activation of monocytes, lympho-
`cytes, fibroblasts, and other host cells.
`Engagement of these cellular elements by bacte-
`rial factors, in particular bacterial lipopolysac-
`charide (LPS), is thought to stimulate production
`of both catabolic cytokines and inflammatory
`mediators including arachidonic acid metabolites
`such as prostaglandin E 2 (PGE2 ). Such
`cytokines and inflammatory mediators in turn
`promote the release of tissue-derived enzymes,
`the matrix metalloproteinases, which are destruc-
`tive to the extracellular matrix and bone. 89,70
`Once defensive mechanisms have been
`averted, the subgingival bacterial microflora has
`established itself as a predominantly anaerobic,
`Gram-negative infection. The pathologic appear-
`ance of the periodontitis lesion and the media-
`tors, mediator precursors, and mRNA protein
`templates recognizable either in the GCF or
`within cellular elements of the gingival tissues are
`consistent with the expected outcome of a local
`infection with Gram-negative bacteria. Cytokines,
`molecules which are released by host cells into
`the local environment, provide molecular signals
`to other cells thereby affecting their function.
`Many cytokines are produced by cells in peri-
`odontitis lesions. Among the cytokines and
`inflammatory mediators most consistently found
`to be associated with periodontitis are the follow-
`ing:
`1. Interleukin 1 (IL-1) 71 is a pro-inflammatory,
`multifunctional cytokine, which among its many
`biological activities enables ingress of inflamma-
`tory cells into sites of infection, promotes bone
`resorption, stimulates eicosanoid (specifically,
`PGE2) release by monocytes and fibroblasts,
`stimulates release of matrix metalloproteinases
`that degrade proteins of the extracellular matrix,
`and participates in many aspects of the immune
`response. IL-1 levels in general are elevated in
`both tissues 72,73 and GCF74-77 from diseased,
`inflamed periodontal tissues compared to health-
`ier sites, and elevated levels have been shown to
`be associated with active disease in animal mod-
`els. 78 The predominant form in the periodontal
`tissues is IL-la, which is produced primarily by
`macrophages. 79,80
`2. Interleukin 6 (IL-6) 81 is a cytokine that stim-
`ulates plasma cell proliferation and therefore
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`antibody production and is produced by lympho-
`cytes, monocytes, and fibroblasts. 80 Levels of IL-
`6 have been shown to be elevated in inflamed tis-
`sues, higher in periodontitis than in gingivitis
`tissues, and higher in GCF from refractory peri-
`odontitis patients. 82-84 IL-6 has also been shown
`to stimulate osteoclast formation. Thus, this
`cytokine may in large part account for both the
`predominance of plasma cells in periodontitis
`lesions as well as bone resorption.
`3. Interleukin 8 (IL-8) 85 is a chemoattractant
`that is mainly produced by monocytes in
`response to LPS, IL-1, or tumor necrosis factor
`alpha (TNF-a). It is present at high levels in peri-
`odontitis lesions, mainly associated with the
`junctional epithelium and macrophages, 86,87 and
`its levels in GCF are higher in periodontitis
`patients than in healthy controls. 88 In addition to
`serving as a chemoattractant for neutrophils, it
`appears to selectively stimulate matrix metallo-
`proteinase (MMP) activity from these cells, thus
`in part accounting for collagen destruction within
`periodontitis lesions.
`4. Tumor necrosis factor alpha (TNF-a) 89,90
`shares many of its biological activities
`(pro-inflammatory properties, matrix metallopro-
`teinase [MMPI stimulation, eiscosanoid produc-
`tion, and bone resorption) with IL-1. In addition,
`its secretion by monocytes and fibroblasts is
`stimulated by bacterial LPS.
`5. Prostaglandin E2 (PGE2 ), 91,92 a vasoactive
`eicosanoid produced by monocytes and fibro-
`blasts, induces bone resorption and MMP secre-
`tion. Many studies have shown the association of
`elevated levels of PGE2 in tissues and GCF with
`periodontal inflammation, progressive periodonti-
`tis, and high-risk periodontitis patients (e.g.,
`early-onset periodontitis, refractory periodontitis,
`diabetes mellitus). 93-1 m The likely importance of
`eicosanoids in periodontal disease pathogenesis
`is underscored in several studies demonstrating
`the beneficial effects of both systemic and topical
`non-steroidal anti-inflammatory drugs on peri-
`odontitis in both animal models and in
`humans.91,101-105
`In summary, a simplified model for pathogen-
`esis of periodontitis within the local lesion is the
`following: virulent microorganisms capable of ini-
`tiating or propagating periodontal attachment
`loss must be present in the local lesion at a criti-
`cal minimal infective dose. In susceptible individ-
`uals, or in susceptible periodontal sites within
`
`susceptible individuals, protective mechanisms
`are breached exposing the underlying tissues and
`cells to bacterial components. Consequently, cel-
`lular components, including monocytes and
`fibroblasts, are stimulated by bacterial compo-
`nents such as LPS to produce many or all of the
`cytokines described above. These cytokines are
`capable of acting alone, or in concert, to stimu-
`late inflammatory responses and catabolic
`processes such as bone resorption and collagen
`destruction via the MMPs.
`
`Genetic Factors Promoting Periodontitis
`As in any infectious disease, host susceptibility
`plays a major role in determining whether or not
`the presence of an infectious agent will ultimately
`lead to expression of disease or progression of
`preexisting disease. Genetic risk, one aspect of
`such host susceptibility, has been and is being
`examined. A summary of these data for specific
`periodontal diseases, appears below.
`Adult periodontitis. Studies of adult periodon-
`titis and periodontal health in twins have demon-
`strated that heredity accounts for a significant
`proportion of the population variance in various
`measures of periodontal diseases, such as gingi-
`val inflammation, probing depth, and radi-
`106-108
`ographic bone levels. (cid:9)
`Recent data indicate
`that a genetic variation or polymorphism in the
`gene encoding IL-1 (see above) is associated
`with severity of, and likely susceptibility to, peri-
`odontitis. 109 These polymorphisms are variations
`in the DNA sequence of genes coding for IL-la
`(the IL-1A gene) and IL-18 (the IL-1B gene). In a
`population of adult, non-smoking subjects of
`Caucasian Northern European heritage, a higher
`percentage of individuals with severe periodontal
`destruction tested positive for one of the genetic
`forms (alleles) of the IL-1A gene plus one of the
`Il- 1B alleles more frequently than did subjects
`with less severe disease. Furthermore, one of the
`two alleles associated with risk for periodontitis is
`also known to be associated with elevated pro-
`duction of IL-18, thus providing a possible bio-
`logical explanation for the enhanced susceptibil-
`ity of patient with this genotype for periodontitis.
`Early-onset periodontitis: localized juvenile
`periodontitis (1-JP), generalized juvenile peri-
`odontitis (GJP), rapidly progressive periodonti-
`tis (RPP). These diseases are characterized by
`their age of onset (usually post-pubertal), by the
`extent and severity of disease, by their often-
`times characteristic bacterial microflora, and to a
`
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`lesser extent by associated pathological and
`immunological characteristics. 110 These post-
`pubertal forms of EOP have a familial distribu-
`tion,111-114 and a number of clinical and biologi-
`cal characteristics of EOP, including the
`epidemiology and immunologic responses,
`appear to be strongly influenced by raCe. 115-117
`These data imply that it is possible that risk for
`EOP may be genetic. Although a number of
`genetic models have been tested using genetic
`segregation analysis, no consistent mode of
`inheritance for all forms of EOP has been
`observed. 1 18-124 One study has demonstrated
`genetic linkage of LJP with the Gc locus on chro-
`mosome 4 in one extended family, but this find-
`ing may not be generalizable to all families with
`EOR118,125
`A number of hypotheses have been proposed
`implicating candidates for genetic risk factors.
`The observation that many patients with EOP,
`particularly LJP, have neutrophil chemotactic
`defects, point to factors related to neutrophil
`function such as receptors for chemotactic
`agents or molecules participating in signal trans-
`duction. 126-128 Associations of EOP with some
`antigens of the major histocompatibility complex
`(HLA) region have been demonstrated, indicat-
`ing that heritable factors related to immunologic
`responsiveness may be associated with risk for
`EOP. 129 Additionally, poorly functional heritable
`forms of monocyte FcyRII, the receptor for
`human IgG2 antibodies, have been shown to be
`disproportionately present in patients with LJP.
`Such receptors cause monocytes to function
`poorly in phagocytosis of periodontal pathogens
`such as A. actinomycetemcomitans, because
`most of the antibody produced against this bac-
`terium is of the IgG2 subclass. 130 Finally, studies
`have demonstrated hyperresponsiveness of
`monocytes from EOP patients with respect to
`their production of PGE2 in response to LPS. This
`hyper-responsive phenotype could lead to
`increased connective tissue or bone loss due to
`inappropriately excessive production of these
`catabolic factors. 131 ' 132
`It is noteworthy that transmission of EOP in
`families, and many of the biologic characteristics
`of these diseases, may be explained by environ-
`mental factors as well as genetic factors, and
`some could be consequences of bacterial infec-
`tion rather than the cause of such infections.
`
`Pre-pubertal periodontitis. Prepubertal forms
`of periodontitis are usually subcategorized into a
`localized form (L-PP) and a generalized form (G-
`PP). L-PP is most commonly found in patients
`with no obvious health problems. Some, but not
`all, patients with L-PP display relative defects in
`neutrophil function and such patients can be fre-
`quently members of families in which other