Autoimmunity—Basics and link with periodontal disease

    Autoimmunity – Basics And Link With Periodontal Disease Gagandeep Kaur, Kanika Mohindra, Shifali Singla PII: DOI: Reference:

S1568-9972(16)30208-7 doi:10.1016/j.autrev.2016.09.013 AUTREV 1924

To appear in:

Autoimmunity Reviews

Received date: Accepted date:

27 July 2016 8 August 2016

Please cite this article as: Kaur Gagandeep, Mohindra Kanika, Singla Shifali, Autoimmunity – Basics And Link With Periodontal Disease, Autoimmunity Reviews (2016), doi:10.1016/j.autrev.2016.09.013

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ACCEPTED MANUSCRIPT TITLE – Autoimmunity – Basics And Link With Periodontal Disease RUNNING TITLE – Autoimmunity And Periodontal Disease

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Ph : 9417108009 Email id : [email protected]

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1. Dr. Gagandeep Kaur (Corresponding Author) BDS, MDS Department Of Periodontology & Oral Implantology Genesis Institute Of Dental Sciences & Research Punjab

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NAME OF THE AUTHORS

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2. Dr. Kanika Mohindra BDS,MDS Department Of Periodontology & Oral Implantology Laxmi Bai Dental College & Hospital Patiala Punjab

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Ph: 9888873083 Email id: [email protected]

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3. Dr. Shifali Singla BDS, MDS Department Of Oral And Maxillofacial Surgery Adesh Institute Of Dental Sciences And Research Bathinda Punjab Ph: 9463654982 Email id: [email protected]

ACCEPTED MANUSCRIPT ABSTRACT

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Autoimmune reactions reflect an imbalance between effector and regulatory immune responses, typically develop through stages of initiation and propagation, and often show phases of resolution (indicated by clinical remissions) and exacerbations (indicated by symptomatic flares). The fundamental underlying mechanism of autoimmunity is defective elimination and/or control of self-reactive lymphocytes. Periodontal diseases are characterized by inflammatory conditions that directly affect teeth supporting structures which are the major cause of tooth loss. Several studies have demonstrated the involvement of autoimmune responses in periodontal disease. Evidences of involvement of immunopathology have been reported in periodontal disease. Bacteria in the dental plaque induce antibody formation. Autoreactive T cells, natural killer cells, ANCA, heat shock proteins, autoantibodies, and genetic factors are reported to have an important role in the autoimmune component of periodontal disease.The present review describes the involvement of autoimmune responses in periodontal diseases and also the mechanisms underlying these responses.

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KEYWORDS : Autoimmunity, Periodontal disease, Antibodies, Immunopathology

ACCEPTED MANUSCRIPT 1 INTRODUCTION

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1.1 Autoimmune diseases are the result of specific immune responses directed against structures of the self (Burnet and Fenner, 1949). The immune system is an intricate constellation of cellular and molecular elements that have evolved to guard the body against attack. Under normal conditions, the immune system exhibits tolerance (an inability to react) to molecules recognized as ‗‗self,‘‘ and thus does not respond to elements (whether carbohydrate, nucleic acid, or protein) that are expressed in endogenous tissues. When self-tolerance is lost, the immune system is deployed against one or more of the body‘s own molecules. The civil war directed against autologous tissue resulting from the loss of self-tolerance is the hallmark of the autoimmune diseases (AIDx).

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1.2 Periodontal diseases are characterized by localized infections and inflammatory conditions where anaerobic Gram-negative bacteria are mainly involved and directly affect teeth-supporting structure. In 1965, Brandtzaeg and Kraus were the first to postulate the autoimmune basis in the pathogenesis of periodontal disease. It has been more than 30 years since the concept of autoimmunity has been considered for periodontal disease. An increasing number of reports in the past decade have lent support to the concept of an autoimmune component of periodontal disease [1]. This review is an attempt to throw light on the autoimmune basic concepts and highlighting the autoimmune component in the etiopathogenesis of periodontal disease. 2 CONCEPT OF AUTOIMMUNITY

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2.1 Theories of immune system recognition and AIDx development have evolved extensively over the past fifty years. During the mid twentieth century, the ‗‗self–non-self‘‘ (SNS) model was the prevailing explanation for immune reactivity [2,3]. The key perils envisioned in this paradigm as means for invoking an immune response were external invaders (i.e., pathogenic microbes and parasites) and internal threats (e.g., neoplasia). Inadvertent attacks directed against ‗‗self‘‘ molecules were thought to result from immune system confusion in distinguishing between true foreign molecules and structurally similar ‗‗self‘‘ constituents. Three decades later, the ‗‗infection–non-self‘‘ (INS) model was devised [4] as a modified version of the traditional SNS scheme. In this scenario, the focus of the SNS discriminatory capacity resides in the requirement by antigen-presenting cells (APCs) that antigens be presented in combination with a co-stimulatory molecule before an immune response will be mounted; thus, resting APCs will be activated when one of their germ line-encoded pattern recognition receptors (PRRs) recognizes a microbial pathogen-associated molecular pattern (PAMP). The most recent hypothesis is the ‗‗danger‘‘ model [5], in which the spur that activates quiescent APCs is the generation of one or more alarm signals by injured cells. The injury can result from many causes (neoplasia, pathogens, toxicants, trauma, etc.), since all can release elements that comprise a damageassociated molecular pattern (DAMP). However, programmed cell death would not activate APCs since apoptotic cells are scavenged before their ‗‗self‘‘ constituents are released to interact with nearby cells. Further adaptations to our understanding of immunity will arise in the future

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because the INS and danger models begin with divergent assumptions about what elicits an immune response and thus provide different predictions about the immune system‘s responsiveness to foreign-but-harmless (i.e., fetuses) and self but- harmful (i.e., certain mutations) materials. At present, the danger model appears to provide the more useful perspective of potential AIDx pathogenesis since its tenets encompass possible AIDx mechanisms that fall outside the SNS/INS model, such as the induction of cell death by excessive stress or toxicants as well as disruption in the extent and clearance of physiologic cell death [6].

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2.1.1 Basic Immunological Mechanisms of autoimmunity

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The distinction between ‗‗self‘‘ and ‗‗non-self‘‘ by the mature immune system depends on an intricate meshwork of sequential and well-regulated interactions between the afferent arm (APCs) and the efferent branch (effector cells and their products) to ensure that self-elements are tolerated. In general, such self tolerance is mediated chiefly by constituents of the acquired immune system (i.e., highly specific but must first be built), in particular the complement of Band T-lymphocytes with their membrane-bound, antigen-specific recognition molecules.

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Current dogma is that both spontaneous and induced AIDx are launched and perpetuated primarily by T-lymphocytes [7,8,9]. Cells of the CD4+ T-helper (Th) class are especially potent in this regard, releasing a broad spectrum of cytokines that promote the actions of other immune effector cells. Multiple classes of Th-lymphocytes have been defined. The most notable contributions to promoting AIDx appear to come from the Th1 class, which boosts immune cell activity; the Th2 class, which stimulates the humoral (antibody) response; and the Th17 class, which secretes factors to recruit and stimulate neutrophils. These master Th-cell phenotypes are activated by immediate proximity to APCs (commonly dendritic cells but on occasion also mitogen-stimulated B-cells) that express major histocompatability complex (MHC) type II as well as a co-stimulatory molecule (e.g., B7 [CD80/86]). Lymphocyte activation occurs only if the T-cell forms an immune synapse with an APC using three signals at once: (1) the primary Tcell receptor (TCR) binding to MHC II, (2) the T-cell co-stimulatory receptor (e.g., CD28) linking with the APC‘s co-stimulatory molecule, and (3) APC secreted cytokines interacting with T-cell receptors in a paracrine fashion. Stimulation by a single receptor-ligand modality is not sufficient to prime the lymphocyte. A comparable receptor-mediated event in which surfaceanchored immunoglobulin (Ig) serves as the B cell receptor is required for B-cell activation. In AIDx, autoreactive T- and B-lymphocytes engage in mutually assisted positive feedback to perpetuate the disease over time [10]. 2.1.2 Cellular Mechanisms of Autoimmunity Normal individuals preserve self-tolerance in T-lymphocytes through many mechanisms, all of which must be actively maintained throughout life. Accordingly, the loss of self-tolerance may occur through multiple mechanisms. The three main cell-oriented means for preventing

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autoimmunity are deletion (removal), anergy (relaxation), and suppression (restraint). The first option, deletion, involves irreversible pruning of self-reactive T-cells. This process of ‗‗central tolerance‘‘ (i.e., occurring in a core immune organ) occurs mainly in the thymus, the primary lymphoid organ for lymphocyte production. In the thymic cortex, naı¨ve lymphocytes (Th0 class) that learn during development to ignore self elements as potential targets are positively selected for continued survival, while T-cell precursors that exhibit any affinity for self antigens are eliminated via apoptosis. The survivors migrate to the thymic medulla where they are exposed to self-antigens in the presence of MHC type I receptors (present on most body cells as a demonstration of ‗‗self‘‘ status) but not MHC type II receptors (the form on APCs) or costimulatory molecules. Any T-cells that will bind self-antigens with high affinity in the absence of MHC type II and a co-stimulatory signal are negatively selected and diverted into an additional round of TCR-mediated apoptosis. Together, these two rounds of programmed cell death confer central tolerance. If needed, additional apoptosis is undertaken in secondary lymphoid organs. The programmed cell death responsible for this central tolerance is controlled by interactions between Fas and Fas ligand [11,12]. The absence of these molecules results in reduced pruning of autoreactive T-cells during development, which promotes systemic autoimmunity.

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Other processes used to reduce autoreactive immune cell lineages take place in secondary lymphoid organs and/or sites of inflammation. Collectively, these mechanisms are termed peripheral tolerance as they occur downstream from the core (‗‗central‘‘) immune organs. The second cell-based alternative for preventing autoimmunity is anergy, an induced state of unresponsiveness that quenches the function of the autoreactive clones while leaving them alive. The main means by which T-cell anergy is induced is for an APC to present a self-antigen as a target in the absence of a co-stimulatory signal [13]. The anergic state induced by insufficient costimulation may be reversed later in life. The final cell-based approach is clonal suppression, where anti-self responses are quenched by factors derived from other leukocytes (e.g., CD4+ CD25+ regulatory T-cells [Treg] or CD8+ suppressor [Ts] cells). This repression may be mediated by cytokines with negative feedback activity (e.g., transforming growth factor-b [TGFb]), by protein cross-linking to neutralize surface receptors with affinity for a given antigen, or by the genesis of antiautoantibodies (anti-idiotypes) that recognize the antigen receptors on autoreactive lymphocytes [14]. Xenobiotics can interfere with T-cell suppression by modifying the cytokine profile produced by newly recruited leukocytes. Breakdown of one or more of these central or peripheral, T-cell–based tolerance mechanisms is a common feature of AIDx. Similar principles apply to B-lymphocyte self-tolerance. Most of these mechanisms take place after cells have left the bone marrow (i.e., as facets of ‗‗peripheral tolerance‘‘). The simplest means for reducing the number of autoreactive B-cells is to induce anergy by exposing them to self-antigens in the absence of T-cell support [15]. Anergy is especially likely if soluble selfantigen is bound by naıve B-cells as this event will down-regulate cell surface Ig expression, thereby decreasing the number of potential receptors to permit cell activation in the future. Such

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downregulation may be transient, thereby allowing autoreactive cells to reenter the surveillance pool at a later time [16]. Receptor crosslinking in B-cells with high affinity for self-antigens leads to suppression or deletion. At least three additional cell-based measures for maintaining self-tolerance have been identified. These represent further aspects of ‗‗peripheral tolerance.‘‘ The first is by developing obstacles to stop immune effector cells from reaching segregated antigens. This mechanism usually involves the presence of a physical barrier to isolate an entire organ and all the cryptic epitopes within it. Examples of this barrier strategy are the brain and the testes. Breaching the barrier (generally by trauma or a nearby area of invasive inflammation or neoplasia) will lead to substantial inflammation, typically involving multiple leukocyte lineages, directed against the unmasked antigens. A second possibility is to maintain a stable population of circulating lymphocytes [17]. The existence of this mechanism is implied by the observations that lymphopenia is a common precursor to AIDx [18] and that numbers of autoreactive T-cells that are both persistently activated and constantly circulating is high in some AIDx [19]. The putative mechanism is increased access of autoreactive T-cells to APCs due to the decreased competition from conventional T-cells. A third option is from a defect in pluripotent stem cells. This mechanism leads to functional deficits in both B- and T-cells, which permits an autoimmune response to begin [20].

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2.1.3 Molecular Mechanisms of Autoimmunity

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The pathogenesis of AIDx is also driven by numerous mechanisms at the molecular level. These pathways all ultimately promote dysregulated intercellular communication in one form or another. Both innate immune cells and elements within the acquired immune system have been determined to be involved at the molecular level. 2.1.3.1 Innate immune mechanisms for autoreactivity: The induction of autoimmunity is often considered to be an acquired response, but innate immune cells play important roles in moderating self-tolerance. Activated dendritic cells can prime autoreactive T cells. Natural killer T (NKT) lymphocytes, a small subset of innate immune cells that recognize glycolipid antigens associated with the antigen-presenting molecule CD1+ instead of MHC class I or II, can suppress or exacerbate autoimmunity depending on a constellation of animal-specific factors. While they have potent immunomodulatory properties, NKT cells are distinct from the CD4+ CD25+ Treg cells that participate in the adaptive (acquired) immune response. In the innate immune system, three endosomal Toll-like receptors (TLR) have been identified as major participants in some AIDx [21]. These molecules, which are highly conserved across species, have evolved as receptors to recognize specific forms of microbial (viral) nucleic acid: TLR-3 for double-stranded (ds) RNA, TLR-7 for single-stranded RNA, and TLR-9 for ds DNA. Binding of the appropriate nucleotides induces a pro-inflammatory signal. Unfortunately, these TLR have also been shown to recognize certain human antigens. The expression patterns for these three TLR are often cell type–specific; B-cells bear TLR-7 and TLR-9, dendritic cells harbor either TLR-3 alone or both TLR-7 and TLR-9, and fibroblasts carry only TLR-3. These TLRs are

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thought to foment AIDx by directing the cells that express them to attack self molecules and enhance their expression of proinflammatory cytokines. In addition, initial B-cell activation may be undertaken by TLR (especially TLR-9) in the absence of T-cell support, so that B-cell clones break tolerance first21. Activated B-cells then in turn activate naı¨ve T-cells, which is necessary for initiation of a full-blown AIDx [22].

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2.1.3.2 Acquired immune mechanisms for autoreactivity: Most alternatives for autoimmune induction and progression are tallied to the acquired immune system. This preponderance likely reflects both the specific nature of the defense responses by this immune effector arm and the greater resources spent to date on exploring in detail the biological pathways that control these responses. Cytokine imbalances in the acquired immune system are well-recognized accomplices in the induction and progression of AIDx. In general, current thinking is that AIDx develops when the normal balance between proinflammatory and anti-inflammatory signals within a target organ is disrupted, leading to a chronic relative excess of local pro-inflammatory stimuli. The exact mixture of pro-inflammatory chemokines and cytokines varies among different AIDx. Traditionally, most proinflammatory signals in AIDx have been thought to be generated by CD4+ T-lymphocytes, but recent data have shown that mediators released by B-cells also play an important role [23]. However, the constellation of signals produced in a particular target organ differs as well, even among patients with a clinically equivalent presentation of AIDx.

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This finding is consistent with the nature of AIDx, where multiple factors—genetic background, hormonal status, microbiome, and xenobiotic exposure, cooperate in launching the autoreactive process. More importantly, this principle derived from animal research is mirrored in human patients with comparable conditions. The most common pro-inflammatory phenotypes in AIDx are attributed to enhanced activity of CD4+ T-helper lymphocytes. Three distinct phenotypes are especially important in this regard: Th1, Th2, and Th17. As a general rule, organ-specific AIDx are driven by cell-mediated processes designed to attack intracellular pathogens and thus develop when Th1 cytokines like IL-2 and interferon (INF)-g predominate. In contrast, multisystem AIDx typically include a vigorous humoral (antibody-based) response and are characterized by raised levels of Th2 cytokines such as IL-4, IL-5, and IL-10; extensive autoantibody production and immune complex deposition; and cell targeting by complement-mediated lysis. The Th2 response usually is associated with higher induction of macrophages, which leads to exacerbated fibrosis in many AIDx. Some AIDx, such as multiple sclerosis, are not easily classified as their cytokine signature exhibits both organ specific and systemic characteristics. The Th17 phenotype contributes to the genesis of AIDx by producing IL-23 as a neutrophil chemotactic and activating factor. Some Th cells appear to have a mixed Th1/Th17 phenotype as they can generate both IFN-g and IL-17, but in general both Th1 and Th17-cells are produced in parallel because they overlap only partially in their functions. Importantly, Th17- cells can drive AIDx in the absence of a concomitant Th1 response [24,25]. Dysregulated intracellular signal transduction is an important abnormality in many AIDx.

ACCEPTED MANUSCRIPT 3 The Resolution Of Autoimmunity

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The control of autoimmune reactions likely involves the induction and activation of regulatory mechanisms that limit the effector response and restore the effector/regulatory balance. The most important of these control mechanisms appear to be Tregs. Tregs, which are best identified by expression of the transcription factor FOXP3, develop in the thymus and peripheral (secondary) lymphoid organs. Both populations of Tregs likely acquire their potent suppressive function only after encountering their target antigen, which in most cases is likely to be a self-antigen. Some of these activated Tregs may survive in tissues as long-lived populations that are capable of controlling autoimmune reactions in that tissue, termed ―effector Tregs‖ or ―effector memory Tregs‖[26,27]. In addition to Tregs, other mechanisms that have been proposed to limit autoimmune reactions include the activation of various inhibitory receptors. For example, following activation, T cells begin to express two receptors of the CD28 family, CTLA-4 and PD-1, which function to suppress various immune responses. Genetic deletion of these receptors in mice and blockade in humans (for cancer immunotherapy) are associated with autoimmune inflammation of variable severity. Two recent studies have described immune dysregulation in humans who inherit one mutant allele of CTLA-4 [28,29]. These patients developed multiple autoimmune clinical features and extensive CD4+ T cell infiltration into different organs. Although Treg numbers were elevated in these patients, CTLA-4 protein expression in Tregs was markedly decreased and suppressive function was impaired. It is currently debated whether CTLA-4 and other inhibitory receptors exert their inhibitory effects primarily in a cell intrinsic (Teffs) or extrinsic (Tregs) manner, as both Tregs and Teffs express these receptors. 4 EVIDENCE OF AUTOIMMUNITY IN PERIODONTAL DISEASE There are records of both human as well as animal studies documenting the role of autoimmunity in periodontal disease. The majority of reports deal with the detection of antibodies to host components, in particular, collagen, although antibodies to DNA and aggregated IgG have also been reported (Table 1).      

Possible Causes of Autoimmunity in periodontal disease Enhanced presentation of self-antigens through increased expression of the molecule associated with antigen presentation, namely, the IgA antigen; altered T helper or T suppressor cell function; polyclonal activation of cells which have the ability, for reasons unclear, to produce autoantibodies; idiosyncrasies of the antigen idiotype network; bacterial or viral cross reactivity with self-antigens leading to production of cross reactive antibodies; genetic predisposition factors.

4.1 Increased IgA Expression: In several autoimmune diseases, increase in autoantibody is associated with an increase in molecules which are involved in antigen presentation, in particular

ACCEPTED MANUSCRIPT on cells which do not normally express these molecules. When these cells which are normally not involved in antigen presentation become involved, it may lead to self-antigen presentation to the immune system and the resultant production of autoantibodies.

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4.2 Altered T-Helper and T Suppressor Cell Function: In relation to periodontal disease, it has been explained as follows: a reduction in the T cell population of lymphocytes from patients with periodontal disease led to an increase in the B cell component of the spontaneous lymphoblastic proliferation. This would suggest that T suppressor activity would increase in patients with periodontal disease.

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4.3 Polyclonal Expansion of B Cell Pool: Natural autoantibodies (Nab), to a range of selfcomponents, are found in the absence of disease and are presumed to be a natural phenomenon. Such a pool of Nab may be expanded polyclonally by one of the polyclonal B cell activators found in periodontal plaque (LPS) or selectively antigenically by the release of tissue components which expose these natural antigens to the immune system to a greater extent than usual.

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4.4 Autoantigen Presentation and Autoreactive T Cells: All nucleated cells of the body possess class I MHC molecules so that gingival epithelial cell and fibroblast killing reported to occur in periodontal disease in vitro could be mediated by this mechanism of presentation of antigen, in association with class I MHC molecules, to cytotoxic T cells. However, in the lymphocytotoxicity seen in periodontal disease, both allogeneic and syngeneic target cells have been used with similar results. Increased expression of class II MHC molecules has been observed in the surface of basal and suprabasal gingival sulcular epithelial cells in inflamed tissues. 4.5 Idiosyncrasies of the Antigen Idiotypic Network : Jerne proposed a network theory of the immune response in which the antigen stimulated the production of antibody exhibiting an idiotype that elicited the formation of an anti-idiotype bearing an ―internal image‖ of that antigen. This latter antibody in turn stimulated the production of anti-anti-idiotype antibody leading to an open ended network. In periodontal disease there is so far no evidence for existence of anti-idiotype antibodies. The antibodies to immunoglobulin detected in humans and experimental animal periodontal disease are directed to the Fc end of the molecule not the idiotype region. 4.6 Viral and Bacterial Infection and the Immune System: Viral and bacterial infections may play a role as an exogenous factor triggering an autoimmune response. Activation and clonal expansion of autoreactive lymphocytes is a critical step in the pathogenesis of autoimmune diseases. In experimental models of autoimmunity, disease can be transferred by activated, but not resting, autoreactive T cells, indicating that activation of autoreactive T cells is required for the development of autoimmune diseases.The infectious agents act as a stimulating factor such responses. Thus the existence of such a microorganism in periodontal pocket may not only

ACCEPTED MANUSCRIPT stimulate the production of antibody to this microbe but also stimulate autoantibody production to serum components or degenerated host periodontal tissues [30,31].

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4.7 Genetic Predisposing Factors: Several investigators have reported an association between a high incidence of selected histocompatibility complex antigens and certain autoimmune diseases, for example, rheumatoid arthritis with HLA-DRw4, systemic lupus erythematosus in association with HLA-DR3 and HLA-B8. This could be an underlying predisposing factor for the development of autoimmune disease. The evidence relating HLA phenotype distribution and the prevalence of periodontal disease has been contradictory. Reports relating HLA phenotype and susceptibility to periodontal disease are mainly associated with HLA class I antigen distribution. A possible role of HLA class I antigens in the development of periodontal disease might be either in relation to cell mediated cytotoxicity and the T cell response or in association with the structural features of the antigens themselves. Patients with periodontitis juveniles and patient with periodontitis were tissue typed. In the juvenile group, frequencies of tissue type specificities HLA-A9, HLA-A28, and HLABJ‘V15 were significantly increased as compared to the findings in the general population. In the periodontitis groups, no significant tissue type deviations were found as discussed by Reinholdt et al. Several theories have been advanced to explain the associations between HLA and a variety of diseases [32].

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4.8 Role of Antibodies: Perhaps the most pertinent aspect of the antibodies detected in periodontal disease is their role: protective, destructive, or inconsequential. Pathologic changes appear to occur in those circumstances where the otherwise physiologic autoimmune response leads to the initiation of further humoral and or cellular immune activity capable of causing tissue damage or disease. It should be noted that ―natural‖ autoantibody is generally of the IgM class. In adult periodontitis local antibody to collagen type I is predominantly IgG rather than IgM, a reversal of the situation in serum, suggesting that continued antigenic stimulation has led to class switch. In periodontal disease there is alteration in the various subclasses of antibodies, with increasing severity of the disease, such that IgG1 and IgG3 decrease and IgG4 increase. The latter antibody is protective in nature, as it does not form complexes with antigen which activate complement. Studies suggest that the autoantibodies detected in periodontal disease are derived from preexisting natural antibodies and play a physiological role in the elimination of dead cells and damaged tissue constituents that have appeared during the tissue degradation which occurred in periodontal disease. However, the possibility still remains that this system, established to deal with the consequence of tissue damage, may in certain circumstances become excessive and actually contribute to the progress of the disease [33]. 4.9 Antineutrophil Cytoplasmic Autoantibodies (ANCA): ANCAs represent a heterogeneous group of antibodies that target antigens that are primarily present in azurophil granules of polymorphonuclear leukocytes (PMNs). Some ANCA associated diseases are known to coexist during periodontitis in humans. Such diseases include the rheumatoid arthritis and to a lesser extent systemic lupus erythematosus (SLE). More studies are required to explore the link between these conditions and a probable common mechanism in these disease processes.

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Exposure of the host to the periodontal pathogens, along with a genetic susceptibility, could trigger ANCA by two different mechanisms. The production of TNF- would sensitize the neutrophils to express its granule contained enzymes, such as MPO and PR-3, which in turn could trigger the production of ANCA. In addition, periodontal pathogens are known to possess a ―superantigen‖ property, where they can directly activate the autoreactive B lymphocytes in a T cell independent and mediated pathway, which can also result in the activation of neutrophils. The activated neutrophils release reactive oxygen radicals, enzymes, and various proinflammatory cytokines, all of which are known to mediate periodontal destruction. ANCA activated neutrophils are also known to delay apoptosis, which can prolong the activity of neutrophils and thereby increase tissue destruction. Delayed apoptosis has been reported in periodontal disease, which can be attributed to ANCA. Furthermore, ANCA is known to have a direct toxic effect on the cells bearing antigens such as endothelial cells, which can result in increased endothelial permeability, a feature common in the inflammatory process [34,35].

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4.10 Role of Natural Killer T Cells in Autoimmunity: Human CD1d molecules present glycolipid antigens such as galactosylceramide to CD1d-restricted natural killer T cells. The natural killer T cells appear to associate with CD1d cells, and it was suggested that they have a regulatory role to play in periodontal disease. Autoimmunity has been suggested to be a feature of periodontal disease. Cross reactivity of human heat shock protein (HSP) 60 and P. gingivalis GroEL, which is the bacterial homologue has been shown in periodontal disease. HSP 60 specific as well as P.g cross reactive T cells have also been demonstrated to accumulate in periodontitis lesions. The study by Yamazaki et al. suggests that an immune response to autoantigens such as collagen type I or HSP60 may be well controlled by natural killer T cells. A relationship between a deficiency in natural killer cell activity and autoimmune diseases has been cited in mice. An impairment of the subtle balance could be involved in the pathogenesis of periodontal disease. The results, however, did show increase of natural killer T cells in periodontitis, suggesting a functional role for these cells, and because of their ability to secrete rapid amounts of cytokines, they may influence the T helper cytokine response. The role of autoimmunity in chronic inflammation is still not clear. It is possible that autoimmunity is a feature of all chronic inflammation. In this context it has been known for many years that gingival fibroblasts are able to phagocytose collagen such as anticollagen; antibodies may facilitate this phagocytosis and hence removal of broken down collagen. At the same time, an anti-HSP response may enhance the removal of dead and dying cells, such that these autoimmune responses may be a natural part of chronic inflammation. Control of these responses would therefore be essential, hence the increase in regulatory natural killer T cells in periodontal tissues. This concept further illustrates that the role of T cells in periodontal disease may be one of immune homeostasis. Further studies are clearly needed to test this hypothesis and to determine the role of regulatory T cells in periodontal inflammation [36,37,38]. 4.11 Oral Microbial Heat Shock Proteins : When exposed to a wide range of environmental stressors (temperature, pH, redox potential, etc.), prokaryotic and eukaryotic cells respond by

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inducing or accelerating the synthesis of specific proteins known as stress proteins, including the heat shock proteins (HSPs) which have a high degree of homology. These HSPs are unregulated under stressful conditions. HSPs act as molecular chaperones in the assembly and folding of proteins, and proteases when damaged or toxic proteins have to be degraded. HSPs thus protect cells from damaging effects associated with stressful conditions. The GroELs and, to a lesser extent, the DnaKs of several pathogenic bacteria may become major antigens, since they are strongly expressed under stressful conditions. These HSPs are antigenic, and the recognition of specific epitopes on such highly conserved antigens may contribute to protective immunity or may have pathological autoimmune responses. Because of the similarities between microbial and mammalian HSPs, a humoral response against microbial HSPs may be destructive for the host due to antigenic mimicry leading to autoimmune response.Three models have been proposed to link microbial infections to subsequent autoimmune reactions involving the HSPs. These models are as follows:

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(1) molecular mimicry between the microbial HSPs and HSPs or constituent proteins from the host, (2) inflammation induced exposure of cryptic cell epitopes that could be a target for immune reactions,

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(3) antigen presentation in infected sites leading to chronic immunological reactions [39,40,41].

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5 Role of Autoreactive B Cells in Autoimmunity of Periodontal Disease: B cells upon activation transform into antibody producing plasma cells. There are reasons to anticipate that immunoglobulins produced by plasma cells directed against subgingival plaque may also be autoantibodies directed to host cells. It was observed that the gingival lesions contained a large number of cells that produce either antibodies directed to type I collagen. In sites of chronic inflammation, polyclonal B cell activators (PBA) are known to exhibit adjuvant activity when combined with foreign antigens. The adjuvant effect of microbial polyclonal B cell activator may be important in anticollagen antibody production, and thus the localization of PBA in periodontal pockets may explain why anticollagen antibody forming cells are restricted to the chronically inflamed periodontal tissues. Interleukin-10 has been reported to selectively promote the expansion of a B lymphocyte lineage which has the propensity for secreting high levels of autoantibody in type I diabetic individuals [42,43]. 6 Role of Anti-CCP in Periodontal Disease and RA : Rheumatoid arthritis (RA) is a common, systemic autoimmune disease causing destruction of the joint architecture leading to disability. Etiology of RA remains unknown; accumulating studies have established a strong association between RA and periodontitis (PD). The anti-cyclic citrullinated peptide antibodies (anti-CCP) are produced locally in the inflamed synovium of rheumatoid arthritis (RA) patient. In scientific literature periodontal bacterial DNA in serum and synovial fluid of RA with periodontal disease patients were found. RA and adult periodontitis share common pathogenetic and immunologic mechanisms. One oral pathogen strongly implicated in the pathogenesis of periodontal disease (PD), Porphyromonas gingivalis, possesses a unique microbial enzyme, peptidylarginine deiminase (PAD), the human equivalent of which has been identified as a susceptibility factor

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for RA. P. gingivalis is the only oral bacterium that possesses peptidylarginine deiminase activity, which is essential for citrullination of arginine, an RA autoantigen, leading to the formation of immune complexes involved in inflammation and joint destruction seen in RA. The anti-cyclic citrullinated peptide (anti-CCP) autoantibody and citrullinated peptide have been realized to be involved in the breaking of self-tolerance and development of autoimmune in RA. The citrullinated peptide is generated by posttranslational modification (citrullination) of proteinbound arginine by peptidylarginine deiminase (PAD). Porphyromonas gingivalis (P. gingivalis), the major aetiological agent of PD and the only bacterium known to express a PAD enzyme, has been reported to be significantly associated with RA. It is also confirmed that bacterial PAD produced by P. gingivalis has the capacity of deiminating arginine in fibrin found in the periodontal lesion. What is more, it has been demonstrated that citrullination of HLA binding peptide causes a 100-fold increase in peptide-MHC affinity and leads to the activation of CD4(+) T cells in HLA DRB1 0401 transgenic mice. Therefore, we postulate that P. gingivalis may play a crucial role in the pathogenesis of periodontitis-associated RA. P. gingivalis, which colonizes in the oral cavity, produces PAD enzyme continuously that leads to the citrullination of RA autoantigen such as fibrin in synovium joint. These PAD engendered antigens, presented in association with major histocompatibility complex (MHC) molecules by antigen-presenting cells (APC), ultimately lead to production of the anti-CCP antibody. The anti-CCP antibodies form immune complexes with citrullinated proteins, which can be bound by inflammatory cells via their Fc receptors. The roles of these immune complexes and inflammatory cells are mediated by a complex cascade involving complement activation. These mechanisms result in a release of mediators of inflammation and joint destruction ultimately leading to the onset of RA. This hypothesis reveals that oral bacterial infection may play a role in peptide citrullination which might be involved in loss of self-tolerance and development of autoimmunity in RA [43,44,45,46,47]. Autoimmunity as a Component in Various Periodontal Diseases

7.1 Host Immune Response Linked to the High Risk of Periodontal Disease in Diabetics Diabetic patients are at a higher risk of developing periodontitis is a known fact, however the mechanism is not fully understood. An autoimmune component cannot be fully ruled out as per the Mahamed et al. study. This research study shows that the autoimmune environment and CD4+ T cells display an unusual hyperactive response when mounting an antibacterial immunity to oral microbial assaults in the experimental diabetic NOD (non obese diabetic) mice, which is similar to human type 1 diabetes. These findings will lead to a new understanding of the potential causes of the high rates of microbial infections in diabetics and future treatments for both periodontal/dental care and medical risk factor management. This study clearly describes the impact of the autoimmunity environment to anaerobic infection in an experimental periodontitis model of type1 diabetes. Moreover, these cells in high-risk diabetic patients may open a new door for the therapeutic potential of treating periodontal disease. In another study a cytokine, interleukin (IL)-10, has been reported to selectively

ACCEPTED MANUSCRIPT promote the expansion of a B lymphocyte lineage (CD5/LY1/B1) which has the propensity for secreting high levels of autoantibody in diabectic patients [48].

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7.2 Role of Autoimmunity in Aggressive Periodontitis Aggressive forms of periodontitis have been intensively investigated due to their aggressiveness, quick progression, and occurrence in adolescents and young individuals. Periodontopathogenic bacteria have been implicated in the pathogenic ability of AgP, and there is evidence in literature that bacterial toxins and autoimmune mechanisms are likely involved in the pathogenesis of AgP. In a recent study carried out, the presences of autoantibodies directed against ECM components were found in the sera of patients. However it does not necessarily mean that these autoantibodies primarily participate in the destructive mechanism of periodontal tissue. Their presence could be a coadjuvant factor rather than the cause of these lesions. It was demonstrated that self-antigens may be altered in the course of infection. Furthermore microbial antigens exhibit molecular mimicry with host self-antigens and thus facilitate the production of autoantibodies [49,50,51]. 7.3 Desquamative Gingivitis It is not a specific disease entity, but a gingival response associated with a variety of conditions. A variety of conditions affect the gingiva, either in part or totally. The gingiva consists of the epithelium, the connective tissue, and the basement membrane separating the two. Consequently, various conditions can involve each component specifically or totally, or, in some cases, can involve specific aspects of each component, such as certain layers of epithelium. In many of these conditions some type of inflammatory process is involved, either acute or chronic. Autoimmune mechanisms appear to be a prominent aspect of etiology in many patients. Thus, similar to periodontal disease, inflammation and the immune response are involved in pathogenesis of the mucocutaneous lesions of the gingival [1,52]. 8 CONCLUSION Understanding and successfully treating human autoimmune disease continues to be a significant challenge. The present review has thrown light on the basic autoimmune mechanism and its component in periodontal disease causation, which may be somewhere underplayed or ignored in its role in the etiopathogenesis of this disease. There is more than enough evidence to quote an autoimmunity aspect to periodontal disease, which could be the main reason why the initiation and progression of this disease is still unclear. Targeted cytokine inhibition has launched the age of biologic therapy for autoimmune component of the disease, but it seems that we are still in the early stages and many more exciting new therapeutics are on their way of development. CONFLICT OF INTERESTS – NONE ACKNOWLEDGMENTS – NONE

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3. Elevated levels of serum antibody to human collagen type I

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4. IgM ,IgA rheumatoid factor antibody to human collegen type I & III produced by mononuclear cells 5. Serum IgG antibodies to native and denatured type I & III bovine collagen detected in juvenile periodontitis.

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CELLULAR 1.Lymphocytotoxicity shown for oral epithelial cells 2. Histological damage observed in gingival human fibroblasts with associated mononuclear cells 3. Lymphocytotoxic killing of autologus fibroblasts with associated mononuclear cells 4. Lymphoblastogenesis detected to native and denatured collagen

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HUMORAL 1. Antibody to aggregated IgG (rheumatoid factor) detected in gingiva & saliva 2. Antibody levels to double stranded DNA were elevated in dog gingival

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Tables

5. Cellular immunity to proteoglycan detected in periodontal disease patients

Table 1 – Role Of Autoimmune Mechanisms in Periodontal Disease