The immune system consists of an innate and an adaptive arm and comprises different cell types as well as non-cellular components such as antimicrobial peptides (Fig 11-1). The innate immune system induces the activation of the adaptive immune response, and both enter a reciprocal interplay1. Autoimmunity can be defined as a breakdown of self-tolerance, the ability to tolerate harmless molecules and structures naturally occurring in the host (self), leading to an activation of the immune system directed against them. Such an immune response may not always be harmful. However, in numerous diseases it is well recognised that activation of the immune system causes self-damage2. This often includes the progressive breakdown of tissues or the formation of thrombi in the blood vessels.
Autoimmune diseases can be divided into two categories: tissue-specific autoimmune diseases (e.g. diabetes mellitus type 1 or multiple sclerosis) and systemic autoimmune diseases (e.g. systemic lupus erythematosus). Despite the wide diversity in clinical symptoms and biological processes, they all share the presence of autoantibodies and/or autoreactive T cells. For the majority of autoimmune diseases, autoantigens have been identified as the targets of autoantibodies and autoreactive T cells3. There is evidence that the development of an autoimmune disease may occur over several years as a consequence of a ‘multi-step’ process. Although this process is not fully understood, autoimmunity is thought to result from a combination of genetic variants and acquired environmental triggers such as infections, and can be characterised by4:
● enhanced presentation of self-antigens
● altered T cell function
● activation of B cells, which have the ability to produce autoantibodies
● bacterial or viral similarity with self-antigens (molecular mimicry) leading to production of cross-reactive antibodies.
In 1965, Brandtzaeg and Kraus5 were the first to postulate an autoimmune basis for the pathogenesis of periodontal disease. An increasing number of reports in the past decade have supported the concept of an autoimmune component to periodontitis and to the potential for periodontitis to be associated with autoimmune diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE)6. There are more than 80 recognised autoimmune disorders7, but only a small number of these have been investigated for a possible association with periodontitis (Table 11-1). In periodontitis, a breakdown of the periodontal tissues takes place during an immune response initially directed against oral microorganisms (Fig 11-2). Autoimmune reactions have been observed towards self-components in periodontitis72,73. However, because of the evident role of infection in periodontitis74, this disease is not classified as an autoimmune disease. In this chapter, autoimmune mechanisms found in periodontitis are outlined and existing studies investigating the possible association between periodontitis and autoimmune diseases and vice versa are discussed.
Table 11-1 In vivo human studies investigating the association between periodontitis and specific autoimmune diseases (for studies regarding other autoimmune diseases discussed in the main text, readers are referred to the respective chapters)
|Autoimmune disease||Overall outcome (summary)||Studies||Study design|
|Systemic lupus erythematosus (SLE)||Only a few studies have been conducted and these show divergent results. However, a recent meta-analysis suggests a mildly, but significantly increased risk of periodontitis in SLE patients.||Rutter-Locher et al8, Zhong et al8a||Meta-analysis|
|Fabbri et al9||Interventional study|
|Wu et al10, Calderaro et al11, Corrêa et al12, Zhang et al13, Al-Mutairi et al14, Wang et al15, Kobayashi et al16, Meyer et al17, Novo et al18, Mutlu et al19||Case-control|
|Pessoa et al20||Cross-sectional|
|Sjögren syndrome||Too few studies with divergent results exist; therefore, no conclusion is possible regarding a possible association of periodontitis and Sjögren syndrome.||Maarse et al21||Meta-analysis|
|Ambrósio et al22||Interventional study|
|Lugonja et al23, Ergun et al24, Antoniazzi et al25, Marton et al26, Pers et al27, Jorkjend et al28, Kuru et al29, Mendonça et al30 Schiødt et al31, Boutsi et al32, Celenligil et al33, Najera et al34, Tseng et al35||Case-control|
|Lin et al36||Prospective cohort|
|Psoriasis||Too few studies with divergent results and partly based on strong confounding factors. A well-conducted cohort study (Keller and Lin41) with >200,000 participants suggests a weak association between both conditions. Currently, no strong evidence exists.||Qiao et al37, Zhang et al37a||Meta-analysis|
|Ucan Yarkac et al38||Interventional study|
|Egeberg et al39, Nakib et al40, Keller and Lin41||Prospective cohort|
|Woeste et al42, Mendes et al43, Sharma et al44, Skudutyte-Rysstad et al45, Fadel et al46, Lazaridou et al47, Preus et al48||Case-control|
|Ankylosing spondylitis||Too few studies exist; however, these provide some evidence for a possible association, and most studies come to similar conclusions.||Ratz et al50||Meta-analysis|
|Schmalz et al51, Abbood et al52, Bautista-Molano et al53, Kang et al54, Keller et al55, Sezer et al56, Suppiah57, Pischon et al58, Helenius et al59||Case-control|
|Ziebolz et al60||Cross-sectional|
|Pemphigoid||Divergent results and too few studies, therefore no conclusion is possible. There is very weak evidence for no existing association between the two diseases. Periodontitis may, however, be increased in oral pemphigus vulgaris due to poor oral hygiene in these patients, rather than the pemphigus directly.||Arduino et al61, Thorat et al62, Schellinck et al63, Akman et al64, Tricamo et al65||Case-control|
|Systemic sclerosis (Scleroderma)||Too few studies, no conclusion possible.||Gomes da Silva et al66, Isola et al67, Pischon et al68, Leung et al69||Case-control|
|Multiple sclerosis||Divergent results in both studies, no conclusion possible.||Gustavsen et al70, Sheu and Lin71||Case-control|
11.2.1 Autoimmune mechanisms of the innate immune system
The innate immune system is crucial for the defence against pathogens and for the induction of primary adaptive immune responses, such as B cell activation. Toll-like receptors (TLRs) are key receptors that activate innate immunity in response to pathogen recognition. Under certain conditions, which are described in this subchapter, activation of innate immune cells can break the state of inactivity of autoreactive cells of the adaptive immune system, thereby provoking autoimmune disease75.
22.214.171.124 Neutrophils and reactive oxygen species
Neutrophils in periodontitis are hyperactive and hyper-reactive76–78: they release excess reactive oxygen species (ROS), which are strongly antimicrobial, with and without bacterial challenge. The release of ROS is a host-defence mechanism employed by neutrophils and a number of other immunoactive cells, including macrophages, mast cells and fibroblasts79. Moreover, microorgansims are able to release ROS80. Oxidative stress is a key feature of many inflammatory and autoimmune diseases, and results in an abundance of ROS that are able to bind to host proteins and lipids, e.g. cell membranes, and to disrupt their function by oxidising them and thus changing their structure, potentially forming new epitopes. These neo-epitopes may directly elicit an adaptive immune response aimed at eliminating these foreign structures81. They may also influence immunological phenomena such as molecular mimicry (a host antigen being perceived as a ‘non-self’ protein), exposure of cryptic epitopes (exposure of amino acid sequences after changes in the three-dimensional structure of a protein), epitope spreading (spreading of antigenicity from a given epitope to other parts of the protein or other proteins) and the coupling of an autoantigen to an exogenous antigen82. Although these mechanisms have been reported in ex vivo models and in autoimmune disorders such as in Hashimoto’s thyroiditis, inflammatory bowel disease (IBD), multiple sclerosis (MS) and RA, there is currently no proof of concept that such a mechanism can exacerbate periodontitis or that periodontitis can enhance autoimmunity via this route.
Another neutrophil antimicrobial mechanism is the generation of neutrophil extracellular traps (NETs), which primarily consist of mitochondrial or nuclear DNA released into the extracellular space. These NETs contribute to autoimmunity: the chromatin DNA backbone is richly decorated with histones and antimicrobial peptides, which are usually located intracellularly in the nucleus and in granules, respectively, and can become autoantigens in the extracellular environment83,84. Thus, antibodies termed anti-neutrophil cytoplasmatic antibodies (ANCA) are produced by B cells. Importantly, ANCAs can enhance pro-inflammatory responses like the activation of neutrophils and monocytes locally and systemically, and some ANCA-associated diseases are known to coexist with periodontitis, e.g. IBD85. Interestingly, Kobayashi et al16 demonstrated that the risk of periodontitis in SLE is associated with Fc-gamma receptor (FcγR) polymorphisms. ANCA engage and activate human neutrophils via FcγRIIa86, thus, periodontitis in SLE may be dependent on both the presence of ANCA and specific receptor polymorphisms, which are highlighted in Section 126.96.36.199 ‘Fc gamma receptor polymorphisms’. Although the role of NETs has not been confirmed in periodontal diseases, it is known that they are present in inflamed periodontal pockets87. An important intracellular step prior to NET release is the citrullination of histones88–90. Also, certain periodontal bacteria such as Porphyromonas gingivalis can citrullinate host proteins. Citrullinated proteins stimulate the production of anti-citrullinated protein antibodies (ACPA), and were shown to play a major role in RA91.
Recent findings from animal models suggest that macrophages exacerbate autoimmune disease by presenting self-antigens taken up by scavenger receptors in response to tissue damage. Evidence is emerging that macrophages, particularly the proinflammatory M1 macrophage subtype, are also pathogenic in autoimmune encephalomyelitis, RA and SLE, by maintaining the self-directed inflammation, e.g. by releasing excess ROS, and thus contributing to tissue destruction92,93. Moreover, macrophages can prolong inflammation by failing to effectively remove other immune cells (efferocytosis) and damaged tissue components. A non-resolving macrophage response can also supply the progression and tissue destruction seen in periodontitis94; however, a role of activated macrophages in the initiation of autoimmune diseases has not been confirmed.
188.8.131.52 Mast cells
Mast cells (MCs) are tissue-resident immune cells, which, upon activation and degranulation, release a large number of biologically active substances including matrix metalloproteinases, being key enzymes in the degradation of gingival extracellular matrix. They activate adaptive immune cells like T and B lymphocytes, and these interactions are thought to play a role in autoimmune diseases like RA and MS95. Furthermore, MCs participate in hypersensitivity and allergic reactions such as allergic asthma and urticaria. Limited attention has been given to the role of MCs in periodontal diseases. Huang et al96 suggested a significant correlation among MC density in periodontal tissues, the degree of their degranulation and the severity of periodontitis. Lagdive et al97 reported that the number of MCs is significantly increased in periodontitis compared to gingivitis and health, whilst Steinsvoll et al98 concluded that MCs are a key cell in inflamed periodontal tissues and that their role in periodontitis needs to be revisited. Therefore, it is not currently known whether MCs may constitute a link between periodontitis and autoimmune disorders.
184.108.40.206 Dendritic cells
Dendritic cells (DCs) are the peripheral sentinels of the human mucosal immune system and key regulators of immune tolerance and self-tolerance, thereby minimising autoimmune reactions99. DCs capture, process and present antigens, express immune-stimulatory molecules and cytokines needed for antigen presentation to B and T lymphocytes. Thus, DCs play a key role in deciding whether to mount a vigorous immune response against pathogenic bacteria, and whether to tolerate commensal microbes or self-antigens. Antigen-bearing DCs interact with T cells and are subsequently rapidly eliminated by activated T cells100. The importance of DC death after antigen presentation was shown in patients with autoimmune lymphoproliferative syndrome (ALPS)101. The lifespan of DCs might thus be an important checkpoint to control for the induction of tolerance, priming and chronic inflammation. In the periodontal tissues, Langerhans cells (LCs) rather than other DC subsets have been identified. In gingivitis and periodontitis, LCs are increased in the inflamed oral epithelium, where they are very responsive to bacterial biofilms102. Many studies have focussed on the role of human leukocyte antigens (HLAs)-encoded molecules, which present antigens for recognition by T helper (Th) cells (see Section 220.127.116.11 ‘HLA phenotypes and major histocompatibility complex’). Strong associations between almost all autoimmune diseases and the HLA-encoded molecule HLA-DR have been reported103. Interestingly, HLA-DR has been detected at increased levels in oral LCs during experimental gingivitis104. However, there are currently no data establishing a link between HLA-DR in oral LCs and autoimmunity.
18.104.22.168 Natural killer cells
Most of the knowledge of natural killer (NK) cells in human autoimmune diseases is derived from analysing NKs from patients in several clinical stages of disease105, and several conflicting results exist. Limited data suggest that NK cells are activated particularly in aggressive (Grade C) periodontitis106,107 and they have been suggested to play a regulatory role in periodontitis108. To date, their exact role and functions in periodontitis as well as in autoimmune diseases remain elusive.
11.2.2 Adaptive autoimmune mechanisms
The adaptive immune system creates immunological memory after an initial response to a pathogen, leading to a more efficient response to subsequent encounters with that pathogen. Activation of autoreactive T and B lymphocytes is a critical step in the pathogenesis of autoimmune diseases109, and infectious agents such as microorganisms can activate these autoreactive lymphocytes. Thus, the biofilm in periodontal pockets may not only stimulate the production of antibodies to microbes but may also stimulate autoreactivity of B and T cells110. In addition, periodontal pathogens are known to possess proteins named superantigens, which enable them to directly drive a tremendous activation and expansion of T cells111,112.
22.214.171.124 Th17 cells
Th17 cells were identified as a separate T-cell population only recently, and are related to autoimmune responses. Although controversially reported in the literature, TLR-2 and -4 appear to drive Th17 responses in both infectious and autoimmune diseases113,114. The signature cytokine of Th17 cells is interleukin-17A (IL-17A), which is thought to be important for the recruitment of neutrophils, as they upregulate CXCL8 expression115. Increased IL-17A levels have been detected in individuals with autoimmune diseases including RA116. It was demonstrated that Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans activated Th17 cells117,118. Thus, it is possible that increased Th17 activity in the periodontal tissues leads to enhanced neutrophil recruitment locally, followed by pro-inflammatory cascades including self-directed immune responses. This hypothesis is supported by a finding by de Aquino et al119, who reported that periodontal pathogens induced Th17 in a mouse model, which led to a T cell-driven arthritis in these animals. Gaffen and Hajishengallis120 emphasise the importance of further elucidation of Th17 responses in periodontitis. They further suggest conducting studies that monitor the periodontal condition in patients who receive autoimmune therapies, in order understand the associations between Th17, periodontitis and autoimmunity120.
126.96.36.199 Regulatory T cells
Regulatory T cells (Treg cells) are widely regarded as the primary mediators of self-tolerance, thus preventing autoimmune responses121. The exact role of Treg cells in mediating periodontal disease continues to be controversial. Nakajima et al122 demonstrated that periodontitis patients showed an increased percentage of Treg cells in gingival connective tissues compared to gingivitis patients. It was concluded that Treg levels were upregulated in periodontitis lesions in order to provide protection against self-antigens, such as collagen type 1 (see Section 188.8.131.52 ‘B cells and autoantibodies’). Ernst et al123 reported that Treg cells downregulated the expression of RANKL in periodontitis, a molecule crucial for osteoclast activation. Interestingly, some authors have suggested that Treg cells may be converted into Th17 cells in periodontitis124,125. Further support for the role of Treg cells in controlling periodontal inflammation was lent by Garlet et al126, who reported that Treg cells led to an amelioration of experimental periodontitis in mice. Thus, there is evidence that Treg cells take part in the control of periodontal inflammation, whilst being crucial for mediating immune-tolerance. However, whether Treg cells act as a link between periodontitis and autoimmune diseases, possibly through their conversion into Th17, has not yet been established.
184.108.40.206 Other T cells
Natural killer T cells (NKTC), gamma delta T cells (γδ T cells), the T helper subsets Th1, 2, 9 and 22 as well as cytotoxic T cells and memory T cells are all thought to be implicated in autoimmune disorders, although their specific roles in the pathogenesis of these diseases have only partly been investigated127–129. NKTC bridge the innate and adaptive immune system, as they have biological and functional features of both arms, and are implicated in regulating immune responses against autoantigens. Several studies have identified NKTC as attractive targets for treatment of human autoimmune diseases130. They were found to be increased in periodontal lesions131,132 and were suggested to control immune responses to autoantigens, such as collagen type I or heat shock protein 60 (HSP60) (see Sections 220.127.116.11 ‘B cells and autoantibodies’ and 18.104.22.168 ‘Heat shock proteins’) in periodontitis133.
γδ T cells appear in several infectious and autoimmune diseases, e.g. tuberculosis and SLE. They also reorganise self-antigens via the γδ T cell receptor and enhance the production of IL-17134. Results regarding their presence in healthy versus inflamed periodontal tissues are controversial, and only a limited number of studies exist135–137. However, γδ T cells were found to be systemically increased in patients with periodontitis138, thus providing a potential pathway in activating systemic autoimmune responses.
Autoimmune pathogenesis often involves self-reactive T helper cells, whose effector mechanisms include the production of pro-inflammatory cytokines that initiate inflammation and also induce autoreactive B cells. Depending on the cytokines they produce, these T cell subsets have very different properties. In periodontitis research, studies investigating these T-helper cell subsets are limited and their role is controversial139 or, in the case of cytotoxic T cells, is largely unknown140. Some subsets, like Th22, have not been investigated to date in periodontal tissues. Therefore, possible mechanisms by which these cells could associate periodontitis with autoimmune diseases are speculative.
22.214.171.124 B cells and autoantibodies
B cells upon activation through the process of antigen presentation transform into antibody-producing plasma cells (Fig 11-3). Apart from releasing antibodies directed against exogenous antigens, natural autoantibodies (Nabs) to a range of self-components are found in the absence of disease and are presumed to be a natural phenomenon141. They play a physiological role in the elimination of dead cells and damaged tissue constituents. Autoantibodies have been detected in periodontitis and are thought to be derived from pre-existing Nabs144–148. It was observed that gingival and periodontal lesions contained a large number of B cells that produced antibodies directed against type 1 collagen, fibronectin and laminin149,150. In addition, Hendler et al151 reported a systemic increase of autoantibodies to native and ROS-modified collagen type 1 and 3 as well as autoantibodies to citrullinated peptides. These were observed exclusively in patients with aggressive (Grade C) periodontitis and not in those with other forms of periodontitis or gingivitis151.
At sites of chronic inflammation, polyclonal B cell activators (PBA), such as lipopolysaccharide (LPS), can lead to anti-collagen antibody production, and thus the localisation of PBA in periodontal pockets may explain why anti-collagen antibody forming cells were found to be restricted to the chronically inflamed periodontal tissues152. It is possible that the production of Nabs is increased by the PBAs found in periodontal biofilms, or by the increased exposure of tissue components to the immune system. This system, established to deal with the consequence of tissue damage, may thus become excessive and contribute to the progression of periodontitis. Berglundh et al153 demonstrated a significantly increased number of circulating CD19-positive B cells in periodontitis patients compared to healthy subjects. CD19 is a B cell surface marker often associated with autoimmunity; therefore, the authors concluded that these B cells were autoreactive153. Although it is possible that periodontitis may result in elevated systemic (natural) autoantibodies, there is no evidence that periodontitis can trigger autoimmune diseases via this pathway.
11.2.3 Interfaces of innate and adaptive immunity
Intracellular signalling proteins and cell surface receptors that bridge both the innate and adaptive immune system are important for host defence, as they are found across all immune, stromal and parenchymal cells (e.g. epithelial cells and osteoclasts) and thus enable immediate communication between cells, followed by a timely appropriate immune response.
126.96.36.199 Heat shock proteins
When exposed to a wide range of environmental stressors (temperature, pH, ROS), prokaryotic and eukaryotic cells respond by inducing the synthesis of stress proteins, including the highly homologous heat shock proteins (HSPs). HSPs facilitate the assembly and folding of proteins and the degradation of damaged or toxic proteins154. HSPs thus protect cells from damaging effects. HSPs are antigenic, and the recognition of epitopes on such highly conserved antigens can cause autoimmune diseases. In periodontitis, elevated levels of antibodies to HSP60 have been demonstrated145. Furthermore, the bacterial homologues GroELs can lead to cross-reactivity with human autoantibodies and T cells in periodontitis145,155.
Anti-HSP autoantibodies were also found in asthma, SLE, diabetes mellitus type 1 and RA151. Interestingly, Sims et al157 found that the titres to HSP70 were significantly higher in patients with type 1 diabetes and periodontitis than in nondiabetic controls. However, this study could not provide evidence of a direct association between these two diseases through this mechanism157. Three models have been proposed to link microbial infections to subsequent autoimmune reactions involving the HSPs:
● molecular mimicry between the microbial and human HSPs, attracting anti-HSP autoantibodies158
● inflammation-induced exposure of otherwise hidden cell epitopes that could be a target for immune reactions159
● chronic (repeated) antigen presentation in infected sites leading to autoimmunity.
188.8.131.52 HLA phenotypes and major histocompatibility complex
All nucleated cells of the body possess class I major histocompatibility complex (MHC) molecules, encoded by the HLA complex. The function of MHC molecules is to bind peptide fragments derived from pathogens and to display them on the cell surface for recognition by T cells. The highly polygenic and polymorphic nature of MHCs is responsible for their ability to bind to a wide range of peptides, and this enables the immune system to respond to a multitude of different and rapidly evolving pathogens160. Several investigators have reported an association between a high incidence of some HLA/MHC polymorphisms and autoimmune diseases including RA, diabetes mellitus type 1 and SLE103,161,162.
The evidence relating HLA phenotype distribution to the prevalence of periodontitis has been contradictory. However, studies that tissue-typed patients with aggressive (Grade C) and with other forms of periodontitis found an association between HLA-A9, HLA-B15 and Grade C periodontitis163–172. This was further supported by a meta-analysis including 12 studies, which concluded that HLA-A9 and -B15 seem to represent susceptibility factors for Grade C periodontitis, whereas HLA-A2 and -B5 are potential protective factors against periodontitis among Caucasians173. Whilst HLA-A9 has not been demonstrated in autoimmune diseases, HLA-B15 was shown to be associated with the occurrence of spondyloarthritis (see Section 11.3.5 ‘Periodontitis and ankylosing spondylitis’). Although links between HLA and autoimmunity and links between HLA and T cell activation in periodontitis have been described, it remains unclear whether certain HLA phenotypes in periodontitis can lead to autoimmune reactions locally or systemically.
184.108.40.206 Fc gamma receptor polymorphisms
Fc receptors play an essential role in antibody-dependent immune responses. They are found on many types of hematopoietic cells including macrophages, neutrophils, dendritic cells, eosinophils, basophils, mast cells and NKs. These receptors recognise the Fc portion of an immunoglobulin bound to an antigen (immune complex). Alterations of FcγRs can be linked to autoimmunity in three ways:
● failure to clear immune complexes from the circulation and tissues
● hyper-responsiveness to circulating immune complexes through interaction with FcγRs that activate intracellular pro-inflammatory signalling cascades
● excess antibody production by plasma cells leading to increased immune complex formation174.
Several studies have highlighted a role of FcγR polymorphisms in infectious, inflammatory and autoimmune diseases and are promising targets for autoimmune therapies175–177. Also in periodontitis, such polymorphisms were shown to be a risk factor in several independent studies and different populations176–183. Two meta-analyses were conducted to evaluate the evidence regarding this association and confirmed its plausibility184,185. However, further studies are needed to establish a cause–effect relationship.
● FcγR polymorphisms appear to increase susceptibility to periodontitis as well as to autoimmune diseases; thus, this receptor may constitute a link between them.
● HSPs are commonly found to be elevated in autoimmune diseases as well as in periodontitis. However, no evidence exists that HSPs or HSP-directed autoantibodies are causative of these diseases.
● Furthermore, it is currently unclear whether HLA/MHC phenotypes may be a link between periodontitis and certain autoimmune disorders.
Numerous studies have been undertaken to investigate the association between periodontitis and the prevalent autoimmune diseases diabetes mellitus type I, IBD and RA. These associations are discussed in Chapters 1, 4 and 5 in this book and are therefore not part of this chapter. Also, neurodegenerative disorders like Alzheimer disease and Parkinson disease have recently been considered autoimmune disorders. They are addressed in Chapter 9 ‘Periodontitis and neurodegenerative diseases’. In this chapter, the possible associations between periodontitis and other prevalent autoimmune diseases are unveiled.
11.3.1 Periodontitis and systemic lupus erythematosus
SLE leads to chronic inflammation that affects multiple organ systems, as immune complexes with autoantibodies are formed and deposited in the tissues. SLE commonly exhibits oral symptoms such as xerostomia, caries, difficulties in chewing and swallowing, dysguesia and burning tongue186. SLE is thought to develop when a T-cell receptor binds to the MHC portion of an antigen presenting cell, leading to cytokine release, inflammation, and B-cell stimulation with the subsequent production of autoantibodies. The subsequent organ damage exposes structures that act as antigens and stimulate B cells to produce further autoantibodies against these187, leading to a vicious cycle. Although the precise aetiological mechanism is unknown, genetic, hormonal and environmental factors have been identified. For example, a meta-analysis found that certain FcγR polymorphisms alter the risk of developing SLE188. Associations between SLE onset and age, sex, geography and race have also been established. FcγR polymorphisms provide a possible link to periodontitis, although the specific polymorphisms shown to play a role in SLE have not been intensively investigated in periodontitis.
Interestingly, B cell activation and increased ANCA were also found in SLE, indicating a further possible mechanism common in both diseases18. Another common feature in SLE and periodontitis is TLR2 and -4 activation. Marques et al189 suggested that periodontitis might increase the risk for developing SLE via TLR2 and -4 activation by periodontal bacteria. In support of this, Corrêa et al12 reported that SLE subjects that had higher bacterial loads in dental plaque samples and more severe forms of periodontitis. Bacterial species detected in higher proportions in periodontally diseased and healthy SLE patients were Fretibacterium, Prevotella nigrescens, and Selenomonas. The authors linked changes in the oral microbiota to increased local inflammation, as demonstrated by higher cytokine concentrations in SLE patients with periodontitis12. Accordingly, Fabbri et al9 observed an amelioration of SLE disease activity after successful periodontal therapy. Thus, it is possible that an altered oral microbiome in SLE may contribute to immune activation via TLRs. Overall, only a few clinical studies have been conducted and these show divergent results regarding an association between periodontitis and SLE. However, more recent studies report a mild association between the conditions10,13, and two meta-analyses showed significant associations, however, with a high degree of uncertainty in the latest meta-analysis (OR = 5.32, 95% confidence interval (CI) 1.69 to 16.78)8,8a. Prospective cohort studies with larger population sizes and well-planned intervention studies investigating the effects of SLE treatment on the periodontal status and vice versa need to be carried out in the future.
11.3.2 Periodontitis and Sjögren syndrome
Sjögren syndrome is a chronic systemic autoimmune disease characterised by lymphocytic infiltration of exocrine glands. It either presents as an entity by itself (primary Sjögren syndrome [pSS]), or in conjunction with another autoimmune disease (secondary Sjögren syndrome [sSS]). A range of autoantibodies is often found in Sjögren syndrome: anti-SSA/Ro and anti-SSB/La antibodies, rheumatoid factor, cryoglobulins and antinuclear antibodies. The heterogeneity of signs and symptoms has led to the development of multiple classification criteria. However, there are no universally accepted classification criteria for the diagnosis of Sjögren syndrome190. Regarding a possible association with periodontitis, patients with pSS and periodontitis reportedly have high levels of B cell activating factor (BAFF), which correlated with periodontal pocket depth in a case-control study conducted by Pers et al27. They suggested that BAFF could activate B cells in the periodontium of these patients and thus aggravate periodontitis27. Scardina et al191 observed evident alterations in the gingival microcirculation in patients with Sjögren syndrome with a reduced calibre of capillaries and a greater number and tortuosity of capillary loops. They concluded that this may be related to the development of periodontal inflammation in these patients191.
Several case-control and association studies, one prospective cohort study and an interventional study have been conducted, and most of these indicate that no association exists. This was also confirmed by a recent systematic review, which included ten studies and reported no significant differences in gingival inflammation, plaque levels, CAL, and pocket depth between patients with Sjögren syndrome and controls.21 However, these results need to be interpreted carefully, as some studies show methodological weaknesses, such as inclusion of only a few index teeth in the clinical assessment of periodontitis35, lack of healthy control groups29,32 and small study population sizes22. A 2019 prospective cohort study carried out on 135,190 individuals with and without periodontitis showed, however, that periodontitis patients developed Sjögren syndrome more often than non-periodontitis controls over a period of 7 years (adjusted hazard ratio 1.47, 95% CI 1.36 to 1.59)192. Although this study used a large sample size and a relatively long follow-up period, a limitation is that the data were obtained from the National Health Insurance Research Database of Taiwan. Thus, it is difficult to determine how periodontitis was assessed and the diagnostic criteria. In order to establish evidence for an association or non-association of these conditions, further mechanistic studies as well as large-scale cohort studies using well-established disease definitions need to be carried out.
11.3.3 Periodontitis and psoriasis
Psoriasis has been defined as a chronic dermatological autoimmune disease featuring epithelial hyperplasia. This clinically presents as cutaneous erythematous papules and plaques covered by white scales commonly observed on the extensor-dorsal cutaneous surfaces. A cohort study with large population numbers of > 100,000 per group was carried out by Keller and Lin41. Their results identified a weak association between periodontitis and psoriasis and suggested periodontal status may be an independent risk factor for psoriasis. Their conclusions are supported by the findings of most, but not all, other studies investigating this association. However, the number of such studies is small, and some do not employ sufficiently robust methodological standards to permit establishing a cause–effect relationship between the diseases. For example, Nakib et al40 assessed the presence of periodontitis through self-reporting by the participants, whereas Preus et al48 diagnosed the presence of periodontitis based on bitewing radiographs. A large 2016 cross-sectional study assessed the whole Danish population above the age of 18, including 54,210 and 6988 patients with mild and severe psoriasis, and 6428 with psoriatic arthritis, regarding their risk of developing periodontitis. They found a significant psoriasis-associated increased risk of periodontitis, which was highest in patients with severe psoriasis and psoriatic arthritis (adjusted incidence rate ratios 1.66 (95% CI 1.43 to 1.94) for mild psoriasis, 2.24 (95% CI 1.46 to 3.44) for severe psoriasis and 3.48 (95% CI 2.46 to 4.92) for psoriatic arthritis. However, all data were obtained from the Danish National Patient Register, therefore assessment and diagnosis of periodontitis may have varied significantly39.
Interestingly, it was shown in one case report that any bursts and remissions of periodontitis also correlated with exaggerations and remissions of psoriatic episodes193. Both diseases have high levels of IL-17, an exaggerated immune response by dendritic cells to microbial complexes and upregulation of TLRs in common194. It is therefore possible that oral pathogens may stimulate psoriasis through activation of these pathways.
11.3.4 Periodontitis and respiratory allergies
One of the most common respiratory allergies is allergic rhinitis, which is a symptomatic disorder of the nose induced by exposure to allergens and mediated by immunoglobulin E (IgE). The prevalence of allergic rhinitis is increasing worldwide. Antigen presenting cells, such as dendritic cells in the mucosa, present allergens on the MHC class II molecule. This complex acts as a ligand of T-cell receptors, resulting in differentiation into allergen-specific Th2 cells. These secrete cytokines, inducing B cells to produce specific IgE and proliferation of eosinophils, mast cells and neutrophils195. Allergies are a form of autoimmunity, and the associations between periodontitis and some allergies have been investigated in several clinical studies. Existing studies on periodontitis and asthma are discussed in Chapter 6 (Periodontitis and respiratory diseases), Table 6-1. Consistent with the “hygiene hypothesis”, some researchers have suggested that certain bacteria including periodontal pathogens might be protective against the development of asthma and other allergic diseases196,197. Currently, there is a need for further research to verify whether the oral microflora has the potential to prevent allergies. Very few studies have attempted to explore the concept of associations between periodontitis and allergies.
Ramesh Reddy et al198 reviewed existing studies and summarised their limitations. As cross-sectional study designs were employed in the majority of cases, they contended that these studies generated a hypothesis of putative associations rather than providing evidence for or against a causal relationship198. Interestingly, however, these studies were unanimous in suggesting an inverse association between the conditions. Most of the studies were conducted either in American or European populations. Because variations in genetic background and susceptibility patterns to various pathogens exist among different populations, the authors suggest a need for conducting multi-centre studies to find such variations and to assess the validity of the hygiene hypothesis within specific populations. Prospective birth cohort studies and interventional studies that examine associations between periodontitis and allergic diseases (allergic rhinitis, atopic dermatitis, food allergy and asthma) are needed to fully understand a possible mechanistic link.
11.3.5 Periodontitis and ankylosing spondylitis
Spondyloarthropathies are a group of interrelated inflammatory arthritides that share clinical features and genetic predisposing factors. This group includes ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis, Crohn disease and juvenile-onset spondyloarthritis. Their major clinical features are sacroiliitis, loss of spinal mobility and spinal inflammation, leading to fibrosis and ossification199. AS has an unknown aetiology, and although it is a chronic inflammatory disease, it is also considered an autoimmune disease. The HLA-B27 subtype is strongly associated with AS. Additionally, IL-17 and Th17 could play a role in the pathogenesis of this disease, although the precise pathways are currently unknown200.
Ratz et al50 conducted a meta-analysis of existing studies investigating possible associations between AS and periodontitis. They determined that the prevalence rates of periodontitis in AS patients ranged from 37.5% to 87.8%, compared to a range from 25.9% to 71.4% in non-AS controls. The existing studies are consistent in finding the prevalence of periodontitis in AS patients to be higher than in non-AS patients. However, only the results obtained by Keller et al55 and Helenius et al59 reached statistical significance. On the other hand, a recent case-control study by Bautista-Molano et al53 using age- and gender-matched controls and involving 78 patients with spondlyoarthritis demonstrated no association between the conditions. In a 2015 study by Kang et al54, it was reported that whilst the prevalence of moderate-to-severe periodontitis was no different between patients with AS and controls, periodontitis was positively associated with impaired spinal mobility of patients with AS after multivariate analyses taking into account a variety of possible influencing factors. Interestingly, patients with AS had more risk factors than controls in this study, such as fewer dental visits within the previous 12 months and lower daily tooth brushing frequency54. Overall, the number of studies is small and many show methodological weaknesses (e.g., inconsistent reporting of clinical parameters), which makes comparison difficult. There is a need for further studies with sufficient statistical power, taking into account potential confounding factors, such as age, and using validated measures of AS and periodontitis. Such studies would benefit from collaborations between rheumatologists, dental practitioners and epidemiologists50.
11.3.6 Periodontitis, pemphigoid and pemphigus vulgaris
Pemphigus vulgaris is a chronic autoimmune mucocutaneous disease that initially manifests in the form of intraoral lesions, which spread to other mucous membranes and to the skin. In pemphigus vulgaris, autoantibodies are produced against desmoglein 3, which is found in desmosomes in the keratinocytes of the epidermis. As a result, the keratinocytes separate from each other, and are replaced by interstitial fluid, forming a blister. Pemphigus vulgaris affects people of all races, age and sex201. Pemphigoid is more common than pemphigus, and is characterised by immunoglobulin G (IgG) autoantibodies against structural proteins of the dermal–epidermal junction (basement membrane) 202.
Studies investigating associations between periodontitis and pemphigoid or pemphigus vulgaris exhibit several limitations and confounding factors: small study population sizes were used and sparse characterisation of patients regarding their clinical status was commonly found (e.g. sites of involvement and autoantibody specificity; unknown disease duration; lack of uniform, standardised severity score indices for both the autoimmune and periodontal disease; incomplete information on smoking habits, comorbidities and administered drugs)203. Most studies reached the conclusion that no association exists between the diseases; however, the outcomes need to be interpreted with care due to the methodological shortcomings. Nevertheless, it seems plausible that patients with oral pemphigus vulgaris may be prone to the development of periodontitis, as oral hygiene is often limited in these patients due to oral pain and discomfort204.
11.3.7 Periodontitis and systemic sclerosis (scleroderma)
Systemic sclerosis is one of the most complex systemic autoimmune diseases. It targets the vasculature, (myo-)fibroblasts and components of the innate and adaptive immune system. The various clinical manifestations of systemic sclerosis are the result of:
● immune system abnormalities leading to production of autoantibodies and cell-mediated autoimmunity
● microvascular endothelial cell and small vessel fibroproliferative vasculopathy
● fibroblast dysfunction, generating excessive accumulation of extracellular matrix in the skin and internal organs.
All three of these pathological processes interact and affect each other. Different genetic or triggering factors (i.e. infection) are thought to underlie systemic sclerosis205. In the context of periodontitis, Alexandridis and White206 reported widening of the periodontal ligament in scleroderma patients. Moreover, dilated and thickened capillaries were observed in the oral mucosa and gingiva of systemic sclerosis patients207,208. The authors concluded that localised fibrosis, vasculitis and ischaemia may contribute to the pathogenesis of periodontal breakdown. Overall, the low number of clinical studies, namely four case-control studies, that have been conducted to date does not allow for a conclusion regarding a possible association between these two diseases. However, a recent well-designed study conducted by Isola et al67, which took into account a large variety of confounding factors, reported a higher number of missing teeth and an increased odds of 2.95 (95% CI 1.26 to 6.84) of periodontitis defined as clinical attachment loss, compared to non-diseased controls (6.83, 95% CI 1.94 to 24.36). This study confirmed the results of earlier research by Pischon et al68 and Leung et al69.
11.3.8 Periodontitis and multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterised by autoreactive immune cells directed against oligodendrocytes, astrocytes, neurons or other CNS components. Although numerous experimental, genetic and epidemiological studies have been conducted, the trigger mechanisms of this autoimmune disorder remain elusive. It has been proposed that MS is caused by a complex interplay of genetic and environmental factors (e.g. infections and the composition of the gut microbiome). While over the past decades T cells have been considered key players in the pathogenesis of MS, it has now become evident that B cells have a major contributing role by producing autoantibodies. However, despite tremendous efforts, the target antigen(s) of B cells in MS are yet to be identified209. Sheu and Lin71 investigated the association between MS and having been previously diagnosed with periodontitis, adjusting for a range of influencing factors. They reported an association between MS and periodontitis in females only71. Gustavsen et al70 conducted a similarly designed study using a larger study population, and reported no such association. Further studies are needed to shed light on possible associations between periodontitis and MS, particularly well-controlled intervention studies and oral microbiome association studies.
11.3.9 Effect of autoimmune disease therapies on periodontitis
The introduction of a wide range of drugs targeting different aspects of the immune system in the past decade and their successful clinical application have enabled mechanistic studies of immuno-inflammatory pathways in humans. The increasing efforts in anti-cytokine pharmaceutical research have yielded drugs targeting tumour necrosis factor α (TNF-α), IL-1β, IL-6 and interferons. They are used as therapies for RA, spondyloarthritis, SLE, systemic sclerosis and other autoimmune diseases210. As a new development, an antibody targeting IL-17 has been approved recently211. While these drugs are clearly effective in treating RA, Crohn disease and some other autoimmune conditions, their impact on common infections such as periodontitis is poorly defined. Such studies would shed light on the true nature of the cytokine responses in humans that are commonly found during infections.
Mayer et al212 reported that patients with autoimmune diseases have higher periodontal indices and higher TNF-α levels in gingival crevicular fluid than healthy controls, and that anti-TNF-α treatment reversed this phenomenon. Kobayashi et al213 observed a beneficial effect of tocilizumab, an IL-6 receptor inhibitor used in RA therapy, on periodontal inflammation in patients with RA and periodontitis. The authors suggested that this effect might be related to the decrease in systemic inflammatory mediators213. Coat et al214 reported that anti-B lymphocyte therapy (rituximab) used in RA treatment significantly decreased periodontal pocket depth and attachment loss. Pers et al215 found that anti-TNF-α treatment with infliximab reduced periodontal clinical attachment loss in RA patients, but increased gingival and papillary bleeding, whereas the nucleic acid synthesis inhibitor methotrexate had no effect on the periodontal status. The authors concluded that TNF-α blockade could be beneficial in the treatment of periodontitis215. These findings also further support an aggravating role of pro-inflammatory cytokines and B cells in periodontitis. Further large-scale well-controlled intervention studies including periodontal treatment in patients receiving such autoimmune therapies can help to establish the effectiveness of these drugs against periodontitis.
Corticosteroids are widely used immunosuppressants and have been shown to effectively reduce self-directed inflammation in RA, SLE, Crohn disease and others. Beeraka et al216 reported that patients taking corticosteroids exhibited significantly higher levels of candidiasis, clinical attachment loss and probing pocket depths. Bone density was significantly lower in this group compared to the controls216. Similarly, Mendonça et al30 concluded in their 2019 case-control study of Sjögren syndrome patients that the cumulative dose of corticoids statistically corresponded to higher pocket depths. In contrast, Safkan and Knuuttila217 observed no differences in probing depth, gingival recession and alveolar bone height between patients with MS receiving corticosteroid therapy and controls. Other immunosuppressive medications, such as calcineurin inhibitors (cyclosporine A, tacrolimus) or inflammatory pathway (mTOR [the mammalian target of rapamycin]) inhibitors (sirolimus, everolimus), which are often used as therapeutics in autoimmune diseases, can elicit gingival overgrowth as a common side effect218. Thus, suppressants of the immune system do not appear to promote periodontal healing and stability.
● There is limited evidence for an increased prevalence of periodontitis in patients with ankylosing spondylitis. Furthermore, limited evidence for a weak association between periodontitis and psoriasis exists, and poor periodontal status has been suggested as an independent risk factor for psoriasis.
● With the exception of RA studies, there is a pronounced lack of studies investigating associations between periodontitis and autoimmune diseases, and many studies show methodological weaknesses, such as the inconsistent use of clinical indices. Thus, limited conclusions can be drawn at present, and these need to be interpreted with caution.
● Drugs that target specific components of the immune system, such as infliximab, can improve clinical periodontal parameters in patients with periodontitis, whereas general immunosuppressants, such as corticosteroids or calcineurin inhibitors, do not seem to improve periodontitis and can elicit gingival overgrowth.