SYSTEMATIC REVIEW AND META-ANALYSIS
|Year : 2020 | Volume
| Issue : 4 | Page : 615-620
|Autoimmunity and periodontal disease: Arguing a possible correlation
Giovanna Rosa Degasperi1, Marina Vian Ossick2, Sérgio Luiz Pinheiro2, Augusto Etchegaray2
1 Immunology League, Faculty of Medicine, Pontifical Catholic University of Campinas, Campinas, SP, Brazil
2 Post-graduation in Health Sciences, Pontifical Catholic University of Campinas, Campinas, SP, Brazil
Click here for correspondence address and email
|Date of Submission||07-Sep-2017|
|Date of Decision||13-Jun-2018|
|Date of Acceptance||14-Jul-2018|
|Date of Web Publication||16-Oct-2020|
| Abstract|| |
Currently, there is a growing interest in studying systemic conditions associated with periodontal disease such as autoimmune disorders. Periodontal disease is a destructive inflammatory disease of the dental supporting tissues. The microorganisms associated with periodontal disease constitute diverse species that can colonize the oral cavity and influence the emergence or evolution of autoimmunity, characterized by a breakdown in the mechanisms of tolerance to self-antigens. Here, we reviewed and discussed a possible correlation between periodontal disease and autoimmunity, placing periodontal-pathogenic microorganisms as orchestrators of these pathological conditions.
Keywords: Autoimmunity, food intake, periodontal disease, periodontal pathogens
|How to cite this article:|
Degasperi GR, Ossick MV, Pinheiro SL, Etchegaray A. Autoimmunity and periodontal disease: Arguing a possible correlation. Indian J Dent Res 2020;31:615-20
|How to cite this URL:|
Degasperi GR, Ossick MV, Pinheiro SL, Etchegaray A. Autoimmunity and periodontal disease: Arguing a possible correlation. Indian J Dent Res [serial online] 2020 [cited 2020 Oct 31];31:615-20. Available from: https://www.ijdr.in/text.asp?2020/31/4/615/298408
| Introduction|| |
The oral cavity is an open ecosystem, with a dynamic balance between the entrance of microorganisms, colonization modalities and host defences aimed to their removal. Endogenous microorganisms contribute to metabolic, physiological and immunological functions of the host.
Dental biofilm is primarily composed of microorganisms existing within an intercellular matrix that consists of organic and inorganic materials derived from saliva, gingival crevicular fluid and bacterial products. If the production and accumulation of dental biofilm is aggravated due to systemic problems, poor hygiene or eating habits, the balance of oral microbiota is lost, resulting in associated diseases as dental caries and/or periodontitis. Periodontal disease (PD) is an aggravation of periodontitis, which leads to inflammation of gingival tissues, loss of the insertion of the periodontal junction, loss of the osseous support and other undesired systemic effects. [Figure 1] shows a typical case of PD observed at clinic.
There is a correlation between nutrition and oral health. Healthy eating prevents tooth decay and PD. Macronutrients such as carbohydrates, proteins and fats are required in higher amount. However, a high intake of sugar, along with poor hygiene, increases the risk of caries and, potentially PD, due to plaque accumulation and higher growth rate of the aggressive microorganisms. Systemic conditions such as obesity also contribute to PD. Patients that accumulate fat have increased risk of developing gingival problems, when compared to those that have adequate body weight. An explanation is that obesity induces the circulation of pro-inflammatory cytokines aggravating any inflammatory process.,,, In addition, diabetes mellitus is another risk factor for the initiation and progression of PD.
On the other hand, PD can lead to systemic diseases too. The inflammation caused by PD affects pancreatic β cells, leading to insulin resistance and higher levels of blood sugar. Thus, it worsens diabetes condition and makes it more threatening.
PD is linked to an increase in cardiovascular disease and is associated with rheumatoid arthritis, basically due to the same pathological mechanisms.,
In this review, we would like to suggest that there is a correlation between PD and autoimmune disease (AD).
Genetic susceptibility, environmental stimuli and a failure of immune regulating self-antigens are responsible for the development of autoimmunity.
Several factors of genetic, environmental, and inflammatory origin may collectively contribute to the establishment of autoimmune diseases. This is particularly true when there is a failure of the immune system to tolerate its own antigens. Regarding genetic factors, several studies suggest that there is a strong association between gene polymorphisms and autoimmune diseases. Most polymorphisms are within the regulatory regions of genes involved in immune protection. Of all the genes correlated to autoimmunity in humans, the most relevant are associated with HLA and cytokine receptors, such as IL-23R. IL-23 is a cytokine connected to inflammatory response, since it increases the pro-inflammatory capacity of Th17 cells. Genetic polymorphisms, other than IL23R have been discovered in some inflammatory bowel diseases, as well as in psoriasis. Aggravation of inflammatory response also results from tissue damage that occurs during inflammation or infection. These conditions define the presence of antigenic epitopes leading to further activation of lymphocytes essential for the amplification of the inflammatory response. Furthermore, the new epitopes constitute novel recognition sites for T and B-lymphocytes, favouring autoimmunity.
Basic immunological mechanisms of autoimmunity
Thymic education: positive and negative selections prevents T cell recognition of self-antigens
T-lymphocyte precursors generated in the bone marrow migrate to the thymus, where they are selected (either positively or negatively). Thymocytes undergo exhaustive selection processes that require interactions between the T cell receptors (TCRs) and peptide-major histocompatibility (peptide-MHC) complexes, on thymus antigen-presenting cells. The immature thymocytes are presented as double negative cells, since they do not express CD4 and CD8 molecules.
In positive selection, occurring at the thymic cortex, the immature thymocytes start to express the CD4 and CD8 molecules. In this case, they become double positive CD4+ and CD8+ cells, which interact with the MHC class I, and class II of the epithelial cells of thymic cortex. If recognition of the antigen involves TCR binding to the peptide-MHC class II complex, this cell will turn into CD4+ and CD8- T cells. However, if MHC class I mediates this presentation, a differentiation of CD4-/CD8+ T cells will be induced. Thymocytes that interact with low affinity to self-peptide-MHC complexes displayed in the thymic cortex are induced to survive. However, those that do not show adequate interaction will enter programmed cell death.
After positive selection, TCD4 and TCD8 cells migrate to the thymic medulla, where they will pass through the negative selection process. The positively selected thymocytes begin to express the CCR7 chemokine receptor, which leads to its attraction to the spinal cord region. Within the thymic medulla, these cells are exposed to a large diversity of self-antigens, presented by dendritic cells and medullary thymic epithelial cells with the objective of teaching the lymphocyte to recognize only non-self-antigens. Medullary thymic epithelial cells activate a promiscuous gene-expression program, leading to the synthesis of wide array peripheral, tissue-restricted, self-antigens. Autoimmune regulator (Aire), a nuclear protein expressed in a fraction of Medullary thymic epithelial cells (mTECs), contribute to promiscuous gene expression. High-affinity TCR interactions with those self-antigens displayed in thymic medulla induce deletion of positively selected thymocytes or differentiation into regulatory T (Treg) cells. This contributes to self-tolerance, thus preventing the development of autoimmune diseases. Tregs differentiate in the thymus, but the mechanisms that control this process are not fully stablished., Following successful thymic education, TCD4 and TCD8 cells are exported to periphery. [Figure 2] reveals the positive and negative selection processes occurring at human thymus.
|Figure 2: Schematic representation of positive and negative selection in the human thymus|
Click here to view
Immune Tolerance: the control of autoreactive T and B lymphocytes
The central tolerance mechanisms that occur in the thymus and within the marrow to control a generation of auto-reactive T and B lymphocytes are not perfect, allowing auto-reactive T-and B-cells to maturate and enter peripheral tissues. The central and peripheral tolerance are mechanisms to effectively regulate positive response to foreign antigens and negative response to self-antigens in peripheral tissues. Central tolerance refers to the triggered cell death of intra-thymic (immature T cells) with high affinity for self-antigens, as discussed above. Peripheral control mechanisms are defined as T cell anergy, T cell deletion, and of Treg activity.
Anergy represents a state of inactivation that results from insufficient co-stimulation of self-reactive T cells. The co-stimulatory molecule CD28 is required for T cell activation after antigen presentation to TCR. Similarly, the co-stimulatory molecules CD80 and CD86 are involved in inhibition, which takes place upon binding to T lymphocyte-associated antigen 4 (CTLA-4) on previously activated T-cells. In this condition, CD28 co-stimulatory signalling is interrupted, leading to incomplete T-cell activation and, consequently, to a state of anergy. On the other hand, a deletion results from apoptosis by extrinsic or intrinsic pathways that are induced upon self-antigen recognition.
Treg cells play major role in immune homeostasis by preventing or limiting T-cell activation. FOXP3 is a transcription factor required for these cells, which develop primarily in the thymus and are designated CD4+ and CD25+. Although they can also be differentiated in the periphery, in which case, they are known as TH3- and Tr1-cells. In addition, Tregs modulate the activity of reactive T-cells to self-antigens through production of regulatory cytokines IL-10, TGF-β, and IL-35.
Main aspects correlated to periodontal disease
Periodontal disease comprises a wide range of inflammatory conditions that affect the supporting structures of the teeth (gingiva, bone and periodontal ligament), which can lead to tooth loss as well as to systemic inflammation. Gingivitis, constituting a milder form of periodontal disease, is highly prevalent and reversible through effective oral hygiene. On the other hand, periodontitis is more aggressive, as it leads to the loss of connective tissue from the support and alveolar bone., The severity of periodontal disease is influenced by genetic, environmental and nutritional factors.,
The correlation of nutrition and PD may be described in terms of macro and micronutrient ingestion. While macronutrients such as carbohydrates and fats have indirect effects, micronutrients pose stronger influence. For instance, vitamin A, which is liposoluble, contributes to the integrity of epithelial cells. Due to its strong antioxidant activity, it protects the periodontium. Complex B vitamins act in cellular metabolism, repair and proliferation.,, Vitamin C regulates the synthesis of collagen and acts as antioxidant. It is important for all cells as it regulates the production of reactive oxygen and nitrogen species (ROS). Deficiency of vitamin C causes scurvy, a disease associated with bleeding and inflammation of the periodontium. Supplementation with vitamin C helps to reduce inflammation as it promotes the activity of phagocyte cells. Another important vitamin is vitamin D, which facilitates mineral absorption. Some studies correlating vitamin D and periodontal health are still controvert. However, it is common knowledge that adequate quantities of vitamin D and calcium are essential for bone structure. Vitamin D deficiency can induce complications such as cancer, infections, chronic inflammation, autoimmune diseases, and rheumatoid arthritis, among others. Thus, vitamin D has important functions on immune and inflammatory response and on its absence, the symptoms of PD become worse. Vitamin D has anti-inflammatory properties as it inhibits inflammatory cytokine expression. In addition, it stimulates monocytes and macrophages to produce and secrete molecules with potent antibiotic properties, as the antimicrobial peptide cathelecidin.,,,,
Therefore, the inflammatory condition observed in PD is ameliorated by antioxidants. Inflammation occurs due to production of ROS by immune cells, which are stimulated by pathogenic agents. Free radicals produced by the body alter molecular structures. Thus, when antioxidants are present there is reduction in ROS production. However, if an excessive amount of ROS is produced, the antioxidant system is not able to minimize oxidative effects. Therefore, periodontal disease corresponds to a state of oxidative stress due to induction of an inflammatory response that was caused by disease or trauma.,,
Therefore, vitamins have an important role in disease suppression. By acting as antioxidants, they modulate the defence system and the supplementation of these have protective activity to fight PD. Recent studies have shown that additional substances that are present in food such as lycopene, melatonin, cocoa, and cathechins, in addition to minerals such as calcium, magnesium, iron and zinc are other important factors in the diet. To keep periodontal health, it is, therefore, necessary to have an equilibrated diet, that is low in carbohydrates and rich in vitamins and minerals, mainly vitamin C, D and other antioxidants that significantly reduce periodontal inflammation.,
The initial trigger of PD, as well as a propulsion thereof, is dysbiosis of the oral commensal microbiota. The strong influence of immune modulation observed in periodontal disease is induced by lipopolysaccharides (LPS) that are produced by Gram-negative bacteria like Porphyromonas sp., which effectively induce bone resorption and immunoglobulin degradation by the host. Studies suggest that predominance of the genera Prevotella and Veillonella in the salivary microbiota is associated with periodontal disease, whereas high levels of the genus Neisseria More Details is indicative of oral health. The interaction of several species is thought to be the actual cause of disease progression; that is, a single microorganism does not cause the onset of periodontal disease.
Prevention is performed by daily self-performed oral hygiene and professional removal of microbial biofilm. For treatment, in some cases the microbial biofilm must be removed therapeutically and, as a last option, the affected tooth must be removed. New actively exploited treatments include antimicrobial therapy, host modulation therapy, laser therapy (including photodynamic therapy), and tissue engineering for tissue repair and regeneration.,, Due to similarities in the immune status of certain pathologies with periodontal disease, theories have been developed that relate PD to autoimmune conditions.
Is there really an association between autoimmunity and periodontal disease?
Many studies have shown potential associations between PD and autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Classically, it is accepted that these diseases are developed due to failures during thymic education or antigen tolerance processes, involving B-and T-cells The first report on the association of autoimmunity and periodontal disease was published by Brandtzaeg and Kraus in 1965. Thereafter, a number of related research has been reported to link the immunological mechanisms involved in PD.
Microorganisms associated with periodontal disease constitute diverse species that are able to colonize the oral cavity and influence systemic immune response. Studies have shown that the bacterium Porphyromonas gingivalis is involved in periodontal disease and produces the calcium-dependent enzyme, peptidyl-arginine deiminase, which promotes the citrullination of human proteins, by converting peptidyl-arginine sequences to peptidyl-citrulline sequences.,, This post-translational modification of proteins has been associated to a number of diseases. The existence of a variety of auto-antibodies in serum and synovial fluid of patients with RA has been described. In the last ten years, a series of studies have shown that the family of auto-antibodies, which are predominantly immunoglobulins G (IgGs), and are more specific for the disease, are in fact directed against citrullinated proteins., These antibodies are associated to loss of self-tolerance mechanisms such as anergy, deletion, and of Treg cells activity, thus contributing to autoimmune diseases. Auto-antigens recognized by anti-citrullinated protein antibodies (ACPA) include extracellular cytoplasmic and nuclear proteins such as collagen II, vimentin and histones, respectively. Binding of these antibodies to their self-antigens leads to inflammatory response and, consequently, tissue damage. Studies demonstrate the involvement of Th17-cells in the pathogenesis of RA. These cells express the RORYt transcription factor and play predominantly a pro-inflammatory role in their ability to recruit polymorphonuclear cells (macrophages) and to amplify the inflammatory response, producing TNF-alpha and, especially IL-17. The prevalence of the Th17 type response is also due to an imbalance between regT cells and Th17 cells, leading to a destructive immune response. Exacerbation of the Th17 inflammatory response favours periodontal disease.
Besides the production of peptidyl-arginine deiminase (citrullinating enzyme), the periodontal-pathogenic microorganisms also stimulate overexpression of heat shock proteins (HSP) such as HSP60. High temperature and mechanical stress are environmental stimuli to the production of these proteins that also participate in vital physiological cellular processes. In PD, HSPs enhance pro-inflammatory cytokines produced by mature antigen presenting cells such as macrophages. The persistence of the stimuli, can induce self-immune response, causing the onset of autoimmune diseases.
Periodontal-pathogenic microorganisms in sites with periodontal involvement constitute a high antigenic load. This leads to local B-cell hyperreactivity, resulting in polyclonal activation of these cells, a fact that may be responsible for the generation of anti-neutrophil cytoplasmic antibodies (ANCA) in both rheumatoid arthritis and systemic lupus erythematosus. ANCA is a type of autoantibody directed against enzymes located in the primary granules of polymorphonuclear leukocytes and monocyte lysosomes. They have been detected in a wide variety of inflammatory, infectious and neoplastic diseases.
In addition, it was demonstrated that, during periodontal disease, microorganisms also promote the release of various enzymes such as collagen degrading enzymes, trypsin-like proteases, aminopeptidases and lipopolysaccharide (LPS). Immune responses induced by LPS are mediated by Toll-like receptors (TLRs); for instance, TLR-4, on target cells. In addition, there is evidence that TLRs might play an important role in development of rheumatoid arthritis and SLE., TLRs are involved in innate immune response, and act as tools for triggering the inflammatory response to microbial invasion, thus leading to production of proteins and inflammatory cytokines. In humans, there are at least 10 different TLRs. Each one recognizes a specific pathogen-associated molecular pattern (PAMP), including LPS., Interestingly, in SEL, TLRs increase the expression of antibodies to self-antigens by the expression of high levels of interferon. Resuming, there is a possible association between nutrition, lack of hygiene and the onset of PD. [Figure 3] resumes and shows that all these factors are potentially correlated with autoimmunity.
|Figure 3: Possible mechanisms associating nutritional disbalance, periodontal disease and periodontal-pathogenic microorganisms with autoimmunity|
Click here to view
| Conclusion|| |
Patients with periodontal disease should be promptly treated as the disease can influence the development of existing auto-immune diseases or contribute to the emergence of this problem, especially if there is genetic susceptibility, depending on HLA or flaws in immune tolerance mechanisms. Further studies are still needed to understand the link between autoimmunity and periodontal disease. A balanced diet and hygiene prevent PD, however, other conditions such as diabetes may influence or worsen the state of periodontal health. Considering its possible correlation with autoimmune disease, it is important to keep a healthy periodontium.
Financial support and sponsorship
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes, Brazil) and Fundação de Amparo à Pesquisa do Estado de São Paulo (Fapesp, SP, Brazil).
Conflicts of interest
There are no conflicts of interest.
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Prof. Augusto Etchegaray
Faculty of Chemistry, Pontifical Catholic University of Campinas, Rod. D. Pedro I Km 136, Pq. das Universidades, Campinas (SP)- 13086-900
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
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