Role of CD14+ CD16+ Monocytes in the Pathogenesis of Periodontitis Associated Systemic Diseases

Abstract

Monocytes are immune cells that form an important bridge between the innate and adaptive immune response. These cells exist in various phenotypes based on cell surface marker expression and participate in the pathobiology of many systemic diseases. Periodontitis is an inflammatory condition of the tooth attachment apparatus caused by microbial assault from the dental plaque biofilm. It is noteworthy that monocytes play a key role in mediating tissue destruction in periodontitis. The CD14+ CD16+ monocytes that bear both the surface markers are especially involved and upregulated in periodontitis and produce increased amounts of proinflammatory cytokines following microbial challenge. In this context and exploring the available literature, the present chapter aims to unravel the role of CD14+ CD16+ monocytes in periodontitis and systemic disease and also aims to elucidate the possible pathways by which periodontitis could be a key risk factor for systemic disease based on monocyte selection and participation.

1. Introduction

Periodontitis is a currently recognized as an inflammatory disease affecting the supporting structures of teeth, having its origin in microbiome of the oral cavity, influenced by plethora of local and systemic factors. Many evidences regarding periodontal disease are accumulated over a century now. It is consistently shown that the disease is initiated by bacteria, progressing at various stages, leading to tooth loss. However, over and above the loss of tooth, its immense contribution to systemic inflammatory level and load of cytokines is what affords high importance to this disease [1]. Evidence also supports that the sequel of complex interactions amongst the dysbiotic bacterial biofilm and the immune response of the host leads to disruption of homeostasis, setting a vicious cycle in to motion [2]. Therefore, the host immune system is unable to restore the homeostasis leading to the characteristic pathogenesis of periodontitis. In addition, this is also modified by various risk factors such as diabetes mellitus and smoking habits. They complicate the existing complex relationship between the host and the flora.

In this inflammatory process, monocytes and macrophages are considered to be the major cellular components of the innate immunity. Macrophages are seen as the primary host defense mechanism to neutralize the threat from microbes. They are derived from monocytes from blood and hence can migrate to the site of inflammation quickly [3]. The monocytes leave the blood stream in case of inflammation and differentiate into macrophages. In this process, various cellular subtypes have been identified in monocytes. Of the three monocytes- viz. classical, non-classical, or intermediate monocytes, the classical monocytes are the ones that become macrophages at the site of inflammation [4]. While non-classical monocytes take care of vasculature surveillance, the intermediate monocytes participate in the inflammatory cascade. Monocyte life is short and non-classical monocytes live longer than classical monocytes [4].

With regard to the subtypes, monocytes are also seen to express Cluster of differentiation molecules leading to the classification into various immunophenotypes. These molecules act as receptors or ligands mediating various functions of the cell. These molecules are designated by unique numbers and CD14 and CD16 are considered to be of importance in periodontal inflammation.CD14 cells are involved in recognition of microbial cell wall components and clearance of apoptotic cells [5]. CD16 monocytes induce IL-1beta production and leukocyte recruitment under non-infectious conditions [6].

In the past decades relation between increased presence of these CD14/16 monocytes in blood has been related to periodontal disease [7]. Further, these cells acquire macrophage like features while in circulation in blood [8]. The evidences for implicating them are on the rise. If well understood, these can have immense clinical implications, leading to clues to solve complex clinical conditions. Therefore, a these cells can be channels by which systemic inflammation is increased during periodontal disease. Therefore, it is necessary to understand their role in periodontal disease, based on the existing evidence.

2. Immune system in relation to periodontal disease

The immunology of periodontal disease deals with the interaction of host and the microorganisms in the micro-anatomical regions around the tooth. While the area of concern is small in size, it has complex local and systemic interactions. The science begins with the microbiological aspect. In this sense, the microbial population was initially identified and cultured. The implication of a pathogen to a disease requires satisfying the Socransky’s criteria. According to this theory, the relative severity of disease was related to various groups of pathogens like the red, orange, green, orange-associated and Aggregatibacter actinomycetemcomitans complexes [9].

Subsequent to this stage of understanding, research took a different track to identify the molecular pathways involved in the host-bacterial interactions, which occur as a result of host responding to the microbial attack. It was also seen that response of the host is frequently detrimental to the host itself. In current scenario, the molecular pathways are being constantly studied in addition to identification and characterization of unculturable bacteria by metagenomics.

In current understanding, rather than implicating a single or group of microbes in periodontitis, the focus has shifted to characterizing the so called “dysbiosis” of the oral cavity. It is said that the shift of concentrations of various bacterial species are known to cause disease. Here the shift happens by reducing the symbiotic microbes and increasing the pathogenic ones. Further, what was not a pathogen earlier may become a virulent pathogen when the dysbiosis happens. For the host to be in the state of homeostasis, immune system helps to control the microbial colonization. It may be constituted by the salivary, the systemic and the gingival tissue immune systems.

This discussion pertains to local factors and hence salivary and gingival components take the major role. Gingival crevicular fluid (GCF), derived from gingival capillary beds has both resident and emigrating inflammatory cellular components and a wide range of innate, inflammatory and adaptive immune molecules. Saliva is known to contain enzymes and other defense molecules that act synergistically with GCF components [10, 11]. Therefore, due to interaction with pathogens the transudate of GCF becomes inflammatory exudate, kick starting the classical periodontal pathogenesis.

With respect to the cell mediated component of immunity, both T and B lymphocytes are observed. Further, there is an observation of unique subsets of helper and cytotoxic T-cells were involved in: modulating immune response, co-operating with B-cells in the induction of antibody synthesis, stimulating the release of cytokines for cellular communication to activate phagocytic cells; and aiding in the elimination of many intracellular and viral pathogens. Most circulating T-cells express a combination of cluster determinant (CD) markers, including CD2, CD3, CD4 (helper T-cells) or CD8 (cytotoxic T-cells), and a T-cell antigen receptor [12]. In addition to T-lymphocytes, the second primary cell type involved in activating the adaptive immune response is the monocyte/macrophage, which is responsible for antigen recognition, immune stimulation and the tissue consequences that follow immune stimulation.

Therefore, gingival health at the immune-histological level is the delicate balance between the subgingival microbiota and host resistance. Therefore, even under normal conditions, there exists a minimal inflammation with some inflammatory cells in the tissues. This seems to be crucial in maintaining the local homeostasis [13].

3. Monocytes as an integral part of the immune system

Monocytes are one of the major cellular elements of the innate immune system and have crucial roles to play in the tissue homeostasis. Monocytes are called the largest leucocyte, with their diameter between 12 to 20 μm [14]. These cells are easily identified in the blood due to their relatively large size and convoluted bilobed or kidney shaped nuclei [14]. Macrophages are derived from the monocytes and serves as a phagocyte that gulps the microbes in their vicinity. They can reach the site of inflammation in a very short time [15].

A monocyte can differentiate into various populations of macrophages and dendritic cells in order to regulate cellular homeostasis during infection and inflammation [16]. Monocytes are known to perform two distinct roles as follows:

1. They are the patrolling cells and identify microbial cells to orchestrate an immune response.

2. They express different pattern recognition receptors (PRRs), including toll-like receptors on their surfaces which interacts with pathogen-associated molecular patterns present on the invading microbial cells [17]. It is in response to this stimuli, monocytes exit the bone marrow into the circulating blood to reach and infiltrate the tissues with infection within 12 to 24 hours [18].

Subsequent to their arrival at the affected site, the monocytes attach themselves to the endothelium and roll along the vascular surface. Subsequently, they extravasate and perform diapedesis to reach the area of inflammation. This is regulated by monocyte related, endothelial related and chemotaxis related factors. Monocytes from here on function as phagocytes, which present antigens from the foreign cells, to facilitate ingestion and removal of microbes, foreign materials, and necrotic cells. Further, antigen-presenting cells may also include macrophages, dendritic cells, B lymphocytes, and activated endothelial cells [19].

The role of monocytes is in the immune system is very versatile and is crucially related to various types of disorders of infectious and inflammatory origin. Monocytosis is a characteristic feature of numerous inflammatory and immune disorders such as rheumatoid arthritis, systemic lupus erythematous, and sarcoidosis. Hence, monocytes in periodontal inflammation and systemic circulation has been related in the recent days. Monocytes mediate inflammatory reaction by producing both cytokines mounting an substantial immune response and promoting healing by secreting anti-inflammatory cytokines [20].

Macrophages, present in all tissues are formed by differentiation of circulating peripheral-blood mononuclear cells. Monocytes form the blood stream, migrate into the tissue to old tissue-specific macrophages of the tissue. They become tissue specific as they perform their function. These macrophages can further differentiate into various specialized macrophages based on their location. Examples of this may include histiocytes in the connective tissue and osteoclasts in the bone [21].

4. Monocyte subpopulations

While monocytes are characterized for various functions, it is inevitable to classify it according to the function. Generally, they are classified as classical, non-classical, or intermediate monocytes [22]. Classical monocytes are those that can turn into macrophages at the site of injury. While, non-classical monocytes are mainly involved in vasculature surveillance, the Intermediate monocytes, called hyperinflammatory monocytes have major role in the inflammatory cascade [23]. The non-classical monocytes group accumulate at the sites of chronic bacterial infection, producing low levels of pro-inflammatory, but high levels of anti-inflammatory cytokines. Hence, this is more relevant to periodontal infections.

Recently, macrophages are designated pro-inflammatory macrophages (M1) and anti-inflammatory or resolution macrophages (M2) [24]. M1 macrophages are linked with the inflammatory mediators - interleukin (IL)-12 and IL-8. Hence they activate type 1 T helper cells. On the other hand, M2 macrophages are related with transforming growth factor-beta, vascular endothelial growth factor and epidermal growth factor, activating type 2 T helper cells. Therefore, there is a distinct difference in the roles of various subpopulations. During inflammation, subsequent to diapedesis for reaching the site of action, activation of M1 macrophage occurs, leading to production of tumor necrosis factor -α and IL-12. However, during the resolution of inflammation, M2 macrophages are activated inducing VEGF etc., leading to neo-angiogenesis and healing [25].

In this connection, description of monocytes in relation to CD factors is crucial for the critical understanding about its role. CD14 is known as monocyte/macrophage differentiation antigen on the surface of myeloid lineage. This protein has a major role in immune recognition and reactivation. However, recently CD14 is shown to be associated with the phagocytic clearance of apoptotic cells. The CD14 protein acts as a receptor for binding the lipopolysaccharides [26].

CD16− monocytes are known to produce both pro- and anti-inflammatory cytokines production in addition to leukocyte recruitment during infections, while CD16+ monocytes induce IL-1beta synthesis and leukocyte recruitment under non-infectious conditions [26].

It has been reported that various systemic diseases are associated with change in these proportions of monocyte subpopulations. This lower percentage of CD14+/CD16+ monocytes was found in rheumatoid arthritis [27]. Chronic kidney disease patients also show change in these monocytes [28]. With relevance to the original discussion, CD14 and CD16 were increased in chronic and aggressive periodontitis patients respectively [29]. The CD14+/CD16+ cells occur as about 10% of all blood monocytes. They have allow level expression of the CD14 molecule and a high level expression of the CD16 (Fc gamma R III) molecule. Specifically, phenotypic markers of the CD14+/CD16+ blood monocytes resemble tissue macrophages [30]. In this regard, it is worthwhile to note that these monocytes acquire phagocyte like properties even when they are in the blood stream. Therefore, increased production of these cells due to any reason may raise the systemic phagocyte load leading to unexpected mounting of immune response at a location unrelated to the site of production of these cells. In this regard, periodontal inflammation can play a major role in increasing the systemic inflammatory load, both on the basis of humoral and cell mediated pathways.

5. Periodontitis as an oral disorder with immune system role

Periodontitis as generally known, is characterized by a chronic inflammation of periodontal tissue associated with pathogens and modified by various local and systemic factors [13]. Therefore, the pathogenesis is complicated and slow process. In this regard, various imbalances of the immune system precipitated by the oral floral dysbiosis considered as an important factor in the etiopathogenesis of periodontitis [13]. Numerous works have focused on the external pathogenic factors and the clinical treatment of periodontitis. However there is limited documentation of changes in the molecular aspects of the immune system in such cases [13]. In the recent literature, the importance of the imbalance of the periodontal immune system is being focused. The abnormality of cytokines in the host immune response can have a far reaching impact on the human body [13].

6. Role of monocytes in pathogenesis of periodontitis

In a healthy or normobiotic gingival environment, Gram-positive cocci and rods predominate the system. As the plaque matures, there is a gradual transition in to a complex community that is predominated by gram-negative rods, filaments and the fusiforms [31]. This is one of the first steps towards progression to periodontal inflammation. Previous studies have demonstrated high prevalence of prevotella and fusobacteria in early periodontitis [31]. P. intermedia was found to be the predominant anaerobic species that predisposes to periodontitis [31]. Major periodontal pathogens are Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola. When there is a shift in the microbiome, the host response is stimulated and inflammatory reaction sets in. The reaction may be modified by the composition of the flora. It is also known that this dysbiosis may facilitate a non-pathogenic organism to become a pathogen and express virulence. Therefore, this composition may be important to identify the stage of periodontal disease.

In this line of thinking, the CD14 molecule is recognized as primary factor for the innate recognition of bacteria. This CD14 is a 55-kDa glycoprotein that exist in both soluble and membrane bound form, represented as sCD14 and mCD14 respectively. The membrane bound form is immobilized by glycosylphosphatidylinositol tail and is found mainly on mature monocytes, macrophages, and activated neutrophils. Further, the soluble formin circulation is attributed to protease-mediated shedding/cleavage of mCD14. The main role of sCD14 is to provide non-CD14 cells, sensitivity to bacterial products. These cells may be epithelium, fibroblast and so on. Therefore, it should be recognized that all forms of CD14 function as a receptor for byproducts of bacterial cell wall [32].

With regard to periodontium derived mesenchymal stromal cells, soluble CD14 causes radical increase in inflammatory response to bacterial products. Therefore, CD14 acts as a major factor for mounting an inflammatory response. On the other hand, CD16, a type III Fcγ receptor, is involved in antibody-dependent cell-mediated cytotoxicity. In the absence of CD16, this immunological activity is absent in cells. Further, treatment of CD16- monocytes with inflammatory mediators, would result in expression of CD16 in the cell membrane making them CD16+. Hence production of inflammatory mediators by CD14+ monocytes may result in up-regulation of CD16 in monocytes. This CD16+ monocytes require cell-cell contact by integrin for killing the target, by releasing cytotoxic granules [33].

While mechanisms of the host response to periodontal infection have been extensively studied, CD14 still remains an interesting molecule as its role to periodontitis still remains unclear. Reports have associated increased CD14 and CD16 monocytes in the vicinity of periodontitis [34]. Further, CD14+ monocytes are related to osteoclast development leading to influence on bone homeostasis [35]. Some reports have said that the expression of mCD14 in peripheral monocytes decreased in periodontitis, while some authors report no difference. However, majority of the reports show a positive association of sCD14 levels with periodontal disease. Therefore, an increase in production of sCD14 in moderate-to-severe and generalized periodontal breakdown cases may be expected. As a corollary, local levels of sCD14 can be observed in saliva and GCF. As an additional finding, scaling and root planning reduced salivary sCD14 levels.

Further, soluble CD14 can stimulate inflammation even in the absence of bacterial by products, thereby increasing the secretion of pro-inflammatory cytokines, chemokines, and mediators in the local and systemic cells [35].

An important finding is that P. gingivalis outer membrane vesicles can inactivate the CD14 receptor, cleaving the mCD14 from monocytes, resulting in decreased phagocytosis and pathogen elimination [36]. Therefore, Gingipains of P. gingivalis bypass the CD14 based immunity and invade the tissues. Therefore, resultant sCD14 may sensitize adjacent tissues and may enter blood stream leading to sensitization of somatic cells to bacterial byproducts. While host tries to produce more CD14 cells at the inflammatory site, bacteria cleave the CD14 locally, destroying tissues for its nourishment. In this pathway, it also leads to systemic complication.

In interesting phenomenon here is the vicious cycle of monocyte production by body and inactivation by pathogens, leading to flooding of location with cell debris and inflammatory mediators leading to progress of the disease. Other cells of the immune system contribute substantially to this process, thereby contributing to tissue destruction. Other cells of the immune system lead to secretion of various cytokines that directly and indirectly destroy the pathogens. In this nexus of interaction, if the intervention is successful, the periodontium restored to healthy state.

7. Periodontitis as a risk factor for systemic disease

Periodontal inflammation and systemic inflammation appear to be a two way traffic and is demonstrated in many instances. Several authors have reported the association between systemic diseases and periodontal diseases. Periodontium acts as a constant reservoir of infection due to periodontal flora that enters the blood stream, causing stimulation of systemic immunity. This stimulation leads to production of inflammatory mediators that adversely affects various systems of the body (Figure 1) [37].

Figure 1.

Schematic representation of the role of non-classical monocytes.

Aspiration of oral flora can lead to respiratory infections. Constantly high levels of periodontal inflammation leads to increase of systemic C-reactive protein and interleukin (IL)-6 levels and consequent changes in atherosclerotic lesions. This would give rise to various cardiac or cerebrovascular events [38]. It is also reported that rheumatoid arthritis and periodontitis share common immunological processes [39]. In this line, well known bidirectional link exists between Diabetes mellitus and periodontitis [40]. It is also observed that periodontal flora can also worsen Alzheimer’s disease by two mechanisms, viz. increased inflammatory cytokines and invasion of brain by microbes from periodontium. Other systems like renal, skin, reproductive and so on are affected by rise in systemic inflammation [38].

As discussed above, the relation between periodontal inflammation and systemic diseases is well established. The mechanism widely proposed is through increase in systemic inflammation. It is sensible to relate this with other systemic inflammatory diseases like rheumatoid arthritis, lupus erythematous, etc. This rise in systemic inflammation stimulates various organ systems to secrete their specific inflammatory mediators leading to inflammation in that organ. Like the well-known concept of “focus of infection”, this may be called “focus of inflammation” for the purpose of understanding. Every bite or masticatory process would pump the periodontal inflammatory products into blood stream. In the initial stages the stimulus would be well below the threshold of other organs. With continuous and repeated stimulation of tissues by chemical messengers of inflammation, this would cause multiple pathways to be activated. As every organ system responds uniquely to inflammation, the manifestation may bring the patient to a clinician, who may not have any clue of the origin of inflammation. In the recent general medical practice, awareness of clinicians to this focus of inflammation has increased, and they regularly refer patients for clearance from dentist prior to any procedure or devising a treatment plan. The inflammatory condition most commonly manifests as a non-communicable disease like arthritis, cardiovascular disorders and so on, but indeed it is a product of infection.

Management of such infections systemically frequently includes anti-inflammatory drugs and seldom antibiotics. As periodontal infection is identified as a culprit in systemic disorders of wide range, proper administration of antibiotic is needed to solve the problem completely. Further, rise in periodontal inflammation can also be a byproduct of rise in systemic inflammation. For instance increased blood sugar level can bring about increase in systemic inflammation and its influence of periodontal inflammation. Uncontrolled diabetes is well known to increase periodontal inflammation. Hence therapeutics of periodontal inflammation is well intertwined with systemic inflammatory processes. Therefore, dentist must have opinion from a physician to completely assess and address the condition, to afford a proper and complete treatment.

8. Monocytes role in periodontitis systemic disease link

Monocytes are trafficked during chronic inflammation in a slow and well-orchestrated way. Increased monocytes in a location contributes significantly to the pool of monocytes available in circulation. Monocytosis could be initiated by the infection and it drives the monocyte precursor proliferation. As we have discussed amount of monocyte can be proportional to the size of inflammation. Further, removal of monocytes from circulation would leads to reduction in macrophage in the inflamed tissues. Therefore, periodontally stimulated monocytes can reach the systemic circulation and lead to recruitment of macrophages elsewhere in the body. As with inflammatory mediators stimulating inflammation in various far off organs, monocytes can do the same effect, driving cell based inflammation in the visceral and other organs, presenting clinically with a disease of unknown etiology. In this context, when monocytes reach other organs, the interaction of monocyte with that organ entirely be different and specific [41].

Further, monocytes recruited in chronic inflammatory condition can lead to increase in inflammation while those recruited in acute phase can heal the inflammation. This is due to change in subpopulation and difference in release of mediators of inflammation.

In this regard, many questions remain unanswered with respect to monocytes in chronic inflammation. We know that monocyte recruitment increases inflammation in chronic diseases, however, specific subpopulation that works in every organ is not yet found out. To elaborate, the questions to be answered are:

• What is the phenotype of monocyte that is released in to blood stream from periodontal inflammations?

• What are the systemic organs that are affected by released monocyte subpopulations?

• Does every organ get equally stimulated by released monocyte subpopulation or certain organs are resistant to periodontal inflammation induced monocytes?

• Do CD14+ and CD16+ monocyte alone drive the systemic inflammation? If not, what are the modifying factors?

• Will systemic suppression of monocyte lead to lesser recruitment of macrophage in periodontal inflammation?

• Will subpopulations interact in such a way as to stimulate each other destructively leading to destruction of periodontium?

As previously stated, monocytes appear to be a key factor in periodontal inflammation in this situation. Their CD14 and CD16 play an active involvement in periodontal inflammation that is “yet to be fully investigated.” The role of CD14 and CD16 monocytes in systemic immunity, on the other hand, has been thoroughly investigated. As a result of the spillage of monocytes and their by-products into the bloodstream, somatic cells are stimulated, and inflammation increases brutally. By increasing inflammation, this rise in systemic inflammation would have a vicious effect on periodontal tissues.

9. Clinical implications

Though the complete knowledge of monocytes is yet to be achieved, its clinical implications are profound and need attention by not just dentists but also by physicians and other specialists. As explained in the previous section, every system in the body can be potentially affected by this pathologic process.

With respect to the cardiovascular system, chronic periodontitis is well associated with coronary heart disease (CHD) and increases the risk with other contributory factors. The link may be through direct infection or due to increase in systemic inflammation, coupled with genetic factors. Elevated inflammatory markers reaching the atherosclerotic lesions may increase the risk for cardiac or cerebrovascular events [42]. Further, monocyte increase is associated with cardiac diseases [43].

With respect to respiratory system, in addition to flora directly contributing to various diseases, it is important to note that there is an association of monocyte increase in fibrotic diseases [44]. Hence periodontitis may contribute to poor outcome in such cases.

With regard to muscular system, macrophages are needed to repair the injured skeletal muscles [45]. Circulating monocytes contribute to this process. However, with increase in systemic inflammation due to periodontitis, this healing may be delayed. Nevertheless, evidence to this statement is not clearly available. With regard to skeletal system, it has been well discussed about rheumatic arthritis and periodontitis have similar pathophysiology. Therefore, monocytes from periodontal inflammation can increase the arthritis and lead to poor outcome.

As a major observation, CD16+ and CD14+ monocytes are associated with preterm labor. It has been suggested that CD16 can be a marker of preterm labor [46]. In addition, low birth weight and other adverse pregnancy outcomes have been reported to be associated with periodontitis. However, the contributory role of monocytes, especially CD14+ and CD16+ have not been reported. However, even subclinical periodontal infections can trigger adverse pregnancy outcomes as reported by Raj et al. [47].

Diabetes mellitus and periodontal infection is previously discussed. In addition, role of monocytes in diabetes is well explained recently by Kantar et al. [48]. According to them, monocytes and macrophages may be considered as “protagonists” in the inflammatory pathways of Diabetes mellitus and actually mediate all complications in various organs. However, they do not instigate the process, but only do role play of destruction. Previous authors have also associated obesity with increases CD14+ and CD16+ monocytes [49]. It has been said that periodontal inflammation is associated with malignancy [50]. However, role of monocytes in this mediation is yet to be reported in the literature.

In connection with nervous system disorders, Alzheimer’s disease has been associated with periodontal disorders. Monocytes are useful in clearing the amyloid plaque deposited, but it also increases the pre-existing inflammation in the central nervous system [51]. However, specific role of CD14+ and CD16+ monocytes from periodontal origin is yet unexplored.

With this information, it is to be understood that periodontitis is associated with all these disorders. Immune system of the body is involved with all other systems for defense. However, periodontitis interferes with this system through various pathways including monocytes. Therefore, periodontitis assumes phenomenal importance in all disciplines of medicine and dentistry. The awareness should be spread to all medical and paramedical experts to aid in proper management of patients who come with pain and suffering.

10. Conclusion

With the previous collection of evidence discussed in this chapter, apparently monocytes have large number of roles in the immune system. It has various subpopulations catering to specific needs in specific tissues. In this discussion, CD14 and CD16 cells are focused upon. However, the evidence from literature is scanty in several aspects. It is necessary to study the immunological pathways that involve the said monocytes from periodontal origin. This lacuna should be addressed to improve the standard of care provided to patients. Systemic manifestations of periodontitis may present as a disorder of specific system and the patient may seek advice either from a physician or a specialist of that organ system. In the absence of this background knowledge, the therapy may not be successful, as origin of the disorder is not addressed. Furthering the research in this direction can solve a lot of puzzles in both medicine and dentistry.

In the other direction, role of systemically originated monocytes in periodontium should also be further explored. This bidirectional approach is the key to breaking this vicious cycle. Very few diseases have been thoroughly explored in this regard like Diabetes Mellitus. However, potential role of other inflammatory disorders should be explored. An important fact here is that, in a vicious cycle involving periodontium and other organs, periodontium is easily accessible for therapy that breaks the said cycle compared to other visceral organs. Hence physicians should advice patients to consult dental clinicians to get their periodontitis under good control so that other organs may be prevented from damage. If periodontal therapy can stop a lot of disorders, then the burden of care and expenditure for health would reduce considerably in the global level.

Conflict of interest

The authors declare no conflict of interest.