Stress-Periodontitis-Relationships-A Case for Psychoneuroimmunology?
Deinzer, R., Forster, P., Fuck, L., Kottimann, W., et al., Psychologische Beiträge
The present paper discusses psychoimmunological aspects of periodontitis, an inflammatory disease with high prevalence in adult western communities. A brief introduction into epidemiology and pathogenesis of periodontitis precedes a review of current data on stressperiodontitis relationships. The role of interleukin-16 in the pathogenesis of periodontitis is explained and we briefly summarize data on the effects of stress on interleukin-16. We describe the methods we use to assess the local immune response within the periodontium as well as the experimental gingivitis model we employ to study the interactions between stress and accumulation of microbial plaque. The results of two studies assessing stress effects on local interleukin 113 levels under conditions of continuous plaque accumulation vs. perfect oral hygiene are shown and their implications for the risk of periodontal breakdown in patients discussed. Finally we deal with some interesting aspects of the temporal dynamics of stress-induced immune alterations. Concluding remarks give some ideas of what we believe future PNI research on stress-periodontitis relationships should involve.
Key words: stress, periodontitis, psychoneuroimmunology.
Periodontitis - epidemiology and pathogenesis About 15% of the adult western communities suffer from periodontitis, an inflammation of the periodontal tissue which results in irreversible damage to the alveolar bone and the periodontal tissue. The disease causes attachment loss of the affected teeth and - if untreated - ends up with tooth loss. Indeed, the major reason for tooth loss in German and North American adults seems to be periodontitis and not - as one might assume - caries (Johnson et al., 1988; Micheelis & Reich, 1999). The most prevalent form of periodontitis is adult periodontitis which progresses slowly over years and very often remains undetected for a long time since the clinical signs can be very decent until gingival recessions and increased tooth motility result from the chronic inflammatory process.
The fundamental steps in the etiopathogenesis of marginal periodontitis are well known: Accumulation of supragingival microbial plaque induces gingivitis which results in pseudopockets further hampering oral hygiene. This facilitates subgingival plaque growth which then may result in inflammation of the whole periodontium at the site of infection including the alveolar bone; bacterial enzymes and toxins and the immune reponse of the host induce irreversible tissue damage especially to the alveolar bone. The gingivitis has now become a periodontitis. Periodontal pockets evidence the former inflammation and, even with professional treatments a restitutio ad integrum is not possible anymore at this stage of the disease. Periodontal patients need lifelong professional help in cleaning their periodontal pockets. Accumulation of supragingival plaque is a conditio sine qua non in the pathogenesis of periodontitis. However, once periodontal pockets have established subgingival plaque may exist in the absence of supragingival plaque and thus may further impair periodontal health. Although a gingivitis precedes the first manifestation of periodontitis it seems as if further development of the disease may occur independently of whether clinical signs of gingivitis can be observed or not (Johnson et al., 1988).
Stress - a risk factor in periodontitis? For many years attempts have been made to prevent periodontitis mainly by improving oral hygiene. However, it has now been realized that the level of oral hygiene which is necessary to completely prevent periodontal inflammations, i.e. removement of any plaque at least once daily, cannot be achieved on a community level (Seymour, 1991). Furthermore, while nearly 100% of the western communities show insufficient oral hygiene only about 15% suffer from periodontal disease (Griffiths et al., 1988; Johnson et al., 1988; Micheelis & Reich, 1999). Thus, there seem to exist risk groups especially susceptible to periodontal inflammations. Identifying risk factors for periodontitis has become a new focus in periodontal research (Griffiths et al., 1988; Johnson et al., 1988; Maiden et al., 1990; Wilton et al., 1988). During the last years several groups published data indicating stress to be a risk factor for periodontal inflammations. People suffering from periodontal disease tend to be more depressive and more anxious, to have a history of more negative life events, to have lower marital quality and to suffer from more severe job strain (Baker et al., 1961; Green et al., 1986; Marcenes & Sheiham, 1992; Linden et al., 1996; Monteiro da Silva, 1996). In recent studies we found exam students to report more gingival inflammations and to develop severe gingivitis at formerly healthy sites more frequently than non-stressed controls (Deinzer et al., 1998). Thus, there seems to exist a positive relationship between stress and periodontal disease. The pathways mediating this relationship are, however, unknown. Several pathways have been discussed (see Deinzer & Herforth, 1997): stress-induced behavioral alterations like reduced oral hygiene behavior, increased nicotine consumption or altered nutrition habits; stress-induced physiological alterations like altered blood supply of the periodontium, altered local temperature or saliva pH-levels; stress-induced immunological alterations like reduced immunoglobulin A or increased interleukin 1beta levels.
In our former studies we found that while gingival health deteriorated during an exam period changes in plaque levels during that period did not differ significantly from controls (Deinzer et al., 1998). We therefore wonder, to which extent stress-induced immunological alterations count for the stress-periodontitis-relationship suggested.
Immunological aspects in periodontal disease - the role of interleukin-16 Interleukin 1beta is an important immunological factor in periodontal disease. It has been found to be identical to the osteoclast activating factor and to play a predominant role in periodontal bone resorption (Alexander & Damoulis, 1994; Dewhirst et al., 1985). It can be found in high concentrations in periodontal tissue and gingival crevicular fluid of periodontitis patients (Jandinski et al., 1991; Stashenko et al., 1991; Honig et al., 1989; Preiss & Meyle, 1994; Reinhardt et al., 1993; Tokoro et al., 1996; Tsai et al., 1995), where it seems to originate from macrophages infiltrating the gingival tissue rather than from epithelial cells (Matsuki, Yamamoto & Hara, 1992; Tokoro, Yamamoto & Hara, 1996) . Tissue II-18 levels correlate with attachment loss during a preceding two-months period (Cavanaug, et al., 1998; Lee et al., 1995; Stashenko et al., 1991), furthermore, treatment of periodontitis results in dramatic local decrease of Il-113 (Masada et al., 1990; Matsuki et al., 1993; Tsai et al., 1995).
Taken together this data indicates that periodontal 11-1beta is involved in periodontal breakdown, in which increased Il- IB levels result in an increased risk for alveolar bone loss. Effects of stress on interleukin-111 Only few studies dealt with the effects of stress on interleukin 16, so far. In humans Dugut and coworkers observed a tentative increase of serum II-113 in men but not in women after their first parachute jump (1993) and a small increase in salivary Il-11-18 during sauna heat stress (1996). Patients with combat-related post traumatic stress disorder show increased serum levels of interleukin 113 (Spivak et al., 1997) while monocytes of dementia patient caregivers show a reduced in vitro II-lB response to LPS-stimulation (Kiecolt-Glaser et al., 1996).
In rats subjected to intermittent restraint stress for seven days serum 11-16 levels and those measured after an in vivo LPS challenge are increased (Mekaouche et al., 1994). A tentative increase of Il-llB mRNA expression in the rat colon was observed after three hours restraint on three consecutive days (Collins et al., 1996) and a strong increase of II-lIB levels in rat gastric mucosa was observed after six hours water immersion stress (Hisanaga et al., 1996). LPS-stimulated macrophages of rats subjected to footshock stress secreted more 11- B than controls, in vitro (Persoons et al., 1995).
Taken together, the majority of studies suggest a stress-induced increase of Il-11-18 in serum, after either in vivo or in vitro LPS stimulation and in tissues of the gastrointestinal tract. To the best of our knowledge, however, no study has analysed the effects of stress on II-113 levels in the oral cavity, so far.
Collection of gingival crevicular fluid for the assessment of local immunological factors As indicated earlier, gingival 11-Il-IB can be assessed either in gingival tissue or in gingival crevicular fluid. Assessing II-16 in gingival tissue is rather invasive as it requires tissue biopsies; it usually is accomplished in those patients only who are already undergoing periodontal surgery. On the other hand, collecting gingival crevicular fluid (GCF) is a non-invasive method causing no harm to the patient. GCF is a osmotically induced transudate (at healthy sites) or an inflammatory exsudate (at inflamed sites) from the gingival tissue into the gingival crevice. It consists of intercellular fluid mainly and contains a whole variety of immune parameters, encymes and toxins known to be relevant in periodontal disease (Cimasoni, 1983; Zafiropoulos et al., 1991). Collecting crevicular fluid is very common in periodontal research. Several methods exist. The most prominent is sampling of crevicular fluid by filter paper strips inserted into the gingival crevice (intracrevicular method) or placed next to the gingival crevice (extracrevicular method). The volume sampled is either assessed by determining the size of the wet area of the filter paper strip or by the Periotron . This device which is often used in GCF volume determination determines the dielectric constant of the filter paper strip (Periopaper)) and compares it to a previously computed standard curve. In our laboratory, the reliability of GCF volume assessment is above r1,>0.80 when we employ the intracrevicular method and use the Periotron 8000 for volume determination.
Assessing the effects of continuous plaque accumulation on gingival health - the experimental gingivitis model As mentioned before, the data of our previous study (Deinzer et al., 1998) does not support the hypothesis that stress-induced alterations of plaque accumulation are solely responsible (if at all) for the relationship between stress and periodontitis. Rather, we assume that stress-induced immunological alterations might add to the risk for periodontal disease induction and progress. To prove this assumption it is necessary to standardize plaque accumulation while studying stress effects on immune function. In our studies we established our control for plaque accumulation in two ways. Subjects were instructed to maintain perfect oral hygiene in two antagonistic quadrants after they were carefully trained in efficient oral hygiene behavior. In the remaining two quadrants they were instructed to allow for continuous plaque accumulation by neglecting any oral hygiene procedures. Thereby we were able to compare the effects of an increasing antigen challenge (quadrants with neglection of oral hygiene) to a control condition of virtually no plaque accumulation (quadrants with perfect oral hygiene). The model of continuous plaque accumulation - better known as `experimental gingivitis` - has been used in dental research for more than 30 years (Abbas & van der Velden, 1986; Hillam & Hull, 1977; Danielsen, 1989; Loe, 1965; van der Weijden, 1994; Wiedemann, Lahrsow & Naujoks, 1979). Subjects are asked to discontinue oral hygiene procedures for a given period of time (mostly 14-21 days) which induces a (completely reversible) gingivitis. This model has been used extensively to study the microbiological effects of plaque accumulation and to validy therapeutic and preventive treatment effects (Abbas & van der Velden, 1986; Attin et al., 1995; Brecx et al., 1990; Danielsen, 1989; Hillam & Hull, 1977; Loe, 1965; Netuschil et al., 1995; van der Weijden, 1994; Wiedemann, Lahrsow & Naujoks, 1979;). Surprisingly however, the immunological effects of experimental gingivitis have been studied rarely; no study is available on the effects of experimental gingivitis on Ii- 16 in specific and only one uncontrolled study has been published on the effects of experimental gingivitis on GCF 11-1 concentration, not differentiating between II-la and Il-11-16. In this study Kinane and coworkers (1992) observed an initial increase of II-1 during the first 7 days of experimental gingivitis whereas levels returned to normal within the next 14 days. However, these authors removed dental plaque prior to each measurement thus not allowing for continuous plaque accumulation.
The aim of the studies described in the following was thus to assess the effects of continuous plaque accumulation on GCF 11-16 concentration and to find out whether stress increases the 11-IB response to experimental gingivitis
Alterations of Ii-113 under continuous plaque accumulation during and after academic stress We accomplished two studies on altogether 65 medical students 31 of them participating in a major medical exam either during the study (study I; 13 exam students, 13 controls) or immediately prior to the study (study II; 18 exam students, 21 controls) while the others were not subjected to any exam stress during the study period. Only healthy subjects who did not suffer from periodontitis or any other untreated dental disease were allowed to participate in the study (for additional inclusion and exclusion criteria and further methodological details see Deinzer et al., 1999). At the beginning of each study all subjects were found to show perfect gingival health (which was partly due to careful pretreatments and dental hygiene instructions subjects received prior to the study). Eight days prior to his or her last exam (study 1) or at the day after the last exam (study II) the student and a control subject of the same sex omitted any oral hygiene procedures in two opposite quadrants for 21 days while they continued perfect oral hygiene at the remaining sites. At days 1,5,8,11,15,18 and 21 (study I) or 0,5,8,15,18 and 21 (study II) of this experimental gingivitis period gingival crevicular fluid samples were taken at teeth 15,16 and 25,26 for further Il-16 analysis. Samples were collected and processed as described previously (Deinzer et al., 1999). In short, collection of crevicular fluid and volume determination was done by means of Periopapers (Harco, New York, USA) and a Periotron 8000 (Harco, New York, USA). Papers of one quadrant were shockfrozen at -700 in one vial immediately after collection and remained at that temperature until analysis which was done by a commercial II-11- 18 ELISA-kit (Endogen, USA) and a Tecan, Spectra SLT Reader (Austria).
Interleukin IB levels increased significantly during the experimental gingivitis period both in exam students and controls (Figure 1). However, increases of exam students surpassed that of control subjects in both studies. Areas under the curves (AUC) showed remarkable differences between both groups which were highly significant in study I (exam students 1241396; controls: 698334; t(15)=3.07, p=0.004) and nearly significant in study II (exam students: 1186625; controls 895367; t(28)=1.58, p--0.063). At sites of perfect oral hygiene the 11-lIB levels were in general lower than at sites of experimental gingivitis; in study I levels of exam students were still above those of controls while in study 11 a significant difference was observable at the last day of the study only (Figure 2).
Is the risk of periodontal breakdown increased in patients under psychological stress? Our studies are the first to demonstrate a stress-induced increase of Il- IB in the gingival crevice. Mainly under the condition of continuous plaque accumulation exam students secrete significantly more Il-lB into the gingival crevice than controls. It has been shown that II-1B in inflamed gingival tissue origins mainly from infiltrating immune cells and not from epithelial cells. Furthermore, immunostaining for Il-16 producing cells has been found in the lamina propria but not the epithelium of healthy and inflamed sites; more staining was observed at inflamed sites (Jandinski, et al., 1991). Thus, histologically speaking, II-11-16 found in the GCF seems to stem from cells and areas from where it could also have access to the alveolar bone (Matsuki, Yamamoto & Hara, 1992; Tokoro, Yamamoto & Hara, 1996). Of course, in our study we could not observe alveolar bone loss in any of the patients. Fortunately, it takes more than 21 days to induce the first manifestation of a periodontitis. However, more chronic states of gingivitis and periodontitis are very common in adults. One may assume that in these patients the risk for periodontal breakdown is increased when stress adds to the hampered oral hygiene capabilities of these patients and thus synergizes the effects of plaque accumulation on 11-IB secretion. Our finding on stress effects on 11-18 could perhaps also explain why periodontal breakdown in adults is not a continuous process but rather progresses in episodes of accelerated periodontal breakdown with long periods of nearly no change in between. However, Il-11-18 is only one parameter in a whole variety of immune parameters antagonizing and synergizing each other in their effects on periodontal health (Alexander & Damoulis, 1994). In our studies we measured only one - though important parameter in this immune orchestra; it should be a major issue for future studies to find out whether stress disturbs the harmony of this orchestra by inducing disbalance of the parameters involved or whether it just alters the tone by inducing new balance at another level. Temporal dynamics of stress-induced Il-16 alterations Our data demonstrates that the temporal dynamics of stress-induced immunological alterations deserve special attention. Stress-induced immunological alterations were still in effect when the objective stress was long ago; actually, in the second study they came into effect not earlier but approximately two weeks post-stress. One might now suggest that the subjective stress persisted for that time. However, a stress questionnaire indicated stress levels of exam students to return to control values within three days after the last exam. Our data on Il-11-IB dynamics mirror what we found earlier in salivary immunoglobulin A (IgA; Deinzer & Schiller, 1998; Deinzer et al., 2000b). IgA levels are reduced at the time of an examination and drop further afterwards; during the two week post-stress period we had assessed no recovery to baseline was observable. The data of the present and these previous studies indicate that immunological stress effects might exceed the objective and subjective stress period by far. This is important since most today psychoimmunological research expects maximal stress effects at the time of maximal stress levels. In our studies, however, we could show that maximal stress effects sometimes occur several days to weeks post-stress. Thus we suggest future psychoimmunological research to assess stress effects not only during a stress period but also afterwards.
Conclusion In our studies we have shown that stress increases plaque-induced 11-14 secretion in the human gingiva. Although the clinical implications of this observation are yet unclear we believe analysing local immunological alterations might be a promising way in improving our understanding of stress-periodontitis relationships. Future studies should focus on the mutually synergizing and antagonizing immune parameters relevant for periodontal disease and their relationship to stress.
Future psychoimmunological stress research should take into account that the most interesting immunological stress effects might occur not during stress but afterwards. Understanding these immunological post-stress effects may increase our understanding of psychoimmuno relationships and their implications for health and disease.
Acknowledgement This research was kindly supported by GABA International, Basel, Switzerland. We greatly appreciate the excellent technical assistance of Mrs. Strenz and Mrs. Schulten in running the 11-16 analyses.
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R. DEINZER1, P. FORSTER2, L. FUCK2, W. KOTTMANN2, A. HERFORTH2, RENATE STILLER-WINKLER3, HELGA IDEL3
1Institute for Medical Psychology, 2Department of Periodontology and 3Institute for Hygiene, Heinrich-HeineUniversity, DIO()01 Dtisseldorf…
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Publication information: Article title: Stress-Periodontitis-Relationships-A Case for Psychoneuroimmunology?. Contributors: Deinzer, R. - Author, Forster, P. - Author, Fuck, L. - Author, Kottimann, W. - Author, et al. - Author. Journal title: Psychologische Beiträge. Volume: 42. Issue: 1 Publication date: January 1, 2000. Page number: 70+. © PABST Science Publishers 1999. Provided by ProQuest LLC. All Rights Reserved.
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