Hyperreactive peripheral neutrophils in periodontitis : FCc receptor activation and plasma proteins

It is now well established that adult and juvenile periodontitis are associated with a hyperreactivity of the peripheral neutrophils when measured as increased generation of free oxygen radicals after stimulation of the Fcgamma-receptors.

Aim: The aims of these investigations were to study if the increased radical generation was: 1) located intra- or extracellularly and attributed to a specific oxygen species or various activation pathways, 2) connected with "priming" (pre-stimulation only disclosed by a secondary activation), 3) associated with systemic aberrations in plasma parameters induced by the periodontal disease or cigarette smoking or 4) related to the neutrophil production of the cytokines IL-8 and TNFalpha after stimulation.

Patients: All the patients with adult periodontitis had marked tissue destruction and were matched for age, sex and smoking habits. All participants were generally healthy and without medication, which could influence the inflammatory response. Systemic affections of inflammatory parameters in plasma were checked. Only non-smoking subjects were included in the last study.

Methods: Total generation of the oxygen species was measured with luminol enhanced chemiluminescence while the extracellular part was measured with iso-luminol enhanced chemiluminescence. The intracellular H2O2 generation with dichloro-fluorescein-diacetate was measured by flow cytometry after simulation with opsonized bacteria (Fcgamma-receptors). The neutrophil response to the cytokines, TN17 (x and IL-8 was measured by release of the two cytokines in the incubation medium after stimulation of the Fcgamma-receptors.

Results and discussion: An increased total (extra- plus intracellular) radical generation from the peripheral neutrophils in periodontitis was confirmed, as well as an increased extracellular production, while the intracellular production of H2O2 did not differ between patients and controls. The response to non-specific priming and priming by TNFalpha and LPS did not differ between patients and controls. The inflammatory plasma parameters were normal in patients and controls indicating absence of occasional inflammation, but a slight systemic effect of the periodontitis in the form of increasing CRP and decreasing IgG2 was traced. However, a marked enhancing effect of cigarette smoking was observed on most acute phase parameters in blood. Cigarette smoking also lowered the neutrophil response of IL-8 after stimulation in patients. The generation of oxygen radicals was increased using both FcgammaR, CR3 and PMA activation but the FcgammaR activation was significantly higher in the patients.

Conclusions: These studies confirm a hyperreactivity of peripheral neutrophils in periodontitis, measured as an increased, both total and extracellular, generation of oxygen species. This increased generation is in its initial stimulation step most obviously bound to the Fcgamma receptors, and probably not caused by higher neutrophil sensitivity to neither non-specific priming nor TNFalpha or LPS priming. Systemic effects of inflammatory plasma parameters are mainly correlated to cigarette smoking, meaning that pathogenetic studies on periodontitis should be one on well treated, non-smoking subjects. The systemic effects of periodontitis per se are small because of the minor local inflammation. The hyperreactivity of the neutrophils seems to be of a cell bound genetic nature involving Fc-receptors and their signalling pat ways.

List of scientific papers

I. Fredriksson M, Gustafsson A, Asman B, Bergstrom K (1998). "Hyper-reactive peripheral neutrophils in adult periodontitis: generation of chemiluminescence and intracellular hydrogen peroxide after in vitro priming and FcgammaR-stimulation. " J Clin Periodontol 25(5): 394-8
https://pubmed.ncbi.nlm.nih.gov/9650876

II. Fredriksson M, Gustafsson A, Asman B, Bergstrom K (1999). "Periodontitis increases chemiluminescence of the peripheral neutrophils independently of priming by the preparation method" Oral Dis 5(3): 229-33
https://pubmed.ncbi.nlm.nih.gov/10483069

III. Fredriksson MI, Figueredo CM, Gustafsson A, Bergstrom KG, Asman BE (1999). "Effect of periodontitis and smoking on blood leukocytes and acute-phase proteins. " J Periodontol 70(11): 1355-60
https://pubmed.ncbi.nlm.nih.gov/10588499

IV. Fredriksson M, Bergstrom K, Asman B (2002). "IL-8 and TNFalpha from peripheral neutrophils and acute-phase proteins in periodontitis. Effect of cigarette smoking: a pilot study" J Clin Periodontol 29: (Accepted)

V. Fredriksson M, Gustafsson A, Bergstrom K, Asman B (2001). "More oxygen radicals from neutrophils periodontitis." (Submitted)