Complement split product C3c in saliva as biomarker for periodontitis and response to periodontal treatment

Abstract Background and Objective The complement system is engaged in inflammatory reactions both in the periodontal pockets and in the periodontium itself, where it can mediate tissue destruction. The aim of this study was, first, to compare salivary levels of the total complement system protein C3 and its split product, fluid‐phase C3c in patients with periodontitis and periodontally healthy controls. Next, to determine if C3 and C3c levels had biomarker potential in diagnosing and monitoring periodontitis and its treatment. We hypothesized that salivary levels of total C3 and the split product C3c associated with the severity of periodontitis and reflected decreased inflammatory activity after periodontal treatment. Methods At baseline, stimulated saliva samples were collected from patients with periodontitis (n = 18) and periodontally healthy controls (n = 15). Subsequently, non‐surgical periodontal treatment was performed in the patients, and saliva sampling from patients was repeated two‐, six‐, and twelve weeks post‐treatment (NCT02913248 at clinicaltrials.gov). The patients were grouped as good and poor responders to treatment according to the achieved reduction in bleeding on probing (BOP). Salivary levels of C3 and C3c were quantified using sandwich ELISA. Results Patients with periodontitis had higher baseline levels of both total C3 and the split product C3c in saliva than did periodontally healthy controls (P < .0001). Receiver operating curve (ROC) analyses discriminated patients with periodontitis from controls based on both C3 (AUC (area under curve) = 0.91, P < .001) and C3c levels (AUC = 0.84, P < .001) in saliva. Periodontal treatment improved all clinical parameters (P < .01). Good responders (n = 10) had lower baseline levels of C3c than poor responders (n = 8), (P < .05), and baseline levels of C3c discriminated between good and poor responders (AUC = 0.80, P < .05). Conclusion In conclusion, patients with periodontitis had higher salivary levels of C3c, and the C3c levels were predictive of reductions in BOP, that is, the poor responders. This suggests that salivary C3c levels possess potential to serve as a biomarker predicting the clinical response to non‐surgical periodontal treatment.

[1]  C. Damgaard,et al.  Salivary concentrations of macrophage activation-related chemokines are influenced by non-surgical periodontal treatment: a 12-week follow-up study , 2019, Journal of oral microbiology.

[2]  John D Lambris,et al.  Gingival Exudatome Dynamics Implicate Inhibition of the Alternative Complement Pathway in the Protective Action of the C3 Inhibitor Cp40 in Nonhuman Primate Periodontitis. , 2018, Journal of proteome research.

[3]  P. Eke,et al.  Periodontitis in US Adults: National Health and Nutrition Examination Survey 2009-2014. , 2018, Journal of the American Dental Association.

[4]  David Herrera,et al.  Periodontitis: Consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. , 2018, Journal of clinical periodontology.

[5]  B. Paster,et al.  Influence of periodontal treatment on subgingival and salivary microbiotas , 2018, Journal of periodontology.

[6]  Y. Izumi,et al.  Putative salivary protein biomarkers for the diagnosis of oral lichen planus: a case-control study , 2018, BMC Oral Health.

[7]  J. Slots Periodontitis: facts, fallacies and the future. , 2017, Periodontology 2000.

[8]  K. Skjoedt,et al.  A novel antihuman C3d monoclonal antibody with specificity to the C3d complement split product. , 2017, Journal of immunological methods.

[9]  Crystal I. Bryce,et al.  Adiponectin: Serum-saliva associations and relations with oral and systemic markers of inflammation , 2017, Peptides.

[10]  A. Flyvbjerg,et al.  Comorbidity of periodontal disease: two sides of the same coin? An introduction for the clinician , 2017, Journal of oral microbiology.

[11]  John D Lambris,et al.  Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3. , 2016, Journal of clinical periodontology.

[12]  B. Mealey,et al.  American Academy of Periodontology Task Force Report on the Update to the 1999 Classification of Periodontal Diseases and Conditions. , 2015, Journal of periodontology.

[13]  C. Damgaard,et al.  The complement system and its role in the pathogenesis of periodontitis: current concepts. , 2015, Journal of periodontal research.

[14]  John D Lambris,et al.  Genetic and Intervention Studies Implicating Complement C3 as a Major Target for the Treatment of Periodontitis , 2014, The Journal of Immunology.

[15]  A. Blom,et al.  The complement system in systemic lupus erythematosus: an update , 2014, Annals of the rheumatic diseases.

[16]  V. D’Agati,et al.  C3 glomerulopathy: consensus report , 2013, Kidney international.

[17]  R. Genco,et al.  Diabetes and periodontal diseases: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. , 2013, Journal of periodontology.

[18]  G. Hajishengallis,et al.  The keystone-pathogen hypothesis , 2012, Nature Reviews Microbiology.

[19]  John D Lambris,et al.  Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. , 2011, Cell host & microbe.

[20]  K. Skjødt,et al.  Generation of a C3c specific monoclonal antibody and assessment of C3c as a putative inflammatory marker derived from complement factor C3. , 2010, Journal of immunological methods.

[21]  B. Whitcomb,et al.  Assays with lower detection limits: implications for epidemiological investigations. , 2008, Paediatric and perinatal epidemiology.

[22]  M. Eisenacher,et al.  Gene expression in periodontal tissues following treatment , 2008, BMC Medical Genomics.

[23]  A. Stavljenic-Rukavina,et al.  Proinflammatory factors in saliva as possible markers for periodontal disease. , 2005, Collegium antropologicum.

[24]  Piet Gros,et al.  Structures of complement component C3 provide insights into the function and evolution of immunity , 2005, Nature.

[25]  John D Lambris,et al.  Structure and biology of complement protein C3, a connecting link between innate and acquired immunity , 2001, Immunological reviews.

[26]  C. Niekrash,et al.  Simultaneous assessment of complement components C3, C4, and B and their cleavage products in human gingival fluid. II. Longitudinal changes during periodontal therapy. , 1985, Journal of periodontal research.

[27]  N. Lang,et al.  The relationship of complement cleavage in gingival fluid to periodontal diseases. , 1984, Journal of periodontal research.

[28]  I. Brandslund,et al.  Acute complement activation during an anaphylactoid reaction to blood transfusion and the disappearance rate of C3c and C3d from the circulation. , 1983, Journal of clinical & laboratory immunology.

[29]  W. Mcarthur,et al.  Biosynthesis of complement components in chronically inflamed gingiva. , 1982, Journal of periodontal research.

[30]  P. Toto,et al.  Identification of C 3a, IgG, IgM in Inflamed Human Gingiva , 1978, Journal of dental research.

[31]  R. Genco,et al.  Gingival fluid and serum in periodontal diseases. I. Quantitative study of immunoglobulins, complement components, and other plasma proteins. , 1977, Journal of periodontology.

[32]  R. Boackle,et al.  Detection of Functional Complement Components in Gingival Crevicular Fluid from Humans with Periodontal Disease , 1977, Journal of dental research.

[33]  R. Attström,et al.  Complement factors in gingival crevice material from healthy and inflamed gingiva in humans. , 1975, Journal of periodontal research.

[34]  John D Lambris,et al.  Complement Involvement in Periodontitis: Molecular Mechanisms and Rational Therapeutic Approaches. , 2015, Advances in experimental medicine and biology.

[35]  M. Tonetti,et al.  Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. , 2013, Journal of clinical periodontology.

[36]  Peter P. Egeghy,et al.  Methods of Dealing with Values Below the Limit of Detection using SAS Carry , 2003 .

[37]  R. Boackle The interaction of salivary secretions with the human complement system--a model for the study of host defense systems on inflamed mucosal surfaces. , 1991, Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists.

[38]  A. C. Johannessen,et al.  Deposits of immunoglobulins, complement, and immune complexes in inflamed human gingiva. , 1987, Acta odontologica Scandinavica.