IMMUNOPATHOGENESIS OF PERIODONTITIS: A SYSTEMATIC INTEGRATIVE REVIEW OF CONTEMPORARY EVIDENCE

Background Periodontitis is a chronic inflammatory disease characterized by progressive destruction of the periodontal ligament, cementum, gingiva, and alveolar bone. Contemporary evidence indicates that the disease cannot be explained by bacterial infection alone. Instead, periodontitis develops through reciprocal interactions between a dysbiotic subgingival microbiome, impaired epithelial barrier function, dysregulated innate and adaptive immune responses, and failure of inflammation resolution. Severe periodontal disease affects more than one billion people worldwide and remains a major cause of tooth loss and impaired oral-health-related quality of life. Objective This systematic integrative review aimed to synthesize contemporary evidence regarding the microbial, cellular, and molecular mechanisms involved in the immunopathogenesis of periodontitis, with particular emphasis on neutrophils, macrophages, inflammasomes, T-helper 17 cells, regulatory T cells, osteoimmune signaling, trained immunity, and inflammation-resolution pathways. Methods A PRISMA 2020-oriented search strategy was developed for PubMed/MEDLINE, Scopus, Web of Science Core Collection, and Embase. Publications dated from January 2020 to August 6, 2026 were considered, while foundational studies published before 2020 were identified through backward citation searching. Eligible publications included human observational studies, experimental animal studies, in vitro investigations, systematic reviews, and high-quality mechanistic reviews addressing immune pathways in marginal periodontitis. Studies exclusively investigating apical periodontitis, peri-implantitis, or clinical treatment outcomes without immunological data were excluded. Owing to methodological heterogeneity, findings were synthesized narratively. Results The database searches identified [XX] records, of which [XX] remained after duplicate removal and [XX] publications were included in the final synthesis. The evidence supports a bidirectional model in which microbial dysbiosis initiates and is subsequently reinforced by inflammation. Neutrophils provide essential antimicrobial surveillance but may promote tissue injury through excessive reactive oxygen species, proteases, and neutrophil extracellular traps. Macrophage polarization, complement–Toll-like receptor crosstalk, and NLRP3 inflammasome activation amplify the production of interleukin-1β, interleukin-18, and tumor necrosis factor-α. The Th17–IL-17 axis has context-dependent protective and destructive effects: physiological IL-17 signaling supports neutrophil recruitment and barrier defense, whereas persistent IL-17 production promotes inflammatory amplification and osteoclastogenesis. Periodontal bone destruction is mediated principally through an increased receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio. Single-cell and spatial transcriptomic studies further demonstrate substantial heterogeneity among keratinocytes, fibroblasts, endothelial cells, macrophages, and lymphocyte subsets. Conclusions Periodontitis represents a dysbiosis-driven, host-mediated immunoinflammatory disorder rather than a conventional bacterial infection. Disease progression is determined by the failure to coordinate antimicrobial defense, immune regulation, bone homeostasis, and active resolution of inflammation. Future therapeutic strategies should combine biofilm control with precise modulation of complement, inflammasome, neutrophil, Th17, osteoimmune, and pro-resolving pathways. However, immune-targeted interventions must preserve protective host defense and should be validated in well-designed clinical trials.