Inflammatory and Immunological Basis of Periodontal Diseases
By: Thomas Van Dyke, DDS, PhD; Giacomo Baima, DDS, MSc, PhD; Marion Arce, DDS, PhD; Mario Romandini, DDS, MSc, PhD
In its most common form, periodontitis is viewed as a chronic immunoinflammatory disorder of the tooth-supporting tissues, shaped by host–microbiome disequilibrium, exaggerated immune activation and impaired resolution mechanisms. This review explores the periodontal battlefield through its inflammatory and immunological lens, beginning with the transformation of the lesion from silent immune surveillance to sustained inflammation, connective tissue degradation and alveolar bone loss.
The classical Page and Schroeder model is used as a foundation but reinterpreted in light of current evidence derived from advanced molecular techniques. The immunological architecture is subsequently dissected through the involvement of its principal cellular players, acting in a dynamic battleground composed of saliva, crevicular fluid, epithelial barriers and connective tissues. On the frontlines, neutrophils act as double-edged defenders, capable of both microbial clearance and bystander tissue damage. Like macrophages and dendritic cells, they also serve as strategic sensors and shapers of immunity, bridging innate and adaptive responses. Among these, the T cell arsenal includes inflammatory subsets such as Th1, Th17, and cytotoxic cells, balanced by regulatory T cells. B lymphocytes and plasma cells emerge not only as antibody producers but also as pro-inflammatory effectors, with growing evidence implicating autoreactive subsets in tissue damage, particularly in aggressive forms of the disease. Equally critical are the structural cells: gingival fibroblasts, which transition from matrix architects to immune-active contributors under stress, and osteocytes, recognized as mechanosensitive regulators of bone turnover and immune signaling. Alongside osteoblasts and osteoclasts, these elements form a fragile yet responsive osteoimmune axis that determines the trajectory toward either tissue homeostasis or destruction. The molecular arsenal fueling this conflict — cytokines, chemokines, complement, specialized pro-resolving mediators, neuropeptides, and matrix metalloproteinases — is also examined, highlighting how its dysregulation sustains chronic inflammation and drives structural breakdown. The review also explores how this localized immune conflict echoes systemically, contributing to broader immune activation and comorbidity. By reframing periodontitis as a prototypical immune-mediated disease, this work contributes to a deeper understanding of its pathogenesis and provides a framework for future research aimed at disentangling its immunological complexity and clinical heterogeneity for targeted diagnostic strategies and immune-based therapeutics.
The human immune system and the microbiome have co-evolved over millions of years, shaping each other through a dynamic and intricate interplay.1 This mutual adaptation has resulted in a finely tuned equilibrium in which the microbiome contributes to immune education, while the host immune system exerts selective pressures on microbial communities.2,3 Indeed, the immune system developed not only to fend off pathogens but also to tolerate beneficial microbiota that have co-evolved to live in symbiosis with the host.4 This is exemplified by the paradigm that regulatory T cells recognize not only self-antigens but also commensal antigens to suppress pathological immune responses.5 Conversely, the immune system can mount a response to the same microbiota when tissue integrity is disrupted or other environmental perturbations occur.6 However, how the host immune system develops and responds to the microbiota remains a scientific conundrum.7
Periodontitis exemplifies this complexity, as it is currently viewed as a chronic inflammatory disorder in which immune dysregulation alters the microbial landscape in ways that reinforce tissue destruction.8 This highly prevalent human disease is marked by attachment loss and alveolar bone resorption, associated with a dense immunoinflammatory infiltrate and persistent subgingival microbial biofilms.9-12 At the heart of periodontitis lies a fundamental question: does microbial dysbiosis ignite the inflammatory cascade, or does inflammation itself reshape the subgingival microbiome?13 This debate is central not only to periodontology but also to broader immunological research, as accumulating evidence suggests that immune dysfunction, rather than microbial overgrowth alone, drives the transition from homeostasis to disease.14-16
INFLAMMATION IN A NUTSHELL
Inflammation represents one of the most fundamental biological responses in animals, a finely tuned, evolutionarily conserved defense program evolved to preserve tissue integrity in the face of infection or injury.46 Far from a mere reaction to microbial insult, it orchestrates a complex interplay of immune surveillance, tissue repair, and the restoration of homeostasis. As an adaptive response, inflammation is capable of mounting rapid immune activation while simultaneously encoding mechanisms for self-limitation and resolution.47 Yet, when the inciting stimulus persists or the pathways governing resolution fail, this once-protective response becomes maladaptive, evolving into a chronic, self-sustaining process that drives tissue damage and underpins a wide array of inflammatory diseases.48, 49
The ideal outcome of inflammation is its timely resolution, preventing progression to chronicity. Once considered a passive phenomenon — merely the result of removing inflammatory stimuli, ending chemoattractant production, and diluting chemokine gradients — resolution is now recognized as an active and highly regulated process.61
A central event is lipid mediator class switching, wherein the tissue milieu shifts from pro-inflammatory mediators (prostaglandins, leukotrienes) to specialized pro-resolving mediators (SPMs), including lipoxins (from arachidonic acid), and resolvins, protectins, and maresins (from omega-3 PUFAs).8 These SPMs counteract pro-inflammatory signals and reprogram macrophages to terminate inflammation via efferocytosis (i.e., the clearance of apoptotic neutrophils) while also facilitating the removal of residual cellular debris. In doing so, they promote resolution by limiting further neutrophil recruitment, favoring programmed cell death of inflammatory leukocytes, and driving macrophages toward a nonphlogistic, pro-resolving phenotype.62–67 This self-limiting immune program ensures that inflammation remains proportionate and transient. However, when resolution fails, immune activation persists beyond microbial clearance, promoting a shift from acute defense to chronic, self-sustaining inflammation.68
CONNECTING LOCAL AND SYSTEMIC INFLAMMATION
Periodontitis does not arise in immunological isolation — nor is the oral cavity an immunological sanctuary. Instead, it should be viewed within the broader framework of chronic inflammatory diseases that share a common host susceptibility trait, including dysregulated immune responses, impaired resolution mechanisms, and persistent low-grade inflammation.388, 389 This trait may underlie not only the individual propensity to develop periodontitis but also their vulnerability to a wide range of systemic conditions, including atherosclerosis, diabetes, respiratory and gastrointestinal diseases, as well as rheumatoid arthritis.390–400 The notion of a shared inflammatory endotype has gained traction with accumulating evidence that systemic immune dysregulation is detectable in patients with periodontitis, even in the absence of overt systemic disease.
FUTURE DIRECTIONS
Understanding the immunopathogenesis of periodontitis has been made possible by the continuous evolution of experimental techniques capable of interrogating immune cells, molecular mediators and tissue architecture. Historically, much of what is known about the periodontal immune response stems from histological, immunohistochemical, and enzyme-linked immunosorbent assay (ELISA)-based approaches, which have provided foundational insights into cell infiltration, cytokine presence, and biomarker levels.
Future research should continue to explore the contribution of newly identified cell subtypes and emerging molecular mediators in the pathogenesis of periodontitis. The increasing recognition of cellular senescence, particularly the role of age-associated B cells and specific senescence-prone subsets of periodontal ligament progenitors, opens promising avenues for understanding how aging shapes the immunoinflammatory environment.281, 301, 415 Moreover, regulated forms of cell death such as ferroptosis and cuproptosis have recently emerged as potential players in periodontal tissue dynamics.416 Further attention to immune-epithelial cross-talk, the regulation of junctional epithelium permeability, and neuroimmune interactions is expected to provide additional insights into the complex mechanisms driving disease onset and sustained progression under allostatic load. All of these advancements will ultimately help unravel the clinical heterogeneity of the different forms of periodontitis, defining immunologically and microbiologically distinct disease types with diagnostic and therapeutic relevance.
CONCLUSION
Periodontitis emerges not merely as an infectious or site-specific condition, but as the outcome of a complex, multi- layered failure in immune regulation. The disease trajectory — from the initial epithelial breach to deep connective tissue and bone destruction — reflects the interplay between microbial persistence and immune activation, which can all be tied together by an insufficient capacity for resolution. The immune landscape within the lesion is populated by defenders, destroyers, regulators, and remodelers, each capable of contributing to either homeostasis or pathology depending on the context, timing and control of their activation.
While primarily centered on the most classic form of periodontitis, this review integrates classical histopathology with modern immunology to reframe the disease as a model for all mucosal inflammatory disorders. From innate sentinels and igniters to adaptive orchestrators and resolvers, and from soluble mediators to bone-modifying cells, each component participates in a coordinated yet potentially dysregulated network. Understanding these dynamics — both locally in the gingiva and systemically across immune compartments — may not only clarify disease pathogenesis but also pave the way for future diagnostic and therapeutic strategies targeting immune balance, resolution pathways, and multi-systems interconnectivity.
REFERENCES