The immunological imprint of recurrent periodontitis: From local tissue memory to central trained immunity

Despite successful reduction of bacterial load and clinical inflammation following periodontal therapy, high recurrence rates indicate that prior infections induce lasting host alterations, maintaining latent disease susceptibility AIM: This review elucidates the biological basis of periodontal recalcitrance through innate immune memory (trained immunity), examining durable functional reprogramming at both local and systemic levels.

We comprehensively searched PubMed/MEDLINE and Scopus databases for peer-reviewed literature published primarily within the last decade (up to 2026). The search strategy utilized combinations of terms including "periodontitis", "trained immunity", "epigenetic reprogramming", "bone marrow axis", and "clonal hematopoiesis". Mechanistic, multi-omics, and clinical data were evaluated and synthesized, focusing on local resident cell reprogramming, ectopic lymphoid organogenesis, the periodontium-bone marrow axis, and clonal hematopoiesis.

Current evidence supports the existence of a multi-level immunological imprint. Locally, gingival fibroblasts and resident immune cells acquire stable epigenetic modifications and undergo glycolytic shifts. These changes lower their activation thresholds, generating a hyper-responsive microenvironment sustained by Tertiary Lymphoid Structures. Systemically, periodontal inflammation transmits endocrine signals (IL-1β, type I interferons) to hematopoietic stem and progenitor cells. This central adaptation biases myeloid differentiation and establishes heritable epigenetic priming, accelerating the output of hyper-reactive neutrophils. Additionally, age-related Clonal Hematopoiesis of Indeterminate Potential (CHIP) amplifies this inflammatory dysregulation.

Periodontitis recurrence is fundamentally driven by maladaptive immunological memory. This persistent state is encoded via epigenetic and metabolic reprogramming within local tissues and central hematopoietic niches, exacerbating destruction upon microbial restimulation.

Achieving true biological resolution in periodontitis requires a paradigm shift from solely controlling the biofilm to incorporating targeted host-modulatory therapies that resolve these maladaptive epigenetic and metabolic adaptations.