Autoimmunity and Periodontitis

Autoimmunity arises when central and peripheral immune tolerance fails, allowing self-reactive T and B cells to attack host tissues. Immune attack on host tissues gives rise to a spectrum of autoimmune diseases. This narrative review explains the basic immune mechanisms that may contribute to systemic autoimmunity and exacerbate periodontitis. Current evidence suggests that during T cell development in the thymus, the risk of overt self-reactivity is reduced by the elimination of thymocytes that recognize self-epitopes with high affinity. Despite this stringent editing, some T cells specific for self-peptides escape deletion and persist as dormant cells in the circulation. Dormant cells can remain functionally inactive or anergic due to insufficient co-stimulatory signals, maintaining peripheral self-tolerance. During infection or tissue injury, neutrophil activation, microbial enzymes, and host peptidyl-arginine deiminases (PADs) can catalyze citrullination of self-proteins, generating structurally altered epitopes (neoantigens). In periodontitis, the neoantigen pool is expanded during NETosis, inflammation-driven post-translational modifications of proteins. Modifications are made collectively by peptidyl-arginine deiminases (PADs) produced by Porphyromonas gingivalis and the host. Hence, dormant autoreactive T cells are activated by antigen-presenting cells (APCs) displaying these modified self-antigens or cross-reactive microbial peptides on MHC molecules in the presence of microbial- or danger-associated molecular pattern molecules (MAMPs/DAMPs). Once activated, these autoreactive CD4⁺ T cells differentiate into effector cells. These effector T cells can break tolerance, providing cognate help to B cells to promote autoantibody production. Autoreactive B cells arise stochastically during early B cell development through random somatic recombination of immunoglobulin genes. Affinity maturation and epitope spreading broaden the B cell receptor (BCR) repertoire generating autoreactive B cells. Normally restrained, these B cells become activated when their BCRs engage self-antigens in the presence of strong proinflammatory cues (MAMPs/DAMPs). With cognate help from autoreactive T helper cells, B cells undergo class-switching and sustained autoantibody production. Together, autoreactive T cells and B cell-derived autoantibodies drive cellular and humoral autoimmunity, respectively. Compelling mechanistic and clinical evidence support a model in which periodontal pathobionts like P. gingivalis and A. actinomycetemcomitans contribute to systemic autoimmunity via processes including protein citrullination, epitope spreading and molecular mimicry between microbial and host antigens, which further amplify cross-reactivity. These interactions are most clearly illustrated in RA but increasingly implicated in other diseases such as IBD and AD. Thus, periodontitis not only causes local immune-mediated tissue destruction but also facilitates systemic dissemination of autoreactive T and B cells, thereby contributing to the initiation and/or exacerbation of autoimmune diseases.