Primary immunodeficiencies reveal the essential role of tissue neutrophils in periodontitis

Abstract

Summary Periodontitis is a common human inflammatory disease. In this condition, microbiota trigger excessive inflammation in oral mucosal tissues surrounding the dentition, resulting in destruction of tooth‐supporting structures (connective tissue and bone). While susceptibility factors for common forms of periodontitis are not clearly understood, studies in patients with single genetic defects reveal a critical role for tissue neutrophils in disease susceptibility. Indeed, various genetic defects in the development, egress from the bone marrow, chemotaxis, and extravasation are clearly linked to aggressive/severe periodontitis at an early age. Here, we provide an overview of genetic defects in neutrophil biology that are linked to periodontitis. In particular, we focus on the mechanisms underlying Leukocyte Adhesion Deficiency‐I, the prototypic Mendelian defect of impaired neutrophil extravasation and severe periodontitis.

Neutrophil Extracellular Traps in Periodontitis

“…Different neutrophil defects have been described affecting all stages of neutrophil recruitment and extravasation to periodontal tissue: tethering, rolling, adhesion and endothelial transmigration [23,24]. Most notably, leukocyte adhesion deficiency-I (LAD-I) immunodeficiency, which alters neutrophil extravasation into tissues, presents with periodontitis [25].…”

“…Dysfunctional neutrophil chemotaxis may predispose patients with periodontitis to disease by increasing tissue transit times, thereby exacerbating neutrophil-mediated collateral host tissue damage [29]. The absence of tissue neutrophils due to defective recruitment and extravasation [23] can also lead to persistent periodontal inflammation and bone loss [30,31]. Both an excessive presence or absence of neutrophils in the tissue can lead to periodontitis, indicating how important neutrophil balance is in periodontal homeostasis.…”

The presence of neutrophils causes RANKL expression in periodontal tissue, giving rise to osteoclast formation

“…10,11 Neutrophils are produced in bone marrow, mobilize into the bloodstream, and infiltrate inflammatory sites through extravasation. 12 Integrin (CD11b/ CD18) on neutrophil surfaces is involved during extravasation. [13][14][15] Periodontitis is an inflammatory disease caused by bacteria.…”

Frontline Science: Activation of metabolic nuclear receptors restores periodontal tissue homeostasis in mice with leukocyte adhesion deficiency-1

“…Indeed, neutrophil disorders affecting their numbers or function can readily precipitate periodontitis. [12][13][14][15][16][17][18] Periodontitis, a dysbiotic inflammatory disease that affects the tissues that surround and support the dentition ("periodontium," e.g., gingiva and alveolar bone), typically affects adults. 19,20 However, individuals with disorders affecting neutrophil recruitment to the periodontium (and other peripheral tissues), such as type 1 leukocyte adhesion deficiency (LAD1) rapidly develop severe periodontitis early in life.…”

“…14,15,18,21,22 LAD1 is an autosomal recessive primary immunodeficiency caused by mutations in the CD18-encoding ITGB2 gene that result in defective neutrophil adhesion to the endothelium (since 2 -integrins such as LFA-1 are critical for this function) and hence impaired extravasation. 15,17,23 LAD1 patients thus have few or no neutrophils in the periodontium and other peripheral tissues and typically have recurrent bacterial infections and pathological inflammation in the skin and mucosal surfaces, as well as display profound alveolar bone loss early in life, followed by premature loss of primary and permanent teeth. 14,15,18,21,22 Rare diseases, such as LAD1, constitute an important medical burden cumulatively affecting 25 million patients in North America alone.…”