Oral Microbial and Immunological Characterization of Patients with Immune Dysfun

National Institute Of Dental & Craniofacial Research

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Abstract

Studies in patients with primary immunodeficiencies (PIDs) can uncover roles of specific genes and pathways in human immunity. In this regard, patients with PIDs that present with severe periodontal disease susceptibility demonstrate essential pathways in periodontal homeostatic immunity. Our studies in patients with PIDs uncover the essential role of tissue neutrophils in periodontal immunity. Strickingly, both absence/severe reduction of tissue neutrophils (in the setting of ITGB2/CD18 defects) as well as overabundance/overactivation of tissue neutrophils in the setting of PLG defects (and in common forms of periodontitis) are linked to severe early-onset periodontitis. Our work interrogates neutrophil functionality in periodontal immunity and aims to identify therapeutic targets for rare and common forms of periodontitis. Accomplished: Fibrin is a critical regulator of neutrophil effector function at mucosal barrier sites (Silva et al., Science 2021). Accomplised Work/Abstract: Tissue-specific cues are critical for homeostasis at mucosal barriers. Here, in the setting of Plasminogen Deficiency, we document that the clotting factor fibrin is a critical regulator of neutrophil function at the oral mucosal barrier. We demonstrate that commensal microbiota triggers extravascular fibrin deposition in the oral mucosa. Fibrin engages neutrophils through the alphaM beta2 integrin receptor and activates effector functions, including the production of reactive oxygen species and extracellular trap formation. These immune-protective neutrophil functions become tissue damaging in the context of impaired plasmin-mediated fibrinolysis. Indeed, the accumulation of fibrin due to Mendelian genetic defects in plasmin leads to severe oral mucosal immunopathology in mice and humans. Concordantly, genetic polymorphisms in the human PLG gene, encoding plasminogen, are associated with common forms of the oral mucosal disease periodontitis. Our work uncovers fibrin as a critical regulator of neutrophil effector function within the mucosal tissue microenvironment and suggests fibrin-neutrophil engagement as a pathogenic instigator and therapeutic target for a prevalent mucosal disease.