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 infiltration is a hallmark of periodontitis, a prevalent oral inflammatory condition in which Th17-driven mucosal inflammation leads to destruction of tooth-supporting bone. Herein, we ...document that neutrophil extracellular traps (NETs) are early triggers of pathogenic inflammation in periodontitis. In an established animal model, we demonstrate that neutrophils infiltrate the gingival oral mucosa at early time points after disease induction and expel NETs to trigger mucosal inflammation and bone destruction in vivo. Investigating mechanisms by which NETs drive inflammatory bone loss, we find that extracellular histones, a major component of NETs, trigger upregulation of IL-17/Th17 responses, and bone destruction. Importantly, human findings corroborate our experimental work. We document significantly increased levels of NET complexes and extracellular histones bearing classic NET-associated posttranslational modifications, in blood and local lesions of severe periodontitis patients, in the absence of confounding disease. Our findings suggest a feed-forward loop in which NETs trigger IL-17 immunity to promote immunopathology in a prevalent human inflammatory disease.
Immuno-surveillance networks operating at barrier sites are tuned by local tissue cues to ensure effective immunity. Site-specific commensal bacteria provide key signals ensuring host defense in the ...skin and gut. However, how the oral microbiome and tissue-specific signals balance immunity and regulation at the gingiva, a key oral barrier, remains minimally explored. In contrast to the skin and gut, we demonstrate that gingiva-resident T helper 17 (Th17) cells developed via a commensal colonization-independent mechanism. Accumulation of Th17 cells at the gingiva was driven in response to the physiological barrier damage that occurs during mastication. Physiological mechanical damage, via induction of interleukin 6 (IL-6) from epithelial cells, tailored effector T cell function, promoting increases in gingival Th17 cell numbers. These data highlight that diverse tissue-specific mechanisms govern education of Th17 cell responses and demonstrate that mechanical damage helps define the immune tone of this important oral barrier.
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•Distinct signals shape the Th17 cell network at the oral barrier•Oral barrier Th17 cells develop independently of commensal microbe colonization•Physiologic damage through mastication promotes the generation of oral Th17 cells•Barrier damage triggers oral Th17-cell-mediated protective immunity and inflammation
The signals regulating immunity at the gingiva, a key oral barrier, remain unclear. Dutzan et al. show that oral barrier Th17 cells are induced in response to mastication rather than commensal colonization, identifying physiologic mechanical damage as a unique tissue-specific cue conditioning local immunity and inflammation at the oral barrier.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type 1 (APS-1), is a rare genetic disorder caused most often by biallelic ...mutations in the
gene. Classic clinical findings of the disease are chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues, such as hypoparathyroidism and adrenal insufficiency. Recently, however, it has been appreciated that enamel hypoplasia, together with intestinal malabsorption and a characteristic APECED rash, is a prominent early disease manifestation of APECED which can aid in the diagnosis of disease before other potentially life-threatening disease manifestations occur. To demonstrate this point, we present data from a cohort of APECED patients, approximately 70% of who present with enamel dysplasia at an early age. Importantly, early life presentation with enamel dysplasia was predictive of likelihood of development of a subsequent APECED diagnosis. Furthermore, we present a case of a patient with APECED and severe enamel defects and discuss the utility of medical-dental professional co-operation in the diagnosis and management of this complex disorder.
The oral mucosa remains an understudied barrier tissue. This is a site of rich exposure to antigens and commensals, and a tissue susceptible to one of the most prevalent human inflammatory diseases, ...periodontitis. To aid in understanding tissue-specific pathophysiology, we compile a single-cell transcriptome atlas of human oral mucosa in healthy individuals and patients with periodontitis. We uncover the complex cellular landscape of oral mucosal tissues and identify epithelial and stromal cell populations with inflammatory signatures that promote antimicrobial defenses and neutrophil recruitment. Our findings link exaggerated stromal cell responsiveness with enhanced neutrophil and leukocyte infiltration in periodontitis. Our work provides a resource characterizing the role of tissue stroma in regulating mucosal tissue homeostasis and disease pathogenesis.
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•A single-cell atlas of human oral mucosa in individuals with or without periodontitis•Diverse stromal and immune cell populations promote barrier immunity•Stromal cell inflammatory profile is linked to neutrophil recruitment•Identification of cell-specific expression patterns of periodontitis susceptibility genes
A single-cell atlas of human oral mucosa connects inflammatory signatures in epithelial and stromal cells with neutrophil infiltration in periodontitis and identifies cell-specific expression patterns of periodontitis susceptibility genes.
A patient with leukocyte adhesion deficiency type 1 (LAD1) had severe periodontitis and an intractable, deep, nonhealing sacral wound. We had previously found a dominant interleukin-23-interleukin-17 ...signature at inflamed sites in humans with LAD1 and in mouse models of the disorder. Blockade of this pathway in mouse models has resulted in resolution of the immunopathologic condition. We treated our patient with ustekinumab, an antibody that binds the p40 subunit of interleukin-23 and interleukin-12 and thereby blocks the activity of these cytokines, inhibiting interleukin-23-dependent production of interleukin-17. After 1 year of therapy, our patient had resolution of his inflammatory lesions without serious infections or adverse reactions. Inhibition of interleukin-23 and interleukin-17 may have a role in the management of LAD1. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
Abstract
Neutrophil infiltration is a hallmark of the inflammatory disease periodontitis, a prevalent oral condition in which Th17 driven mucosal inflammation leads to destruction of tooth-supporting ...bone. Herein, we document that in periodontitis, neutrophil extracellular traps (NETs) are early triggers of pathogenic inflammation in periodontitis. In an established animal model of periodontitis, we demonstrate that neutrophils infiltrate disease lesions at early time points after disease induction and expel NETs to trigger mucosal inflammation and bone destruction in vivo. Investigating mechanism by which NETs drive inflammatory bone loss, we find that extracellular histones, a major component of NETs, trigger upregulation of IL17/Th17 responses, and bone destruction. Importantly, human findings corroborate our experimental work. We document, in periodontitis patients, significantly elevated levels of NET complexes and of extracellular histones bearing classic NET-associated post-translational modifications. Strikingly, concentrations of NET components in disease lesions and in circulation, significantly correlate with the severity of bone destruction in patients, even in the absence of known confounding systemic disease. Our findings suggest a feed-forward loop in which NETs trigger Th17 immunity to further amplify neutrophil immunopathology in a prevalent human inflammatory disease.
At mucosal surfaces, epithelial cells provide a structural barrier and an immune defense system. However, dysregulated epithelial responses can contribute to disease states. Here, we demonstrated ...that epithelial cell-intrinsic production of interleukin-23 (IL-23) triggers an inflammatory loop in the prevalent oral disease periodontitis. Epithelial IL-23 expression localized to areas proximal to the disease-associated microbiome and was evident in experimental models and patients with common and genetic forms of disease. Mechanistically, flagellated microbial species of the periodontitis microbiome triggered epithelial IL-23 induction in a TLR5 receptor-dependent manner. Therefore, unlike other Th17-driven diseases, non-hematopoietic-cell-derived IL-23 served as an initiator of pathogenic inflammation in periodontitis. Beyond periodontitis, analysis of publicly available datasets revealed the expression of epithelial IL-23 in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human disease. Collectively, this work highlights an important role for the barrier epithelium in the induction of IL-23-mediated inflammation.
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•Epithelial IL-23 is evident in patients with common and Mendelian forms of periodontitis•Non-hematopoietic-cell-derived IL-23 is a pathogenic driver in experimental periodontitis•Flagellated microbes induce epithelial IL-23 through canonical TLR5 signaling•Epithelial IL-23 is evident across human barrier tissues and increased in Th17 diseases
Epithelial cells at mucosal surfaces provide a structural barrier and an immune defense system, but dysregulated epithelial responses can contribute to disease. Kim et al. reveal that epithelial-derived IL-23 is a pathogenic trigger in the oral mucosal disease periodontitis. Moreover, their findings suggest a broader role for epithelial-derived IL-23 in human Th17-mediated inflammatory diseases across barrier tissues.
Periodontal disease in patients with WHIM syndrome Brenchley, Laurie; McDermott, David H.; Gardner, Pamela J. ...
Journal of clinical periodontology,
April 2024, 2024-04-00, 20240401, Letnik:
51, Številka:
4
Journal Article
Recenzirano
Aim
WHIM (warts, hypogammaglobulinaemia, infections and myelokathexis) syndrome is a rare combined primary immunodeficiency disease caused by gain‐of‐function (GOF) mutations in the chemokine ...receptor CXCR4 and includes severe neutropenia as a common feature. Neutropenia is a known risk factor for periodontitis; however, a detailed periodontal evaluation of a WHIM syndrome cohort is lacking. This study aimed to establish the evidence base for the periodontal status of patients with WHIM syndrome.
Materials and Methods
Twenty‐two adult WHIM syndrome patients and 22 age‐ and gender‐matched healthy volunteers (HVs) were evaluated through a comprehensive medical and periodontal examination. A mouse model of WHIM syndrome was assessed for susceptibility to naturally progressing or inducible periodontitis.
Results
Fourteen patients with WHIM syndrome (63.6%) and one HV (4.5%) were diagnosed with Stage III/IV periodontitis. No WHIM patient presented with the early onset, dramatic clinical phenotypes typically associated with genetic forms of neutropenia. Age, but not the specific CXCR4 mutation or absolute neutrophil count, was associated with periodontitis severity in the WHIM cohort. Mice with a Cxcr4 GOF mutation did not exhibit increased alveolar bone loss in spontaneous or ligature‐induced periodontitis.
Conclusions
Overall, WHIM syndrome patients presented with an increased severity of periodontitis despite past and ongoing neutrophil mobilization treatments. GOF mutations in CXCR4 may be a risk factor for periodontitis in humans.
Studies in patients with genetic defects can provide unique insights regarding the role of specific genes and pathways in humans. Patients with defects in the Th17/IL-17 axis, such as patients ...harboring loss-of-function STAT3 mutations (autosomal-dominant hyper IgE syndrome; AD-HIES) present with recurrent oral fungal infections. Our studies aimed to comprehensively evaluate consequences of STAT3 deficiency on the oral commensal microbiome. We characterized fungal and bacterial communities in AD-HIES in the presence and absence of oral fungal infection compared with healthy volunteers. Analyses of oral mucosal fungal communities in AD-HIES revealed severe dysbiosis with dominance of Candida albicans (C. albicans) in actively infected patients and minimal representation of health-associated fungi and/or opportunists. Bacterial communities also displayed dysbiosis in AD-HIES, particularly in the setting of active Candida infection. Active candidiasis was associated with decreased microbial diversity and enrichment of the streptococci Streptococcus oralis (S. oralis) and S. mutans, suggesting an interkingdom interaction of C. albicans with oral streptococci. Increased abundance of S. mutans was consistent with susceptibility to dental caries in AD-HIES. Collectively, our findings illustrate a critical role for STAT3/Th17 in the containment of C. albicans as a commensal organism and an overall contribution in the establishment of fungal and bacterial oral commensal communities.
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