The implication of the PD-1/PD-L1 checkpoint in chronic periodontitis suggests novel therapeutic opportunities with natural products

Bailly, Christian

doi:10.1016/j.jdsr.2020.04.002

Cited by 25 publications

(12 citation statements)

References 84 publications

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“…Polymorphisms in PD-1 have been linked to susceptibility to autoimmune diseases including SLE, atopy, RA, and progression of MS ( 126 ). PD-1 expression in periodontitis has been evaluated to explain the presence of immunosuppression ( 127 ) and to be used as a therapeutic target ( 128 ). No evidence of their analysis was found in periodontitis in relation to autoimmunity, but the results of the studies open an interesting window.…”

Section: Introductionmentioning

confidence: 99%

Oral Dysbiosis and Autoimmunity: From Local Periodontal Responses to an Imbalanced Systemic Immunity. A Review

et al. 2020

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The current paradigm of onset and progression of periodontitis includes oral dysbiosis directed by inflammophilic bacteria, leading to altered resolution of inflammation and lack of regulation of the inflammatory responses. In the construction of explanatory models of the etiopathogenesis of periodontal disease, autoimmune mechanisms were among the first to be explored and historically, for more than five decades, they have been described in an isolated manner as part of the tissue damage process observed in periodontitis, however direct participation of these mechanisms in the tissue damage is still controversial. Autoimmunity is affected by genetic and environmental factors, leading to an imbalance between the effector and regulatory responses, mostly associated with failed resolution mechanisms. However, dysbiosis/infection and chronic inflammation could trigger autoimmunity by several mechanisms including bystander activation, dysregulation of toll-like receptors, amplification of autoimmunity by cytokines, epitope spreading, autoantigens complementarity, autoantigens overproduction, microbial translocation, molecular mimicry, superantigens, and activation or inhibition of receptors related to autoimmunity by microorganisms. Even though autoreactivity in periodontitis is biologically plausible, the associated mechanisms could be related to non-pathologic responses which could even explain non-recognized physiological functions. In this review we shall discuss from a descriptive point of view, the autoimmune mechanisms related to periodontitis physio-pathogenesis and the participation of oral dysbiosis on local periodontal autoimmune responses as well as on different systemic inflammatory diseases.

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Section: Introductionmentioning

confidence: 99%

Oral Dysbiosis and Autoimmunity: From Local Periodontal Responses to an Imbalanced Systemic Immunity. A Review

et al. 2020

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“…Considering PDL1/PD1 signaling that characterized the subtype S1, it has been found that peptidoglycans from P. gingivalis can lead to the up-regulation of PDL1 expressed by gingival keratinocytes, as well as the overexpression of PD1 expressed on T lymphocytes (Bailly, 2020). The interaction between PDL1 and PD1 can suppress the initial activation and effector function of T cells and thereby promote the progression of periodontal inflammation (Yang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Immune suppression demands the tandem action of multiple immunosuppression genes, several of which have been demonstrated in the context of periodontal pathology. These include programmed cell death 1 (PD1), PD-Ligand 1 (PD-L1) (Bailly, 2020), and Cytotoxic T-Lymphocyte Antigen4 (CTLA4) (Aoyagi et al, 2000), that function as immune checkpoint inhibitors to modulate B-cells, CD8+ T-cells, and CD4+ T-cells, which can amplify infection and promote tissue damage. Therefore, an immune checkpoint blockade has been proposed as a modality to manage periodontitis.…”

Section: Introductionmentioning

confidence: 99%

Deep Learning Reveals Key Immunosuppression Genes and Distinct Immunotypes in Periodontitis

et al. 2021

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BackgroundPeriodontitis is a chronic immuno-inflammatory disease characterized by inflammatory destruction of tooth-supporting tissues. Its pathogenesis involves a dysregulated local host immune response that is ineffective in combating microbial challenges. An integrated investigation of genes involved in mediating immune response suppression in periodontitis, based on multiple studies, can reveal genes pivotal to periodontitis pathogenesis. Here, we aimed to apply a deep learning (DL)-based autoencoder (AE) for predicting immunosuppression genes involved in periodontitis by integrating multiples omics datasets.MethodsTwo periodontitis-related GEO transcriptomic datasets (GSE16134 and GSE10334) and immunosuppression genes identified from DisGeNET and HisgAtlas were included. Immunosuppression genes related to periodontitis in GSE16134 were used as input to build an AE, to identify the top disease-representative immunosuppression gene features. Using K-means clustering and ANOVA, immune subtype labels were assigned to disease samples and a support vector machine (SVM) classifier was constructed. This classifier was applied to a validation set (Immunosuppression genes related to periodontitis in GSE10334) for predicting sample labels, evaluating the accuracy of the AE. In addition, differentially expressed genes (DEGs), signaling pathways, and transcription factors (TFs) involved in immunosuppression and periodontitis were determined with an array of bioinformatics analysis. Shared DEGs common to DEGs differentiating periodontitis from controls and those differentiating the immune subtypes were considered as the key immunosuppression genes in periodontitis.ResultsWe produced representative molecular features and identified two immune subtypes in periodontitis using an AE. Two subtypes were also predicted in the validation set with the SVM classifier. Three “master” immunosuppression genes, PECAM1, FCGR3A, and FOS were identified as candidates pivotal to immunosuppressive mechanisms in periodontitis. Six transcription factors, NFKB1, FOS, JUN, HIF1A, STAT5B, and STAT4, were identified as central to the TFs-DEGs interaction network. The two immune subtypes were distinct in terms of their regulating pathways.ConclusionThis study applied a DL-based AE for the first time to identify immune subtypes of periodontitis and pivotal immunosuppression genes that discriminated periodontitis from the healthy. Key signaling pathways and TF-target DEGs that putatively mediate immune suppression in periodontitis were identified. PECAM1, FCGR3A, and FOS emerged as high-value biomarkers and candidate therapeutic targets for periodontitis.

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“…Ligature‐induced periodontitis mice models have been more frequently used to study periodontal disease mechanisms and to test the potential of novel therapeutic methods. 10 , 11 Although involvement of local PD‐L1 in the progression of periodontitis has been suggested, 5 , 12 the functional contribution of PD‐L1 induced on gingival KCs to periodontal inflammation has not been investigated, because PD‐L1 is up‐regulated in various non‐immune tissue cells as well as immune cells under the inflammatory conditions. In this study, to investigate the role of overexpressing PD‐L1 in gingival basal KCs, we compared periodontal inflammatory responses at an earlier time point (7 days) and alveolar bone resorption at a late time point (7 weeks) between wild‐type (WT) and K14‐PD‐L1tg mice in a ligature‐induced periodontitis model.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of PD‐L1 in gingival basal keratinocytes reduces periodontal inflammation in a ligature‐induced periodontitis model

Wongtim

Ikeda

Ohno

et al. 2021

Journal of Periodontology

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Background:The immune checkpoint programmed cell death 1 (PD-1): PD-1 ligand 1 (PD-L1) pathway plays a crucial role in maintaining immune tolerance and preventing tissue damages by excessive immune responses. PD-L1 is physiologically expressed and upregulated in keratinocytes (KCs) in the oral cavity. We here investigated the contribution of PD-L1 that was overexpressed in gingival basal KCs in a ligature-induced periodontitis model. Methods: Wild-type (WT) BALB/c and K14/PD-L1 transgenic (tg) mice, in which PD-L1 was overexpressed in basal KCs under control of the keratin 14 promoter, were used. To induce periodontitis, a 9-0 silk ligature was placed around the upper right second molar, and lipopolysaccharide from Porphyromonas gingivalis was applied on the suture. Gingival tissues were collected on day 7, after which histological analyses were performed, including by hematoxylin and eosin and tartrate-resistant acid phosphate staining (TRAP) and quantitative PCR for proinflammatory cytokines and bone metabolism-related genes. Alveolar bone loss at 7 weeks after ligature placement was assessed by micro-computed tomography analysis. Results: PD-L1 was overexpressed in the basal KCs of all gingival epithelia in K14/PD-L1tg mice. Early ligature-induced periodontal inflammation, as assessed based on histological changes, elevation of proinflammatory cytokine (IL-1β, IL-6, TNF-α) expression, periodontal ligament degeneration, and osteoclastogenesis as assessed by Rankl and Opg expression and TRAP+ cells, was markedly impaired in K14/PD-L1tg mice. Alveolar bone resorption at a late time point was also clearly minimized in K14/PD-L1tg mice. Conclusion: Overexpression of PD-L1 in gingival basal keratinocytes in K14/PD-L1tg mice reduces periodontal inflammation and alveolar bone resorption in a ligature-induced periodontitis model.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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The implication of the PD-1/PD-L1 checkpoint in chronic periodontitis suggests novel therapeutic opportunities with natural products

Cited by 25 publications

References 84 publications

Oral Dysbiosis and Autoimmunity: From Local Periodontal Responses to an Imbalanced Systemic Immunity. A Review

Oral Dysbiosis and Autoimmunity: From Local Periodontal Responses to an Imbalanced Systemic Immunity. A Review

Deep Learning Reveals Key Immunosuppression Genes and Distinct Immunotypes in Periodontitis

Overexpression of PD‐L1 in gingival basal keratinocytes reduces periodontal inflammation in a ligature‐induced periodontitis model

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