Transcriptomic phases of periodontitis lesions using the nonhuman primate model

Ebersole, Jeffrey L.; Nagarajan, Radhakrishnan; Kirakodu, Sreenatha; González, Octavio A.

doi:10.1038/s41598-021-88803-6

Cited by 16 publications

(26 citation statements)

References 73 publications

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“…However, a critical assessment of the characteristics and kinetics of the changes that occur with disease initiation and progression is limited in the human model. This occurs since the clinical features that can be measured are not necessarily coincident with the biological changes that fundamentally underpin dysbiotic microbiome changes and dysregulated host responses [ 21 ]. Cell biology studies with an array of cells that comprise the gingival tissues, including oral epithelial cells, have demonstrated changes in gene expression and/or product formation in response to oral bacteria [ 36 – 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…Another important question in periodontal biology is related to providing a clearer understanding of the temporal nature of changes in responses reflecting a breakdown in the integrity of the tissues that would be a harbinger of clinical disease outcomes. We have reported on the kinetics of the biology of the lesion using this non-human primate model [ 21 ]. Specifically, we identified patterns within the overall transcriptome that hallmarked health, initiation, progression, and resolution of the periodontal lesion.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously described the use of the non-human primate model of naturally occurring and ligature-induced periodontitis to identify gingival tissue transcriptome patterns and to examine an array of biologic pathways that are altered by disease and affected by aging [ 21 – 30 ]. Recently, we identified unique features of the transcriptome related to epithelial cell biology that is focused on changes that occur with aging in clinically healthy gingival tissues [ 21 , 31 ]. The results indicated that in younger animals, the expression of epithelial genes appeared more developmentally flexible.…”

Section: Introductionmentioning

confidence: 99%

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Comparative Analysis of Gene Expression Patterns for Oral Epithelial Cell Functions in Periodontitis

González

Kirakodu

Linh-Trung

et al. 2022

Front. Oral. Health

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The structure and function of epithelial cells are critical for the construction and maintenance of intact epithelial surfaces throughout the body. Beyond the mechanical barrier functions, epithelial cells have been identified as active participants in providing warning signals to the host immune and inflammatory cells and in communicating various detailed information on the noxious challenge to help drive specificity in the characteristics of the host response related to health or pathologic inflammation. Rhesus monkeys were used in these studies to evaluate the gingival transcriptome for naturally occurring disease samples (GeneChip® Rhesus Macaque Genome Array) or for ligature-induced disease (GeneChip® Rhesus Gene 1.0 ST Array) to explore up to 452 annotated genes related to epithelial cell structure and functions. Animals were distributed by age into four groups: ≤ 3 years (young), 3–7 years (adolescent), 12–16 years (adult), and 18–23 years (aged). For naturally occurring disease, adult and aged periodontitis animals were used, which comprised 34 animals (14 females and 20 males). Groups of nine animals in similar age groups were included in a ligature-induced periodontitis experiment. A buccal gingival sample from either healthy or periodontitis-affected tissues were collected, and microarray analysis performed. The overall results of this investigation suggested a substantial alteration in epithelial cell functions that occurs rapidly with disease initiation. Many of these changes were prolonged throughout disease progression and generally reflect a disruption of normal cellular functions that would presage the resulting tissue destruction and clinical disease measures. Finally, clinical resolution may not signify biological resolution and represent a continued risk for disease that may require considerations for additional biologically specific interventions to best manage further disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparative Analysis of Gene Expression Patterns for Oral Epithelial Cell Functions in Periodontitis

González

Kirakodu

Linh-Trung

et al. 2022

Front. Oral. Health

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“…Recognizing the episodic nature of periodontal lesions with exacerbations and remissions suggests a dynamic process of transition from health to disease initiation, followed by disease progression, and eventually lesion resolution. We have previously identified an array of genes that form a profile of responses coincident with these various phases using a non-human primate of ligature-induced periodontitis [ 55 ]. Although the patterns of genes identified were derived from a range of biologic pathways, there was a clear representation of innate immune and inflammatory genes.…”

Section: Discussionmentioning

confidence: 99%

Oral Microbiome and Gingival Gene Expression of Inflammatory Biomolecules With Aging and Periodontitis

Ebersole

Nagarajan

Kirakodu

et al. 2021

Front. Oral. Health

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Although data describe the presence and increase of inflammatory mediators in the local environment in periodontitis vs. health in humans, details regarding how these responses evolve in the transition from health to disease, changes during disease progression, and features of a resolved lesion remain unknown. This study used a nonhuman primate model of ligature-induced periodontitis in young, adolescent, adult, and aged animals to document features of inflammatory response affected by age. Rhesus monkeys had ligatures tied and provided gingival tissue biopsy specimens at baseline, 0.5, 1, and 3 months of disease and at 5 months of the study, which was 2 months post-ligature removal for clinically resolved tissues. The transcriptome was assessed using microarrays for chemokine (n = 41), cytokine (n = 45), chemokine receptor (n = 21), cytokine receptor (n = 37), and lipid mediator (n = 31) genes. Limited differences were noted in healthy tissues for chemokine expression with age; however, chemokine receptor genes were decreased in young but elevated in aged samples. IL1A, IL36A, and IL36G cytokines were decreased in the younger groups, with IL36A elevated in aged animals. IL10RA/IL10RB cytokine receptors were altered with age. Striking variation in the lipid mediator genes in health was observed with nearly 60% of these genes altered with age. A specific repertoire of chemokine and chemokine receptor genes was affected by the disease process, predominated by changes during disease initiation. Cytokine/cytokine receptor genes were also elevated with disease initiation, albeit IL36B, IL36G, and IL36RN were all significantly decreased throughout disease and resolution. Significant changes were observed in similar lipid mediator genes with disease and resolution across the age groups. Examination of the microbiome links to the inflammatory genes demonstrated that specific microbes, including Fusobacterium, P. gingivalis, F. alocis, Pasteurellaceae, and Prevotella are most frequently significantly correlated. These correlations were generally positive in older animals and negative in younger specimens. Gene expression and microbiome patterns from baseline were distinctly different from disease and resolution. These results demonstrate patterns of inflammatory gene expression throughout the phases of the induction of a periodontal disease lesion. The patterns show a very different relationship to specific members of the oral microbiome in younger compared with older animals.

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“…These findings included specific differences in B cells, 12 T‐cell phenotypes, 42 antigen‐presenting cells, 43 macrophage polarization, 44 and T follicular helper cells 45 in the gingival tissues. The transcriptome also showed some patterns of immunoglobulin gene rearrangements in the gingival tissues at different phases of periodontal lesions in the nonhuman primates 46 . This study focused on the molecular details of the Ig gene transcripts to examine differences with age and the disease process.…”

Section: Introductionmentioning

confidence: 99%

Gingival tissue antibody gene utilization in aging and periodontitis

Ebersole

Linh-Trung

González

2022

J of Periodontal Research

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Objective This study used a nonhuman primate model of ligature‐induced periodontitis to document the characteristics of immunoglobulin (Ig) gene usage in gingival tissues with disease and affected by age. Background Adaptive immune responses to an array of oral bacteria are routinely detected in local gingival tissues and the systemic circulation across the human population. The level and diversity of antibody increases with periodontitis, reflecting the increased quantity of B cells and plasmacytes in the tissues at sites of periodontal lesions. Methods Macaca mulatta (n = 36) in four groups (young – ≤3 years; adolescent >3–7 years; adult – 12–15 years; aged – 17‐23 years) were used in this study. Gingival tissues were sampled at baseline (health), 2 weeks (initiation), 1 and 3 months (progression), and 5 months (resolution) of the lesion development and transcriptomic analysis included 78 Ig‐related genes. Results The results demonstrated extensive variation in Ig gene usage patterns and changes with the disease process that was substantially affected by the age of the animal. Of note was that the aged animals generally demonstrated elevated expression on multiple Ig genes even in the baseline/healthy gingival tissues. The expression levels revealed 5 aggregates of Ig gene change profiles across the age groups. The number of gene changes were greatly increased in adult animals with the initiation of disease, while the young and adolescent animals showed extensive changes with disease progression. Elevated Ig gene transcripts remained with disease resolution except in the aged animals. The response profiles demonstrated selective heavy/light change gene transcripts that differed with age and clustering of the transcript expression was dominated by the age of the animals. Conclusions The results suggested potential critical variations in the molecular aspects of Ig gene expression in gingival tissues that can contribute to understanding the kinetics of periodontal lesions, as well as the variation in episodes, rapidity of progression, and role in resolution that are impacted by age.

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Transcriptomic phases of periodontitis lesions using the nonhuman primate model

Cited by 16 publications

References 73 publications

Comparative Analysis of Gene Expression Patterns for Oral Epithelial Cell Functions in Periodontitis

Comparative Analysis of Gene Expression Patterns for Oral Epithelial Cell Functions in Periodontitis

Oral Microbiome and Gingival Gene Expression of Inflammatory Biomolecules With Aging and Periodontitis

Gingival tissue antibody gene utilization in aging and periodontitis

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