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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 27928

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Dr. Kenichi Kumagai

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Department of Oral and Maxillofacial Surgery, Dentistry and Orthodontics, The University of Tokyo Hospital, Tokyo 113-8655, Japan
Interests: clinical immunology; cancer immunity; oral mucosal disease; T cell receptor; oral microbiome; temporomandibular disorders
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Special Issue Information

Dear Colleagues,

The oral cavity is the port of entry to the gastrointestinal and respiratory tracts, characterised by the juxtaposition of soft and hard tissues, and it is continuously subject to challenges by the external environment, such as foreign antigens or material.

Oral microbial communities are now seen as the fundamental etiological agent in oral diseases through their interface with host inflammatory responses. Thus, it is essential to understand the molecular mechanisms and pathogenicity of oral diseases in terms of immunological and microbiological perspectives. Oral medicine is concerned with the diagnosis and management of oral diseases, including oral mucosal disease, oral cancer, salivary gland disorders, temporomandibular disorders, and the oral manifestations of systemic and infectious diseases. This Special Issue aims to cover all areas of oral medicine to study various oral diseases in terms of immunological and microbiological perspectives.

Dr. Kenichi Kumagai
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

oral immunity
oral microbiology
oral mucosal disease
oral cancer
salivary gland disorders
temporomandibular disorders
oral manifestations of systemic and infectious diseases
T cell
B cell
microbiome

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Oral Medicine and Immunity 2.0 in International Journal of Molecular Sciences (2 articles)

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Research

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13 pages, 2128 KiB

Open AccessArticle

Cross-Reactivity of Intraoral Allergic Contact Mucositis in the Nickel-Sensitized Ear Model of Metal Allergy

by Ryota Matsubara, Kenichi Kumagai, Keisuke Nasu, Takamasa Yoshizawa, Kazutaka Kitaura, Motoaki Suzuki, Yoshiki Hamada and Ryuji Suzuki

Int. J. Mol. Sci. 2023, 24(4), 3965; https://doi.org/10.3390/ijms24043965 - 16 Feb 2023

Cited by 1 | Viewed by 2808

Abstract

Cross-reactivity of metal allergies can make metal allergy treatment complicated because the background of immune response in cross-reactions remains unknown. In clinical settings, cross-reactivity among several metals has been suspected. However, the precise mechanism of immune response in cross-reactivity is unclear. Two sensitizations with nickel, palladium, and chromium plus lipopolysaccharide solution into the postauricular skin were followed by a single nickel, palladium, and chromium challenge of the oral mucosa to generate the intraoral metal contact allergy mouse model. Results showed that the infiltrating T cells in nickel-sensitized, palladium- or chromium-challenged mice expressed CD8+ cells, cytotoxic granules, and inflammation-related cytokines. Thus, nickel ear sensitization can cause cross-reactive intraoral metal allergy. Full article

(This article belongs to the Special Issue Oral Medicine and Immunity)

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17 pages, 2958 KiB

Open AccessArticle

Dual Role of Interleukin-20 in Different Stages of Osteoclast Differentiation and Its Osteoimmune Regulation during Alveolar Bone Remodeling

by Bowen Meng, Benyi Yang, Yan Qu, Yuanbo Liu, Dongle Wu, Chaoran Fu, Yifan He, Xi Chen, Chufeng Liu, Xiaoxing Kou and Yang Cao

Int. J. Mol. Sci. 2023, 24(4), 3810; https://doi.org/10.3390/ijms24043810 - 14 Feb 2023

Cited by 3 | Viewed by 2133

Abstract

Osteoimmunology mediators are critical to balance osteoblastogenesis and osteoclastogenesis to maintain bone homeostasis. A lot of the osteoimmunology mediators are regulated by interleukin-20 (IL-20). However, little is known about the role of IL-20 in bone remodeling. Here, we showed that IL-20 expression was correlated with osteoclast (OC) activity in remodeled alveolar bone during orthodontic tooth movement (OTM). Ovariectomize (OVX) in rats promoted OC activity and enhanced IL-20 expression, while blocking OC inhibited IL-20 expression in osteoclasts. In vitro, IL-20 treatment promoted survival, inhibited apoptosis of the preosteoclast at the early stages of osteoclast differentiation, and boosted the formation of osteoclasts and their bone resorption function at the late stages. More importantly, anti-IL-20 antibody treatment blocked IL-20-induced osteoclastogenesis and the subsequent bone resorption function. Mechanistically, we showed that IL-20 synergistically acts with RANKL to activate the NF-κB signaling pathway to promote the expression of c-Fos and NFATc1 to promote osteoclastogenesis. Moreover, we found that local injection of IL-20 or anti-IL-20 antibody enhanced osteoclast activity and accelerated OTM in rats, while blocking IL-20 reversed this phenomenon. This study revealed a previously unknown role of IL-20 in regulating alveolar bone remodeling and implies the application of IL-20 to accelerated OTM. Full article

(This article belongs to the Special Issue Oral Medicine and Immunity)

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14 pages, 4718 KiB

Open AccessArticle

Type IVb Hypersensitivity Reaction in the Novel Murine Model of Palladium–Induced Intraoral Allergic Contact Mucositis

by Keisuke Nasu, Kenichi Kumagai, Takamasa Yoshizawa, Kazutaka Kitaura, Ryota Matsubara, Motoaki Suzuki, Ryuji Suzuki and Yoshiki Hamada

Int. J. Mol. Sci. 2023, 24(4), 3137; https://doi.org/10.3390/ijms24043137 - 5 Feb 2023

Viewed by 2415

Abstract

Palladium (Pd) is a component of several alloy types that are widely used in our environment, including several dental alloy types that cause adverse reactions such as hypersensitivity in the oral mucosa. However, the pathological mechanism of intraoral Pd allergies remains unclear because its animal model in the oral mucosa has not been established. In this study, we established a novel murine model of Pd–induced allergies in the oral mucosa, and explored the immune response of cytokine profiles and T cell diversity in terms of the T cell receptor. The Pd–induced allergy mouse was generated by two sensitizations with PdCl₂, plus a lipopolysaccharide solution into the postauricular skin followed by a single Pd challenge of the buccal mucosa. Significant swelling and pathological features were histologically evident at five days after the challenge, and CD4–positive T cells producing high levels of T helper 2 type cytokines had accumulated in the allergic oral mucosa. Characterization of the T cell receptor repertoire in Palladium allergic mice indicated that Pd–specific T cell populations were limited in V and J genes but were diverse at the clonal level. Our model demonstrated that a Pd–specific T cell population with Th2 type response tendencies may be involved in the Pd–induced intraoral metal contact allergy. Full article

(This article belongs to the Special Issue Oral Medicine and Immunity)

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14 pages, 3290 KiB

Open AccessArticle

Characterization of Metal-Specific T-Cells in Inflamed Oral Mucosa in a Novel Murine Model of Chromium-Induced Allergic Contact Dermatitis

by Takamasa Yoshizawa, Kenichi Kumagai, Ryota Matsubara, Keisuke Nasu, Kazutaka Kitaura, Motoaki Suzuki, Yoshiki Hamada and Ryuji Suzuki

Int. J. Mol. Sci. 2023, 24(3), 2807; https://doi.org/10.3390/ijms24032807 - 1 Feb 2023

Cited by 1 | Viewed by 2306

Abstract

The element chromium (Cr) is a component of several types of alloys found in the environment, or utilized in dentistry, that may cause intraoral metal contact allergy. However, the pathological mechanism of intraoral Cr allergy remains unclear because there is no established animal model of Cr allergy in the oral mucosa. In this study, we established a novel murine model of Cr-induced intraoral metal contact allergy and elucidated the immune response in terms of cytokine profiles and T-cell receptor repertoire. Two sensitizations with Cr plus lipopolysaccharide solution into the postauricular skin were followed by a single Cr challenge of the oral mucosa to generate the intraoral metal contact allergy model. Histological examination revealed that CD3+ T-cells had infiltrated the allergic oral mucosa one day after exposure to the allergen. The increase in T-cell markers and cytokines in allergic oral mucosa was also confirmed via quantitative PCR analysis. We detected Cr-specific T-cells bearing TRAV12D-1-TRAJ22 and natural killer (NK) T-cells in the oral mucosa and lymph nodes. Our model demonstrated that Cr-specific T-cells and potent NKT-cell activation may be involved in the immune responses of Cr-induced intraoral metal contact allergy. Full article

(This article belongs to the Special Issue Oral Medicine and Immunity)

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13 pages, 3216 KiB

Open AccessArticle

Human β-Defensin 3 Inhibits Porphyromonas Gingivalis Lipopolysaccharide-Induced Oxidative and Inflammatory Responses of Microglia by Suppression of Cathepsins B and L

by Erika Inoue, Shiyo Minatozaki, Yui Katsuta, Saori Nonaka and Hiroshi Nakanishi

Int. J. Mol. Sci. 2022, 23(23), 15099; https://doi.org/10.3390/ijms232315099 - 1 Dec 2022

Cited by 3 | Viewed by 1928

Abstract

Recently, the effects of antibacterial peptides are suggested to have therapeutic potential in Alzheimer’s disease. Furthermore, systemic treatment of Porphyromonas gingivalis (Pg) lipopolysaccharide (LPS) induced Alzheimer’s disease-like neuropathological changes in middle-aged mice. Then, we examined whether human β-defensins (hBDs), antimicrobial peptides produced by the oral mucosa and salivary glands, can suppress Pg LPS-induced oxidative and inflammatory responses by microglia. hBD3 (1 μM) significantly suppressed Pg LPS-induced production of nitric oxide and interleukin-6 (IL-6) by MG6 cells, a mouse microglial cell line. hBD3 (1 μM) also significantly inhibited Pg LPS-induced expression of IL-6 by HMC3 cells, a human microglial cell line. In contrast, neither hBD1, hBD2 nor hBD4 failed to inhibit their productions. Furthermore, hBD3 suppressed Pg LPS-induced p65 nuclear translocation through the IκBα degradation. Pg LPS-induced expression of IL-6 was significantly suppressed by E64d, a cysteine protease inhibitor, and CA-074Me, a known specific inhibitor for cathepsin B, but not by pepstatin A, an aspartic protease inhibitor. Interestingly, hBD3 significantly inhibited enzymatic activities of recombinant human cathepsins B and L, lysosomal cysteine proteases, and their intracellular activities in MG6 cells. Therefore, hBD3 suppressed oxidative and inflammatory responses of microglia through the inhibition of cathepsins B and L, which enzymatic activities are necessary for the NF-κB activation. Full article

(This article belongs to the Special Issue Oral Medicine and Immunity)

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18 pages, 525 KiB

Open AccessArticle

The Role of Polymorphisms at the Interleukin-1, Interleukin-4, GATA-3 and Cyclooxygenase-2 Genes in Non-Surgical Periodontal Therapy

by Kay-Arne Walther, José Roberto Gonzales, Sabine Gröger, Benjamin Ehmke, Dogan Kaner, Katrin Lorenz, Peter Eickholz, Thomas Kocher, Ti-Sun Kim, Ulrich Schlagenhauf, Raphael Koch and Jörg Meyle

Int. J. Mol. Sci. 2022, 23(13), 7266; https://doi.org/10.3390/ijms23137266 - 30 Jun 2022

Cited by 11 | Viewed by 2226

Abstract

Periodontitis is a multifactorial disease. The aim of this explorative study was to investigate the role of Interleukin-(IL)-1, IL-4, GATA-3 and Cyclooxygenase-(COX)-2 polymorphisms after non-surgical periodontal therapy with adjunctive systemic antibiotics (amoxicillin/metronidazole) and subsequent maintenance in a Caucasian population. Analyses were performed using blood samples from periodontitis patients of a multi-center trial (ClinicalTrials.gov NCT00707369=ABPARO-study). Polymorphisms were analyzed using quantitative real-time PCR. Clinical attachment levels (CAL), percentage of sites showing further attachment loss (PSAL) ≥1.3 mm, bleeding on probing (BOP) and plaque score were assessed. Exploratory statistical analysis was performed. A total of 209 samples were genotyped. Patients carrying heterozygous genotypes and single-nucleotide-polymorphisms (SNP) on the GATA-3-IVS4 +1468 gene locus showed less CAL loss than patients carrying wild type. Heterozygous genotypes and SNPs on the IL-1A-889, IL-1B +3954, IL-4-34, IL-4-590, GATA-3-IVS4 +1468 and COX-2-1195 gene loci did not influence CAL. In multivariate analysis, CAL was lower in patients carrying GATA-3 heterozygous genotypes and SNPs than those carrying wild-types. For the first time, effects of different genotypes were analyzed in periodontitis progression after periodontal therapy and during supportive treatment using systemic antibiotics demonstrating a slight association of GATA-3 gene locus with CAL. This result suggests that GATA-3 genotypes are a contributory but non-essential risk factor for periodontal disease progression. Full article

(This article belongs to the Special Issue Oral Medicine and Immunity)

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16 pages, 2562 KiB

Open AccessArticle

Shear Stress Enhances the Paracrine-Mediated Immunoregulatory Function of Human Periodontal Ligament Stem Cells via the ERK Signalling Pathway

by Ravipha Suwittayarak, Nuttha Klincumhom, Utapin Ngaokrajang, Worachat Namangkalakul, João N. Ferreira, Prasit Pavasant and Thanaphum Osathanon

Int. J. Mol. Sci. 2022, 23(13), 7119; https://doi.org/10.3390/ijms23137119 - 27 Jun 2022

Cited by 9 | Viewed by 3205

Abstract

Relevant immunomodulatory effects have been proposed following allogeneic cell-based therapy with human periodontal ligament stem cells (hPDLSCs). This study aimed to examine the influence of shear stress on the immunosuppressive capacity of hPDLSCs. Cells were subjected to shear stress at different magnitudes (0.5, [...] Read more.

^{2}

). The expression of immunosuppressive markers was evaluated in shear stress-induced hPDLSCs using qRT-PCR, western blot, enzyme activity and enzyme-linked immunosorbent assays. The effects of a shear stress-derived condition medium (SS-CM) on T cell proliferation were examined using a resazurin assay. Treg differentiation was investigated using qRT-PCR and flow cytometry analysis. Our results revealed that shear stress increased mRNA expression of IDO and COX2 but not TGF-β1 and IFN-γ. IDO activity, kynurenine and active TGF-

β

1 increased in SS-CM when compared to the non-shear stress-derived conditioned medium (CTL-CM). The amount of kynurenine in SS-CM was reduced in the presence of cycloheximide and ERK inhibitor. Subsequently, T cell proliferation decreased in SS-CM compared to CTL-CM. Treg differentiation was promoted in SS-CM, indicated by FOXP3, IL-10 expression and CD4

^{+}

CD25

^{h i}

CD127

^{l o / -}

subpopulation. In conclusion, shear stress promotes kynurenine production through ERK signalling in hPDLSC, leading to the inhibition of T cell proliferation and the promotion of Treg cell differentiation. Full article

(This article belongs to the Special Issue Oral Medicine and Immunity)

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Review

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13 pages, 1351 KiB

Open AccessReview

Function of Innate Lymphoid Cells in Periodontal Tissue Homeostasis: A Narrative Review

by Zhiyu Ma, Jinsong Wang, Lei Hu and Songlin Wang

Int. J. Mol. Sci. 2023, 24(7), 6099; https://doi.org/10.3390/ijms24076099 - 23 Mar 2023

Cited by 5 | Viewed by 2953

Abstract

Periodontitis is an irreversible inflammatory response that occurs in periodontal tissues. Given the size and diversity of natural flora in the oral mucosa, host immunity must strike a balance between pathogen identification and a complicated system of tolerance. The innate immune system, which includes innate lymphoid cells (ILCs), certainly plays a crucial role in regulating this homeostasis because pathogens are quickly recognized and responded to. ILCs are a recently discovered category of tissue-resident lymphocytes that lack adaptive antigen receptors. ILCs are found in both lymphoid and non-lymphoid organs and are particularly prevalent at mucosal barrier surfaces, where they control inflammatory response and homeostasis. Recent studies have shown that ILCs are important players in periodontitis; however, the mechanisms that govern the innate immune response in periodontitis still require further investigation. This review focuses on the intricate crosstalk between ILCs and the microenvironment in periodontal tissue homeostasis, with the purpose of regulating or improving immune responses in periodontitis prevention and therapy. Full article

(This article belongs to the Special Issue Oral Medicine and Immunity)

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14 pages, 1620 KiB

Open AccessReview

Genetic/Protein Association of Atopic Dermatitis and Tooth Agenesis

by Wanlu Ouyang, Charlene E. Goh, Wei Bo Ng, Fook Tim Chew, Eric Peng Huat Yap and Chin-ying Stephen Hsu

Int. J. Mol. Sci. 2023, 24(6), 5754; https://doi.org/10.3390/ijms24065754 - 17 Mar 2023

Cited by 3 | Viewed by 3372

Abstract

Atopic dermatitis and abnormalities in tooth development (including hypomineralization, hypodontia and microdontia) have been observed to co-occur in some patients. A common pathogenesis pathway that involves genes and protein interactions has been hypothesized. This review aims to first provide a description of the key gene mutations and signaling pathways associated with atopic dermatitis and tooth agenesis (i.e., the absence of teeth due to developmental failure) and identify the possible association between the two diseases. Second, utilizing a list of genes most commonly associated with the two diseases, we conducted a protein–protein network interaction analysis using the STRING database and identified a novel association between the Wnt/β-catenin signaling pathway (major pathway responsible for TA) and desmosomal proteins (component of skin barrier that affect the pathogenesis of AD). Further investigation into the mechanisms that may drive their co-occurrence and underlie the development of the two diseases is warranted. Full article

(This article belongs to the Special Issue Oral Medicine and Immunity)

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12 pages, 303 KiB

Open AccessReview

Chronic Ulcerative Stomatitis (CUS) as an Interdisciplinary Diagnostic Challenge: A Literature Review

by Dominika Cichońska, Dominika Komandera, Magda Mazuś and Aida Kusiak

Int. J. Mol. Sci. 2022, 23(22), 13772; https://doi.org/10.3390/ijms232213772 - 9 Nov 2022

Cited by 2 | Viewed by 3238

Abstract

Chronic ulcerative stomatitis (CUS) is a rarely reported disease affecting the oral cavity, most often affecting middle-aged Caucasian females. The aim of the present study is to present the diagnosis, differentiation, and interdisciplinary treatment of this rare disease. CUS is characterized by the presence of an oral erosive or ulcerative lesion. The autoimmune pathogenesis of CUS includes affecting the antigen’s activity by DNA-breaking and protein-hydrolyzing enzymes. The stratified epithelium-specific antinuclear antibodies (SES-ANA) are associated with CUS development. Clinically, the lesions presented in oral mucosa might resemble an erosive form of oral lichen planus, whereas gingival lesions seem to be similar to desquamative gingivitis related to dermatological diseases manifested in the oral cavity. Patients often report subjective symptoms related to oral mucosa and general symptoms. Histopathological presentation of CUS is often non-specific and includes sub-epithelial separation from underlying connective tissue, atrophic epithelium, and inflammatory infiltrate with an increased number of plasma cells and lymphocytes. Direct immunofluorescence (DIF) might be used in CUS diagnostics. CUS generally remains nonsusceptible to corticosteroid treatments; however, antimalarial drugs and calcineurin inhibitors are more effective. Further research should be conducted in order to implement a diagnostic protocol and observe the long-term results of CUS management. Full article

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