| 1. |
- Bankvall, Maria, et al.
(författare)
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A family-based genome-wide association study of recurrent aphthous stomatitis
- 2020
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Ingår i: Oral Diseases. - : Wiley. - 1354-523X .- 1601-0825. ; 26:8, s. 1696-1705
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Tidskriftsartikel (refereegranskat)abstract
- © 2020 The Authors. Oral Diseases published by John Wiley & Sons Ltd Objectives: The aetiology of recurrent aphthous stomatitis (RAS) remains unknown. Individuals may share features of genetic susceptibility, and there may also be a hereditary component. The aim was to identify patterns of association and segregation for genetic variants and to identify the genes and signalling pathways that determine the risk of developing RAS, through a family-based genome-wide association study (GWAS). Subjects and methods: DNA was extracted from buccal swabs of 91 individuals in 16 families and analysed in an Illumina core exome single nucleotide polymorphism (SNP) array. A family-based association test (dFAM) was used to derive SNP association values across all chromosomes. Results: None of the final 288,452 SNPs reached the genome-wide significant threshold of 5×10–8. The most significant pathways were the Ras and PI3K-Akt signalling pathways, pathways in cancer, circadian entrainment and the Rap 1 signalling pathway. Conclusions: This confirms that RAS is not monogenic but results as a consequence of interactions between multiple host genes and possibly also environmental factors. The present approach provides novel insights into the mechanisms underlying RAS and raises the possibility of identifying individuals at risk of acquiring this condition.
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| 2. |
- Bankvall, Maria
(författare)
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Recurrent Aphthous Stomatitis - A study, with emphasis on host genetics, oral microbiota composition, and immunoregulatory networks
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal lesions. The aetiology is unknown and currently there is no consensus regarding suitable treatment regimens. RAS is recognised as a multi-factorial condition in which both endogenous and exogenous factors contribute to the recurrent oral ulcerations characteristic of this oral mucosal disease. The overall aim of this thesis was to study the aetiological factors associated with RAS. Previously, it has been suggested that genetic factors, a microbiological component, and the abrogation of tolerance to specific food antigens are of importance in RAS. Hence, two clinical studies were conducted to explore the roles in RAS of host genetics and the composition of the oral microbiota. To reveal the actions of food components as exogenous triggering factors for RAS, it is necessary to understand the immunoregulatory networks involved in the induction of tolerance in the oral cavity. Extensive pre-clinical studies of these mechanisms are required before translating the acquired knowledge to the clinical setting. Therefore, two pre-clinical studies in mice were performed to explore the roles of the oral cavity and associated lymphoid tissues in comparison to those of the mesenteric lymph nodes (MLN), which are known to be of importance for oral tolerance induction. The specific aims of the clinical studies were to: (i) identify patterns of association and segregation regarding genetic variants passed down to the offspring within families with RAS and to identify the genes and signalling pathways that determine the risk of developing this condition; and (ii) compare the oral microbiota profiles of patients with RAS and healthy control subjects, so as to define microbiotal changes in relation to disease activity. The specific aims of the pre-clinical studies were to: (i) identify differences between the murine APC and T-cell populations of the oral-associated lymphoid tissues [i.e., the nose-associated lymphoid tissues (NALT) and the cervical lymph nodes (CLN)] and the MLN; and (ii) determine whether the passage of an antigen through the oral cavity contributes to the overall immunological response and the degree of tolerance induced, as compared to gastric administration of the same antigen. Buccal swabs were obtained from non-ulcerative areas of the mouths of patients with RAS (N=60) and healthy age- and gender-matched controls (N=60), with some of the patients (N=42) presenting with lesions upon sampling. Additional swabs from members of 16 families with RAS (N=91) were also included. The human DNA was analysed in a Genome-wide association study (GWAS), using a CoreExome array, and the bacterial DNA was analysed by Terminal-restriction fragment length polymorphism (T-RFLP). Flow cytometry and in vitro proliferation were used to analyse the APC and T-cell subsets at the different sites in the BALB/c mice. To compare oral and gastric administration of the antigen (ovalbumin, OVA), a DO11.10 TCR transfer model and an oral tolerance model, using BALB/c mice, were applied. No pattern of association or segregation for genetic variants being passed down to the offspring within these families was detected. The most significant pathways implicated in RAS were the Ras signalling pathway, the PI3K-Akt signalling pathway, pathways in cancer, circadian entrainment, and the Rap 1 signalling pathway. The oral microbiota profiles differed between patients and controls, especially regarding the profiles of patients who presented with lesions during sampling, which clustered furthest from the profiles of the controls. The NALT contained a higher proportion of APCs and a lower proportion of T cells than the CLN and MLN. The APCs of the NALT displayed few signs of activation, instead showing high-level expression of markers associated with effector and tolerogenic functions. Furthermore, the T cells in the NALT more often showed a memory/effector phenotype, whereas those in the CLN and MLN had a naïve phenotype. In general, the cells of the NALT did not proliferate upon in vitro stimulation with concanavalin A, in contrast to the cells from the CLN and MLN. A similar activation pattern and degree of tolerance induction emerged when the two administration routes were compared. In summary, understanding the genetic basis of RAS may allow the identification of individuals who are at risk of acquiring this condition. Changes to the oral microbiota may trigger the development of lesions or vice versa. The NALT displayed effector and tolerogenic functions as opposed to the other sites that demonstrated a strong capacity for primary immune activation. The contribution of the mucosal immune system, besides the intestine, for induction of oral tolerance remains to be further investigated. Suitable and efficient treatment strategies for RAS can be developed only when the aetiology of this condition is fully understood.
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| 3. |
- Bankvall, Maria, et al.
(författare)
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The engagement of oral-associated lymphoid tissues during oral versus gastric antigen administration
- 2016
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Ingår i: Immunology. - : Wiley. - 0019-2805. ; 149:1, s. 98-110
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Tidskriftsartikel (refereegranskat)abstract
- The role of oral-associated lymphoid tissues during induction of oral tolerance still remains elusive. Therefore, the aim was to compare T-cell activation and induction of tolerance to ovalbumin (OVA) presented through either of two routes; deposited into the oral cavity, or the stomach, thereby bypassing the oral cavity. OVA was administered by the oral or gastric route to BALB/c mice that had received OVA-specific DO11.10+ CD4(+) T cells, stained with CellTrace Violet dye, through intravenous injection. Proliferating OVA-specific T cells were detected in the nose-associated lymphoid tissues (NALT) and the cervical, mesenteric and peripheral lymph nodes at different time-points following OVA exposure. OVA-specific T-cell proliferation was initially observed in the NALT 1hr after oral, but not gastric, administration. However, at day 1, proliferation at this site was also detected after gastric administration and profound proliferation was observed at all sites by day 4. For the oral route the degree of proliferation observed was lower in the peripheral lymph nodes by day 4 compared with the other sites. These results demonstrate a similar activation pattern achieved by the two routes. However, the NALT distinguishes itself as a site of rapid T-cell activation towards fed antigens irrespective of feeding regimen. To evaluate induction of tolerance a semi-effective OVA dose was used, to detect differences in the degree of tolerance achieved. This was performed in a model of OVA-induced airway hypersensitivity. No differences in tolerance induction were observed between the two administration routes.
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| 4. |
- Bankvall, Maria, et al.
(författare)
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The oral microbiota of patients with recurrent aphthous stomatitis.
- 2014
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Ingår i: Journal of oral microbiology. - : Informa UK Limited. - 2000-2297. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Specific pathogenic bacteria have been implicated in recurrent aphthous stomatitis (RAS), a chronic inflammatory condition characterised by ulcerations in the oral mucosa. However, the aetiology behind this condition still remains unclear.
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| 5. |
- Bankvall, Maria, et al.
(författare)
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Tissue-specific Differences in Immune Cell Subsets Located in the Naso-oropharyngeal-associated Lymphoid Tissues
- 2018
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475. ; 87:1, s. 15-27
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Tidskriftsartikel (refereegranskat)abstract
- Defining the immune cells within the naso-oropharyngeal-associated lymphoid tissues would promote the development of efficient orally and nasally delivered immunotherapies. The aim was to compare murine antigen-presenting cells (APCs) and T cell subsets in the nose-associated lymphoid tissues (NALT), cervical lymph nodes (CLN), mesenteric lymph nodes (MLN) and peripheral lymph nodes (PLN) using flow cytometry and in vitro proliferation assays. Overall, the NALT contained a higher proportion of APCs and a lower proportion of T cells compared to the CLN, MLN and PLN. The APCs of the NALT more often belonged to the CD11c(+)CD11b(+) and the CD11c(neg)CD11b(+) subsets as compared to the other sites. Both of these APC populations showed little sign of activation, that is low expression of the markers CD40, CD86 and IAd. Instead, the APCs of the NALT more often co-expressed CX3CR1 and CD206, markers associated with a tolerogenic function. No increase in the proportion of regulatory T cells was observed in the NALT. Instead, the T cells frequently exhibited a memory/effector phenotype, expressing the homing markers 47, CCR4 and CCR9, but rarely the naive phenotype cell surface marker CD45RB. In contrast, the T cells at the other sites were mostly of the naive phenotype. In addition, cells from the NALT did not proliferate upon in vitro stimulation with Con A, whereas the cells from the other sites did. Taken together, these results suggest that the NALT is primarily an effector site rather than one for activation and differentiation, despite it being regarded as a site of induction.
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| 6. |
- Dafar, Amal, et al.
(författare)
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Lingual microbiota profiles of patients with geographic tongue
- 2017
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Ingår i: Journal of Oral Microbiology. - : Informa UK Limited. - 2000-2297. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Geographic tongue (GT) is an oral mucosal lesion that affects the tongue. The association between GT and the bacterial colonization profiles of the tongue is not clear. Lingual swabs were collected from lesion sites and healthy sites of 35 patients with GT (19 males and 16 females; M-age = 54.3 +/- 16.1 years) and 22 controls (12 males and 10 females; M-age = 56.3 +/- 15.8 years). Bacterial DNA was extracted and sequenced by next-generation sequencing. At the phylum level, Fusobacteria were significantly less abundant, while Spirochaetes were significantly more abundant in GT patients compared to controls. At the operational taxonomic units level, multivariate analysis revealed distinct clusters for the three groups based on the lingual microbiota composition. Acinetobacter and Delftia were significantly associated with GT lesion and healthy sites. However, Microbacterium, Leptospira, Methylotenera, and Lactococcus were significantly associated with GT lesion sites. Additionally, Mogibacterium and Simonsiella were significantly associated with GT healthy sites and controls. The changes in the lingual microbiota profiles of patients with GT imply a shift in the lingual bacterial ecology. However, it remains unknown if this shift is a consequence of the lesions or of factors associated with the initiation and progression of the disease.
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| 7. |
- Dafar, Amal, et al.
(författare)
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Salivary levels of interleukin-8 and growth factors are modulated in patients with geographic tongue
- 2017
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Ingår i: Oral Diseases. - : Wiley. - 1354-523X .- 1601-0825. ; 23:6, s. 757-762
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 John Wiley & Sons A/S.Objectives: The aim of the study was to determine the levels of salivary epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) as well as interleukin-8 (IL-8) in patients with geographic tongue (GT), as compared to control subjects. Methodology: An enzyme-linked immunosorbent assay was used to measure the levels of IL-8, EGF and VEGF in whole saliva samples collected from 34 patients with GT and 38 control subjects. The patients and controls were grouped and matched according to age, gender and the presence of systemic diseases, which are factors that may influence the levels of salivary biomarkers. Results: All patients with GT displayed significantly higher levels of IL-8 than the controls (P < 0.001). The young female patients also showed reduced levels of EGF (P < 0.05) and VEGF (P < 0.05), as compared to the young male patients where no such differences were observed. Interestingly, high levels of IL-8 (P < 0.001) and VEGF (P < 0.05) were detected in the patients with GT who also suffered from hypertension. Conclusion: We consider IL-8 an inflammatory mediator, which contributes to the acute inflammatory response found in GT. EGF and VEGF also seem to be involved in the pathophysiology of GT.
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| 8. |
- Einarsdottir, Margret, et al.
(författare)
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Topical clobetasol treatment for oral lichen planus can cause adrenal insufficiency.
- 2024
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Ingår i: Oral diseases. - 1601-0825. ; 30:3, s. 1304-1312
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids suppress the hypothalamic-pituitary-adrenal axis, which may lead to glucocorticoid-induced adrenal insufficiency. The study aimed to investigate the prevalence of this state in patients with oral lichen planus treated with topical clobetasol propionate.In this cross-sectional study, 30 patients with oral lichen planus receiving long-term (>6weeks) clobetasol propionate gel 0.025% were invited to participate. Adrenal function was assessed by measuring morning plasma cortisol after a 48-h withdrawal of clobetasol treatment. In patients with plasma cortisol <280nmol/L, a cosyntropin stimulation test was performed.Twenty-seven patients were included. Twenty-one (78%) patients presented with plasma cortisol ≥280nmol/L (range 280-570nmol/L), and six (22%) <280nmol/L (range 13-260nmol/L). Five of these six patients underwent cosyntropin stimulation that revealed severe adrenal insufficiency in two patients (cortisol peak 150nmol/L and 210nmol/L) and mild adrenal insufficiency in three patients (cortisol peak 350-388nmol/L).In this study, approximately 20% of patients receiving intermittent topical glucocorticoid treatment for oral lichen planus had glucocorticoid-induced adrenal insufficiency. It is essential for clinicians to be aware of this risk and to inform patients about the potential need for glucocorticoid stress doses during intercurrent illness.
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| 9. |
- Zad, Mikael, 1990, et al.
(författare)
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Salivary mucin MUC7 oligosaccharides in patients with recurrent aphthous stomatitis
- 2015
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Ingår i: Clinical Oral Investigations. - : Springer Science and Business Media LLC. - 1432-6981 .- 1436-3771. ; 19:8, s. 2147-2152
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The aetiology of recurrent aphthous stomatitis remains unknown. In this study, we investigate the composition of oligosaccharides from mucin MUC7 in recurrent aphthous stomatitis as these heavily O-glycosylated mucins confer many of saliva's protective properties such as defence against mucosal pathogens. Materials and methods Unstimulated whole saliva samples were collected from six individuals, three with recurrent aphthous stomatitis and three corresponding sibling, without this condition. Oligosaccharides from salivary MUC7 were isolated and analysed by liquid chromatography-tandem mass spectrometry. Results The types of oligosaccharides identified in the patients and control subjects were similar; however, statistical evaluation indicated semi-quantitative differences between specific oligosaccharide classes. These changes focused on a reduction in terminal glycan residues including fucosylation, sialylation and sulfation on galactose. Conclusions This study was able to show differential MUC7 glycosylation in the patients suggesting functional changes to salivary mucins in this condition. The terminal glycans altered in disease have been shown to be important for a range of immunological and bacterial binding roles. Further investigation of these epitopes in a larger study may provide critical insights into the pathology of recurrent aphthous stomatitis. Clinical relevance MUC7 glycosylation is altered in recurrent aphthous stomatitis. This may change the protective properties of this mucin against mucosal pathogens, which may effect this condition.
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