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ISSN : 1225-1577(Print)
ISSN : 2384-0900(Online)
The Korean Journal of Oral and Maxillofacial Pathology Vol.48 No.1 pp.1-8
DOI : https://doi.org/10.17779/KAOMP.2024.48.1.001

Usefulness of Plasma Pentraxin-3 as a Biomarker for Oral Lichen Planus and Burning Mouth Syndrome

DoYeon Kim1),5), Bok Hee Woo1), Jae-Min Song2), Ji-Young Joo3), Soo-Min Ok4)*, Hae Ryoun Park1)*
1)Department of Oral Pathology, School of Dentistry, Pusan National University
2)Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University
3)Department of Periodontology, School of Dentistry, Pusan National University
4)Department of Oral Medicine, School of Dentistry, Pusan National University
5)Education and Research Team for Life Science on Dentistry, Pusan National University
* Correspondence: Soo-Min Ok Pusan National University, 49, Busandaehak-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, Republic of Korea Tel: +82-52-510-8248 Email: oksoomin@pusan.ac.kr
Hae Ryoun Park, Pusan National University, 49, Busandaehak-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, Republic of Korea
Tel: +82-52-510-8248 Email: parkhr@pusan.ac.kr
October 11, 2023 January 19, 2024 February 16, 2024

Abstract


The limitation of markers for chronic oral diseases such as oral lichen planus (OLP) and burning mouth syndrome (BMS) is a diagnostic challenge for clinicians. The pathogenesis of OLP and BMS is not yet fully understood. Therefore, diagnoses are mainly based on the observation of clinical features and history, rather than established markers. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are used to determine the state of inflammation; however, these markers have some limitations.



Recently, a new inflammatory marker, pentraxin-3 (PTX3), has been identified in other systemic inflammatory diseases. PTX3 is a member of the pentraxin family and is classified as a long pentraxin. PTX3 is found in various human tissues, whereas the classical short pentraxin, CRP, is secreted only in the liver. PTX3 is a marker of autoimmune diseases and periodontitis. However, there are no studies on PTX3 in OLP and BMS; therefore, we sought to determine if PTX3 can be a diagnostic marker for OLP and BMS.



PTX3 was found to be correlated with other inflammatory markers, suggesting its diagnostic value for inflammatory oral diseases. We also found that the PTX3 levels were lower in patients with OLP and BMS. ESR levels were elevated in the OLP and BMS groups, but CRP levels were not. Despite these associations, no correlation was found between PTX3 expression and other known clinical features of OLP and BMS. We suggest that PTX3 plays a role in the immunological and neurological pathways involved in the complex pathogenesis of OLP and BMS.


Plasma Pentraxin-3 , Biomarker , Oral Lichen Planus , Burning Mouth Syndrome

구강편평태선과 구강작열감증후군의 생체표지자로써 혈장 펜트라신-3의 유용성

김도연1),5), 우복희1), 송재민2), 주지영3), 옥수민4)*, 박혜련1)*
1)부산대학교 치의학전문대학원 구강병리학교실
2)부산대학교 치의학전문대학원 구강악안면외과학교실
3)부산대학교 치의학전문대학원 치주과학교실
4)부산대학교 치의학전문대학원 구강내과학교실
5)부산대학교 치의생명과학교육연구팀

초록

    Ⅰ. INTRODUCTION

    The absence of established markers for chronic oral diseases, such as oral lichen planus (OLP) and burning mouth syndrome (BMS), makes a definite diagnosis challenging. Unlike periodontitis, which has definitive clinical diagnostic criteria, the diagnosis of chronic oral diseases, including OLP and BMS, is difficult because of the lack of objective markers and/or clinicopathologic findings. OLP is known to be an autoimmune disease in which the patient’s cytotoxic T cells attack epithelial basal keratinocytes, and its pathogenesis is not clearly defined; thus, its diagnosis is based on speculation rather than specific markers.1 Diagnosis of OLP can be made when Wickham’s striae are clinically found and typical histologic features are observed.2 However, the histopathologic features are nonspecific, and there are other clinical types, such as erosive and ulcerative types, that may not exhibit Wickham’s striae. These types are more injurious and clinically aggressive because they cause discomfort and pain.1 Hence, it is necessary to identify a specific marker that can diagnose OLP correctly and initiate prompt treatment, based on an accurate diagnosis. BMS is also a common oral chronic disease whose pathogenesis is not fully understood.3 Since it is diagnosed as an exclusionary diagnosis, finding an objective biomarker for BMS is required to enable patients to receive their treatment earlier.

    Long Pentraxin-3 (PTX3) is a member of the pentraxin superfamily, which includes classical short pentraxins such as C-reactive protein (CRP) or serum amyloid P (SAP).4 PTX3 is detected in many types of cells, including smooth muscle cells, myeloid dendritic cells, epithelial cells, and tumor cells, whereas CRP is only secreted by hepatocytes.5 This implies that PTX3 can play more diverse and complicated roles in various types of inflammatory diseases. Recently, pentraxin-3 has shown greater utility in diagnosing some systemic chronic diseases, including systemic lupus erythematosus, rheumatoid arthritis, and ankylosing spondylitis.6-8 It has been established that PTX3 can be useful in the diagnosis of oral chronic diseases. For example, in periodontitis, PTX3 levels in the plasma, saliva, and gingival crevicular fluid are upregulated, correlating positively with clinical periodontitis parameters.9,10 However, there are no reports on PTX3 levels in other chronic oral diseases, such as OLP and BMS.

    In this study, we explored the potential of plasma PTX3 levels as a disease marker for OLP and BMS, revealing that PTX3 could be a potential biomarker for these conditions.

    Ⅱ. MATERIALS and METHODS

    1. Patient selection

    Patients who visited Pusan National University Dental Hospital for several oral diseases, including periodontitis, OLP, and BMS, were selected for the study. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were measured for each sample, and the patient’s medical histories were recorded. Samples that displayed elevated ESR (Male: higher than 10 mm/hr, Female: higher than 15 mm/hr) and CRP (higher than 0.5 mg/L) levels were excluded.

    2. Blood Samples Collection

    Peripheral venous blood samples were obtained via venipuncture in a vacutainer with ethylenediaminetetraacetic acid (EDTA) as an anticoagulant. Blood samples were centrifuged (3000 rpm for 10 min), and the plasma was aspirated and stored at −80°C until use.

    3. Measurement of PTX3 in plasma samples

    An enzyme-linked immunosorbent assay (ELISA) kit (Bio Techne, Minneapolis, MN, USA; Cat. No. DY1826-05) was used to measure plasma PTX3 levels in both patients and controls, according to the manufacturer’s instructions. The absorbance intensity was measured using an ELISA plate reader using 405 nm as the primary wavelength. Concentrations were estimated using a standard curve.

    4. Statistical analysis

    Data were analyzed using unpaired Student’s t-test for independent means and one-way analysis of variance (ANOVA) for independent means, as appropriate. Correlation tests were performed using Pearson’s correlation coefficient. Receiver operating curve tests were conducted, and the sensitivity, specificity, and area under the curve were measured using a software program. All analyses and visualizations were performed using the GraphPad software (GraphPad, Boston, MA, USA). Statistical significance was set at P < 0.05.

    Ⅲ. RESULTS

    1. PTX3 shows a negative correlation with ESR

    To determine the diagnostic value of PTX3 in oral diseases, we measured plasma PTX3 levels in patients who visited the Pusan National University Dental Hospital (Table 1.). We found that PTX3 levels were not correlated to CRP levels, though the factors belong to the same pentraxin family with the same C-terminal domain (Fig 1A). Notably, PTX3 was negatively correlated with ESR, despite both being known as inflammatory markers (Fig 1B). Additionally, CRP and ESR were positively correlated with each other (Fig 1C).

    2. Plasma PTX3 levels are reduced in both OLP and BMS

    Since several studies have shown that PTX3 is upregulated in acute inflammation and periodontitis, we focused on the chronic diseases, OLP and BMS, which have no established diagnostic markers. Surprisingly, the plasma PTX3 levels were reduced in patients with OLP and BMS (Fig 2A). ESR was elevated in patients with OLP and BMS but did not change in periodontitis (Fig 2B). There were no differences in CRP levels between OLP, BMS, and healthy controls, whereas periodontitis showed elevated levels (Fig 2C). The receiver operating curve (ROC) demonstrated the diagnostic value of PTX3 levels for OLP (sensitivity, 70.83%; specificity, 86.96%; 95% CI, 0.6977–0.9508) and BMS (sensitivity, 72.73%; specificity, 86.96%; 95% CI, 0.7244– 0.9713) (Fig 2D, E). These findings indicate that PTX3 levels, in conjunction with ESR rate, could serve as valuable diagnostic markers for individuals with OLP and BMS.

    3. Plasma PTX3 is not associated with clinical features of OLP and BMS

    We investigated the relationship between PTX3 and other clinical features of the disease. Unfortunately, we did not find any such association. In OLP, patient sex and age, numeric rating scale of pain (NRS), clinical type of disease, presence of plaques, and serum cortisol levels were not associated with PTX3 (Fig 3). In BMS, patient age, sex, NRS score, and the presence of systemic diseases were not correlated with PTX3 (Fig 4). Serum cortisol levels were not correlated with PTX3 levels in either the OLP or BMS groups (Data not shown). These results imply that PTX3 may be a clue to the pathogenesis of OLP and BMS, as none of the distinct pathways have been identified to be related to the clinical characteristics of these diseases. Our findings also demonstrated that the decreased plasma PTX3 levels were not affected by other factors, proving the value of PTX3 as an independent marker.

    Ⅳ. DISCUSSION

    Although some inflammatory markers, such as CRP and ESR, are already being used to determine the inflammatory states of these diseases, their clinical utility is hampered by variability across diverse conditions. ESR can be influenced by various immune and nonimmune factors, including changes in the quality and quantity of red blood cells, female menses, and pregnancy; thus, it cannot be used as a definitive marker in oral chronic diseases.11 CRP, a marker of acute phase inflammation, did not yield conclusive results in OLP and BMS.12,13 Additionally, a discrepancy in 33% of all patients was observed between CRP and ESR.14 The disparity between CRP and ESR is likely attributed to their distinct response dynamics to the initiation of the inflammatory process. CRP responds rapidly, while ESR is slower.15 CRP levels peak 36–50 h after the onset of inflammation and drop rapidly with treatment, whereas ESR levels rise 24–48 h after the onset and take weeks to return to normal levels.11. Taken together, these studies strongly suggest the necessity for new chronic inflammatory markers that can reflect inflammatory mechanisms other than simple inflammation in periodontitis and autoimmune diseases. In our study, PTX3 successfully distinguished patients with OLP and BMS from the normal group, whereas CRP did not. PTX3 is involved in other pathogenic mechanisms of OLP and BMS, in which CRP and ESR are not detected.

    PTX3 exhibits diversity in its role involving the immune systems.16 In innate immunity, PTX3 has an important role in acute phase infection and inflammation, interacting with P-selectin, and modulating the recruitment of neutrophils.17 It also plays a role in the complement cascade system, tuning the activation of the complement.18 However, in chronic inflammation, PTX3 also functions as an anti-inflammatory and tissue remodeling factor.5 In an in vitro study, PTX3 upregulated the anti-inflammatory cytokine interleukin-10 in human peripheral blood mononuclear cells (PBMC).19 In sarcoidosis, PTX3 restrained the formation of granuloma by inhibiting complement-driven macrophage activation.20 In chronic hepatitis B and diabetic renal failure, downregulation of PTX3 caused tissue injury and fibrosis.21,22. Studies have focused on the role of PTX3 in the progression of inflammation-related diseases and revealed that it contributes to the development and resolution of inflammation. In contrast, a decrease in PTX3 levels was related to OLP in our study. In a recent study, deletion of PTX3 caused more aggressive inflammation through the elevation of interleukin- 17 (IL-17) levels and T helper 17 cells (Th17 cells) dominant phenotype in asthma.23 Activated Th17 cells and upregulated IL-17 are also observed in OLP.24,25 Based on these studies, a decreased level of PTX3 in OLP is likely related to increased Th17 cell activity.

    Neurological mechanisms may partially explain the association between decreased PTX3 levels and BMS. Downregulation of PTX3 levels has been reported in depressive disorders,26 and BMS has been reported to be correlated with psychiatric depression,27 suggesting a potential link between decreased PTX3 levels and BMS. Despite the association between psychological depression and PTX3, inflammatory factors associated with BMS cannot be completely ignored. Alison et al. reported that pro-inflammatory cytokine interleukin 8 (IL-8) levels were elevated in the plasma of patients with BMS,28 and Ma et al. found that PTX3, which forms a complex with ficolin-1, suppressed the secretion of IL-8, emphasizing the role of PTX3 in BMS progression.29. Taken together with our results showing a negative correlation between PTX3 and ESR, it can be speculated that the pathogenesis of BMS does not depend on simple, but involves complex multiple origins, including both neurological and immunological pathways.

    Although we identified PTX3 as a new independent disease marker for OLP and BMS, there are some limitations to the present study. First, we did not find any correlation between PTX3 and the clinical factors of OLP and BMS. This may be due to the lack of sufficient sample numbers. Second, there may be other factors that can affect PTX3 levels that we could not identify. Further studies are required to elucidate the detailed mechanisms of action of PTX3 in the pathogenesis of OLP and BMS.

    ACKNOWLEDGMENTS

    This work was supported by a 2-Year Research Grant of Pusan National University.

    Figure

    KAOMP-48-1-1_F1.gif

    Pentraxin-3 (PTX3) is negatively correlated with erythrocyte sedimentation rate (ESR)

    Correlation between pentraxin-3 (PTX3) and other inflammatory markers. (A) PTX3 and C-reactive protein (CRP) did not show a correlation (P value > 0.05). (B) PTX3 and erythrocyte sedimentation rate (ESR) show a negative correlation (R2 = 0.08206, P = 0.0027). (C) CRP and ESR show a positive correlation (R2 = 0.09936, P = 0.0019).

    KAOMP-48-1-1_F2.gif

    Plasma pentraxin-3 (PTX3) levels are reduced in both oral lichen planus (OLP) and burning mouth syndrome (BMS)

    Pentraxin-3 (PTX3) levels in patients with oral lichen planus (OLP), burning mouth syndrome (BMS), and periodontitis, and healthy individuals. (A) PTX3 levels are significantly lower in OLP(P = 0.0004) and BMS (P = 0.0005). (B) ESR levels are significantly higher in OLP (P < 0.0001) and BMS (P < 0.0001) but not in periodontitis. (P value > 0.05). (C) CRP levels are elevated in the periodontitis group (P = 0.0381), but no changes in CRP levels are seen in OLP and BMS (P value > 0.05).

    KAOMP-48-1-1_F3.gif

    Plasma pentraxin-3 (PTX3) is not associated with clinical features of oral lichen planus (OLP)

    Pentraxin-3 (PTX3) levels did not correlate with clinical factors of OLP. (A) No significant difference is observed in the PTX3 levels between male and female individuals (P value > 0.05). (B) The age groups are separated by 60. There are no significant changes in PTX3 levels across the different age groups (P value > 0.05). (C) CRP levels are not associated with pain. The numeric rating scale of pain (NRS) lower than 5 is indicated as “low NRS,” and NRS value≥ 5 is indicated as “high NRS” (P value > 0.05). (D,E) There are no significant differences in PTX3 levels in the distinct clinical types of OLP (P value > 0.05). (F) The positivity of the anti-nuclear antibody did not alter the level of PTX3 (P value > 0.05).

    KAOMP-48-1-1_F4.gif

    Plasma pentraxin-3 (PTX3) is not associated with clinical features of burning mouth syndrome (BMS)

    Pentraxin-3 (PTX3) levels did not correlate with clinical factors of burning mouth syndrome (BMS). (A) No significant alteration in PTX3 levels is observed in males and females (P value > 0.05). (B) PTX3 levels did not alter with age (P value > 0.05). (C) CRP levels are not associated with pain. NRS scores lower than 5 are indicated as “low NRS,” and a score ≥5 is indicated as “high NRS” (P value > 0.05) (D). The presence of systemic diseases, including diabetic mellitus, hypertension, and hyperthyroidism, is irrelevant to PTX3 levels (P value > 0.05). (E) The positivity of the anti-nuclear antibody is not associated with PTX3 levels (P value > 0.05).

    Table

    Plasma PTX3 levels in patients visited in the Pusan National University Dental Hospital

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