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The role of bacteria in the pathogenesis of oral lichen planus and regulatory effect of estrogen on the physical barrier of oral epithelium : 구강편평태선 병인에서 세균의 역할과 에스트로겐의 구강 상피 장벽 기능 조절 효과

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치의학대학원 치의과학과
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서울대학교 대학원
Oral lichen planusPhysical barrierInflammationBacterial invasionEstrogenAnti-inflammatory effect
학위논문 (박사)-- 서울대학교 대학원 : 치의과학과 면역 및 분자미생물치의학 전공, 2016. 2. 최영님.
Oral lichen planus (OLP) is a mucocutaneous disease of unknown etiology that results from T-cell mediated immune responses. Many factors, such as infectious agents, drugs, autoantigens, and dental materials, have been suggested as the specific antigens that are targeted by CD8+ T cells. However, the exact etiopathogenesis of OLP is not known.
The microbial community of the host body is intimately associated with diverse host biological processes. Changes in human microbiota from a healthy state are associated with diverse localized or systemic diseases. However, the role of bacteria in the etiopathogenesis of OLP is not known.
The role of estrogen in the regulation of epithelial homeostasis, including the regulation of physical barriers and the host immune response, has been suggested by multiple lines of evidence. However, the role of estradiol on the regulation of homeostasis of gingival epithelia has not been studied.
The aim of study was to explore the role of bacteria in OLP and the regulatory effect of 17β-estradiol on gingival homeostasis.

The sections of oral mucosal biopsies, 36 OLP and 10 controls, were subjected to in situ hybridization, which was performed using a digoxigenin-labeled eubacterial probe targeting bacterial 16S rRNA. The presence of CD4+, CD8+ T cells, and macrophages were determined by the immunohistochemistry, and correlations between the levels of in situ bacteria and the levels of infiltrated cells were determined by Spearman's rho. In addition, dual detection of bacterial signals and CD8 was performed. Furthermore, the mucosal microbiota was analyzed by pyrosequencing the 16S rRNA and subsequent analysis.
Purified human CD4+, CD8+, and CD14+ cells were infected with 5-(and 6-) carboxy-fluorescein diacetate succinimidyl ester (CFSE)-labeled bacteria, and the presence of bacteria inside those cells was confirmed via confocal microscopy and flow cytometry. In addition, an antibiotics protection assay was performed. Furthermore, the amounts of secreted chemokines were analyzed by ELISA and multiplex assay.
Confluent monolayers of immortalized human oral keratinocyte (HOK-16B) cells were treated with 17β-estradiol. The transepithelial electrical resistance (TER) was measured at various time points. Furthermore, the levels of TJ proteins were confirmed by real-time RT-PCR or immunofluorescence (IF). In addition, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear translocation was confirmed by IF.

In the oral mucosa, positive signals of bacteria were detected within the lamina propria and the epithelia, and the bacterial invasion into lamina propria was significantly increased in OLP patients. The levels of CD4+ and CD8+ T cells but not those of macrophages had a strong positive correlation with the levels of bacteria detected within the lamina propria. In addition, bacterial signals were observed within CD8- and CD8+ T lymphocytes.
Oral bacterial communities in OLP patients were substantially different compared to healthy subjects. At the species levels, the relative abundances of 42 species were significantly different between healthy and OLP patients. C. gingivalis was significantly associated with increased OLP risk, and induced a significant decrease in TER in a time dependent manner without affecting the viability of HOK-16B cells. All selected bacteria were detected within CD4+, CD8+, and CD14+ cells after 1 h of infection. However, only C. gingivalis could survive within CD14+ cells for 24h. All selected bacteria-induced chemokines have been implicated in OLP.
Under normal conditions, 17β-estradiol enhanced the epithelial physical barrier and induced increased levels of TJ proteins. Furthermore, pretreatment of 17β-estradiol protected against the disruption of the epithelial physical barrier function through the maintenance of TJ protein expression. In addition, 17β-estradiol inhibited NF-κB nuclear translocation via pro-inflammatory cytokine TNF-α.

In conclusion, increased bacterial invasion into mucosal cells/tissues and altered microbial communities may contribute to the etiopathogenesis of OLP. Maintaining the epithelial physical barrier could be targeted by 17β-estradiol to prevent bacterial invasion into tissues and reduce the occurrence of OLP.
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