SummaryOral lichen planus (OLP) is a variant of lichen planus (LP), a common chronic mucocutaneous inflammatory disease. Cutaneous lesions of LP are self-limiting, but OLP lesions are non-remissive, alternating periods of exacerbation and quiescence, and only symptomatic treatments exist for OLP. The precise etiology and pathogenesis of OLP are hardly understood, which is a major obstacle to the development of new therapeutics for this disease. OLP is considered a T-cell-mediated inflammatory disease.Although various antigens have been considered, what actually triggers the inflammatory response of T cells is unknown. Suggested predisposing factors include genetic factors, stress, trauma, and infection. The aim of this review was to determine whether microbial infection can cause OLP. We first reviewed the association between OLP and microbial factors, including viral, fungal, and bacterial infections. In addition, each microbial factor associated with OLP was assessed by modified guidelines of Fredricks and Relman to determine whether it establishes a causal relationship. In conclusion, no microbial factor yet fulfills the guidelines to establish the causality of OLP. By focusing on the unclarified issues, however, the potential roles of microbial factors in the pathogenesis of OLP will be soon elucidated. K E Y W O R D Sbacteria, causality, fungi, oral lichen planus, viruses | INTRODUCTIONLichen planus (LP), first described by Erasmus Wilson in 1869, is a common chronic mucocutaneous inflammatory disease affecting the skin, nails, eyes, urogenital tract, and oral mucosa.1 The prevalence of LP in the general population is 0.22%-5%. Although OLP is sometimes regarded as an autoimmune disorder, it is not classified as an autoimmune disease because no autoantigens have been identified. Suggested predisposing factors include genetic factors, stress, trauma, and infection. 5,6 In this article, microbial factors

Key events in the pathogenesis of Sjӧgren syndrome (SS) include the change of salivary gland epithelial cells into antigen-presenting cell-like phenotypes and focal lymphocytic sialadenitis (FLS). However, what triggers these features in SS is unknown. Dysbiosis of the gut and oral microbiomes is a potential environmental factor in SS, but its connection to the etiopathogenesis of SS remains unclear. This study aimed to characterize the oral microbiota in SS and to investigate its potential role in the pathogenesis of SS. Oral bacterial communities were collected by whole mouthwash from control subjects (14 without oral dryness and 11 with dryness) and primary SS patients (8 without oral dryness and 17 with dryness) and were analyzed by pyrosequencing. The SS oral microbiota was characterized by an increased bacterial load and Shannon diversity. Through comparisons of control and SS in combined samples and then separately in non-dry and dry conditions, SS-associated taxa independent of dryness were identified. Three SS-associated species and 2 control species were selected and used to challenge human submandibular gland tumor (HSG) cells. Among the selected SS-associated bacterial species, Prevotella melaninogenica uniquely upregulated the expression of MHC molecules, CD80, and IFNλ in HSG cells. Concomitantly, P. melaninogenica efficiently invaded HSG cells. Sections of labial salivary gland (LSG) biopsies from 8 non-SS subjects and 15 SS patients were subjected to in situ hybridization using universal and P. melaninogenica-specific probes. Ductal cells and the areas of infiltration were heavily infected with bacteria in the LSGs with FLS. Collectively, dysbiotic oral microbiota may initiate the deregulation of SGECs and the IFN signature through bacterial invasion into ductal cells. These findings may provide new insights into the etiopathogenesis of SS.

Periodontitis is caused by dysbiotic subgingival bacterial communities that may lead to increased bacterial invasion into gingival tissues. Although shifts in community structures associated with transition from health to periodontitis have been well characterized, the nature of bacteria present within the gingival tissue of periodontal lesions is not known. To characterize microbiota within tissues of periodontal lesions and compare them with plaque microbiota, gingival tissues and subgingival plaques were obtained from 7 patients with chronic periodontitis. A sequencing analysis of the 16S rRNA gene revealed that species richness and diversity were not significantly different between the 2 groups. However, intersubject variability of intratissue communities was smaller than that of plaque communities. In addition, when compared with the plaque communities, intratissue communities were characterized by decreased abundance of Firmicutes and increased abundance of Fusobacteria and Chloroflexi. In particular, Fusobacterium nucleatum and Porphyromonas gingivalis were highly enriched within the tissue, composing 15% to 40% of the total bacteria. Furthermore, biofilms, as visualized by alcian blue staining and atomic force microscopy, were observed within the tissue where the degradation of connective tissue fibers was prominent. In conclusion, very complex bacterial communities exist in the form of biofilms within the gingival tissue of periodontal lesions, which potentially serve as a reservoir for persistent infection. This novel finding may prompt new research on therapeutic strategies to treat periodontitis.

Oral lichen planus (OLP) is a chronic T cell-mediated inflammatory disease of unknown etiology. We previously proposed that the intracellular bacteria detected in oLp lesions are important triggering factors for T cell infiltration. This study aimed to identify OLP-associated bacterial species through the characterization of intratissue bacterial communities of OLP lesions. Seven pairs of bacterial communities collected from the mucosal surface and biopsied tissues of oLp lesions were analyzed by high-throughput sequencing of the 16S rRNA gene. The intratissue bacterial communities were characterized by decreased alpha diversity but increased beta diversity compared with those on the mucosal surface. While the relative abundance of most taxa was decreased within the tissues, that of Escherichia coli was significantly increased. Four E. coli strains were isolated from additional OLP biopsies and verified as K12 strains by whole-genome sequencing. The distribution of E. coli in sections of control (n = 12) and OLP (n = 22) tissues was examined by in situ hybridization. E. coli was detected in most OLP tissues, suggesting its potential role in the pathogenesis of OLP. The oral E. coli strains isolated from oLp tissues will be useful to investigate their role as triggering factors for t cell infiltration. Oral lichen planus (OLP) is a T cell-mediated chronic mucocutaneous disease of unknown etiology and is currently incurable. OLP occurs in 0.5-4% of the global population and appears more prevalent in females than males at a ratio of 1.5:1 1-3. The main histological features of OLP include band-like lymphocytic infiltration at the superficial part of connective tissue, the presence of liquefaction degeneration in the basal cell layer and the absence of epithelial dysplasia 4. Although the etiology and pathogenesis of OLP are not completely understood, unknown antigens are thought to trigger T cell infiltration and inflammatory responses of infiltrated lymphocytes such as CD4 + and CD8 + T cells 5. What triggers the activation and recruitment of T cells is an important question to find new therapeutics for OLP. Recently, many researchers have attempted to understand the relationship between human diseases and the human microbiome through high-throughput sequencing technology. To date, four research groups have studied the oral microbiota associated with OLP by sequencing the 16S rRNA gene, and differences in the microbiota of saliva and buccal mucosa between healthy controls and OLP patients have been reported 2,6-9. We previously reported increased bacterial invasion into the lamina propria, the presence of bacteria within basal epithelial cells and T cells in OLP lesions, and the induction of T cell chemokines by oral bacteria 6. In addition, Mizuki et al. reported that Mycoplasma salivarium was detected by immunohistochemistry in the epithelium and lymphocyte infiltrate area in 58.5% of OLP tissues from Japanese patients 10. These results suggest that oral bacteria may have a role in the pathogenesis of OLP. Howeve...

The invasion of red-complex bacteria into gingival connective tissue can suppress the immune response of GFs and can be a source of persistent infection in connective tissue.