Antonio Celentano

Mucosal leishmaniasis with primary oral involvement: a case series and a review of the literature

OBJECTIVE To analyze retrospectively a case series of primary oral leishmaniasis and to review the literature on head-neck primary mucosal leishmaniasis (ML) in immunocompetent patients. SUBJECTS AND METHODS A PUBMED search was carried out from 1950 to 2013. Clinical records of patients with primary head-neck mucosal manifestations of leishmaniasis were analyzed. In addition, clinical records between 2001 and 2012 of patients with primary oral manifestations were collected in two independent hospitals. RESULTS Our multicenter case series revealed seven patients with oral leishmaniasis. The most commonly affected site was the tongue (four patients, 57%), and the most common clinical presentation was an exophytic lesion (six patients, 85%). The literature review showed 11 reports published between 2005 and 2013, describing 13 patients (100% male) affected by head-neck primary ML (54% laryngeal, 31% oral, 23% pharyngeal, and 15% endonasal). The most common clinical presentation was an exophytic lesion (69%). CONCLUSIONS The literature analysis revealed that in immunocompetent patients, the oral mucosa is the second most frequently affected site of the head and neck region. In the oral cavity, the tongue is the most affected site. Diagnosis of oral leishmaniasis represents a challenge but must be considered in any differential diagnosis of exophytic lesions of oral mucosa.

Oral erythema multiforme: trends and clinical findings of a large retrospective European case series.

OBJECTIVE Erythema multiforme (EM) continues to be an underestimated disease with a lack of strict classification and diagnostic criteria. We present the analysis of a case series of 60 oral EM patients from 2 centers and illustrate the range of oral clinical presentations. STUDY DESIGN Clinical data from 60 EM patients with oral involvement, diagnosed and treated between 1982 and 2014, were retrospectively collected from the archives of 2 independent hospitals. Statistical analyses of the data were performed using the Pearson χ-squared test and the Mann-Whitney U test. RESULT Thirty-one patients (51.7%) were male and 29 (48.3%) were female, with a mean (±SD) age of 37.9 years (±18.1). The frequency of previous occurrences ranged from 0 to 10 (mean ± SD: 1.4 ± 2.0). Twenty-nine patients (48%) had no previous occurrence. Medications (particularly antipyretics, food additives, and antibiotics) were the suspected precipitants in 28 patients (46.7%), whereas herpes simplex virus infection was suspected in 18 (30.0%). All but 1 patient had involvement of multiple oral sites, with the buccal mucosa being the most commonly involved oral site (75%), followed by the vermillion border (71.7%). CONCLUSIONS Patients with EM may present initially to oral health care workers. Medications and herpes simplex virus continue to be the most typically involved precipitating factors. Our data highlight the additional role of food-derived antigens. Although laboratory tests can provide support diagnostically, EM diagnosis continues to be based on clinical features. A medication and food diary should be encouraged particularly in patients with recurrent forms.

The Non-Conventional Effects of Glucocorticoids in Cancer.

Synthetic corticosteroids are widely used for the treatment of a variety of diseases, including pre‐malignant and malignant conditions. In striking contrast, recent evidence suggests that corticosteroids can bear tumor‐promoting effects in solid tumors of epithelial origin. We have recently shown that epithelial tissues, including the mucosa of the oral cavity and the skin, are able to modulate the local concentration of active corticosteroids and to produce steroids de novo. This has important clinical and physiopathological implications, because tissue‐specific regulation of glucocorticoids plays a key role in the overall effect of these molecules. In the present review of the current English literature, performed using MEDLINE/PubMed/Ovid databases, we collected published evidence to demonstrate that corticosteroids induce effects that are more complex and controversial than previously acknowledged. Published studies clearly demonstrate that this class of molecules influences pathophysiological processes that are strictly related to malignancy, providing the rationale for further investigation. J. Cell. Physiol. 231: 2368–2373, 2016.

Tissue-specific regulation of CXCL9/10/11 chemokines in keratinocytes: Implications for oral inflammatory disease

The IFN-γ-inducible chemokines CXCL9, CXCL10, and CXCL11 play a key role in many inflammatory conditions, particularly those mediated by T cells. Therefore, the production of these chemokines in peripheral tissues could be instrumental in the pathophysiology of tissue-specific immunological diseases such as oral lichen planus (OLP). In the present study, we assessed the production of keratinocyte-derived CXCL9/10/11 under basal and inflammatory conditions and investigated whether these chemokines were involved in the pathogenesis of OLP. We used semi-quantitative PCR, ELISA, chemotaxis assays, and fluorescence-activated cell sorting (FACS) to assess the expression and functional role of CXCL9/10/11 in oral keratinocytes (three strains of normal human oral keratinocytes (NHOK), and the H357 oral cancer cell line) in the presence or absence of IFN-γ. CXCL9/10/11 were also assessed in tissues from normal patients and those with oral lichen planus (OLP). The time course study in oral keratinocytes treated with IFN-γ showed that expression of CXCL9/10/11 chemokines was significantly enhanced by IFN-γ in a time-dependent manner. In particular, CXCL10, a prominent chemokine that was overexpressed by IFN-γ-stimulated NHOK, was able to effectively recruit CD4 lymphocytes, mainly CD4+CD45RA- cells. Significantly higher levels of CXCL9/10/11 were found in tissues from patients with OLP compared to normal oral mucosa. Taken together, the results demonstrate that normal oral keratinocytes produce chemotactic molecules that mediate T cell recruitment. This study furthers understanding of chemokine production in oral keratinocytes and their role in the pathophysiology of oral mucosa, with particular relevance to OLP.

Characterisation of the cancer-associated glucocorticoid system: key role of 11β-hydroxysteroid dehydrogenase type 2

Background:Recent studies have shown that production of cortisol not only takes place in several non-adrenal peripheral tissues such as epithelial cells but, also, the local inter-conversion between cortisone and cortisol is regulated by the 11β-hydroxysteroid dehydrogenases (11β-HSDs). However, little is known about the activity of this non-adrenal glucocorticoid system in cancers.Methods:The presence of a functioning glucocorticoid system was assessed in human skin squamous cell carcinoma (SCC) and melanoma and further, in 16 epithelial cell lines from 8 different tissue types using ELISA, western blotting and immunofluorescence. 11β-HSD2 was inhibited both pharmacologically and by siRNA technology. Naïve CD8+ T cells were used to test the paracrine effects of cancer-derived cortisol on the immune system in vitro. Functional assays included cell–cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical data of 11β-HSD expression were generated using tissue microarrays of 40 cases of human SCCs as well as a database featuring 315 cancer cases from 15 different tissues.Results:We show that cortisol production is a common feature of malignant cells and has paracrine functions. Cortisol production correlated with the magnitude of glucocorticoid receptor (GR)-dependent inhibition of tumour-specific CD8+ T cells in vitro. 11β-HSDs were detectable in human skin SCCs and melanoma. Analyses of publicly available protein expression data of 11β-HSDs demonstrated that 11β-HSD1 and -HSD2 were dysregulated in the majority (73%) of malignancies. Pharmacological manipulation of 11β-HSD2 activity by 18β-glycyrrhetinic acid (GA) and silencing by specific siRNAs modulated the bioavailability of cortisol. Cortisol also acted in an autocrine manner and promoted cell invasion in vitro and cell–cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical analyses using tissue microarrays showed that expression of 11β-HSD2 was significantly reduced in human SCCs of the skin.Conclusions:The results demonstrate evidence of a cancer-associated glucocorticoid system and show for the first time, the functional significance of cancer-derived cortisol in tumour progression.

Desmosomes in disease: a guide for clinicians.

The large number of diseases occurring when desmosome constituents are impaired provides striking evidence for the key role of desmosomes in maintaining tissue integrity. A detailed understanding of the molecular alterations causing desmosomal dysfunction has, in turn, underpinned the development of novel diagnostic tools. This has salient clinical implications for dentists and oral medicine practitioners because the majority of desmosomal diseases affect the oral cavity. In the present article, we review the autoimmune, infectious, genetic, and neoplastic diseases that target the desmosome, with particular emphasis on clinical manifestations, diagnostic pathways, and relevant laboratory investigations.

Pathophysiology of the Desmo-Adhesome.

Advances in our understanding of desmosomal diseases have provided a clear demonstration of the key role played by desmosomes in tissue and organ physiology, highlighting the importance of their dynamic and finely regulated structure. In this context, non‐desmosomal regulatory molecules have acquired increasing relevance in the study of this organelle resulting in extending the desmosomal interactome, named the “desmo‐adhesome.” Spatiotemporal changes in the expression and regulation of the desmo‐adhesome underlie a number of genetic, infectious, autoimmune, and malignant conditions. The aim of the present article was to examine the structural and functional relationship of the desmosome, by providing a comprehensive, yet focused overview of the constituents targeted in human disease. The inclusion of the novel regulatory network in the desmo‐adhesome pathophysiology opens new avenues to a deeper understanding of desmosomal diseases, potentially unveiling pathogenic mechanisms waiting to be explored. J. Cell. Physiol. 232: 496–505, 2017.

Lichen planus of the lips: an intermediate disease between the skin and mucosa? Retrospective clinical study and review of the literature

Lichen planus of the lips (LPL) is not frequently described in the literature. The objective of this study is to investigate the clinical outline, behavior, and prognosis of LPL.

Antimicrobial activity and regulation of CXCL9 and CXCL10 in oral keratinocytes.

Chemokine (C-X-C motif) ligand (CXCL)9 and CXCL10 are dysregulated in oral inflammatory conditions, and it is not known if these chemokines target microorganisms that form oral biofilm. The aim of this study was to investigate the antimicrobial activity of CXCL9 and CXCL10 on oral microflora and their expression profiles in oral keratinocytes following exposure to inflammatory and infectious stimuli. Streptococcus sanguinis was used as a model and Escherichia coli as a positive control. The antimicrobial effect of CXCL9/CXCL10 was tested using a radial diffusion assay. mRNA transcripts were isolated from lipopolysaccharide (LPS)-treated and untreated (control) oral keratinocyte cell lines at 2-, 4-, 6-, and 8-h time-points of culture. The CXCL9/10 expression profile in the presence or absence of interferon-γ (IFN-γ) was assessed using semiquantitative PCR. Although both chemokines demonstrated antimicrobial activity, CXCL9 was the most effective chemokine against both S. sanguinis and E coli. mRNA for CXCL10 was expressed in control cells and its production was enhanced at all time-points following stimulation with LPS. Conversely, CXCL9 mRNA was not expressed in control or LPS-stimulated cells. Finally, stimulation with IFN-γ enhanced basal expression of both CXCL9 and CXCL10 in oral keratinocytes. Chemokines derived from oral epithelium, particularly CXCL9, demonstrate antimicrobial properties. Bacterial and inflammatory-stimulated up-regulation of CXCL9/10 could represent a key element in oral bacterial colonization homeostasis and host-defense mechanisms.

Immune receptors CD40 and CD86 in oral keratinocytes and implications for oral lichen planus

Lichen planus (LP) is a chronic T-cell-mediated mucocutaneous inflammatory disease that targets stratified epithelia, including those lining the oral cavity. The intraoral variant of LP (OLP) is associated with interferon (IFN)-γ production by infiltrating T lymphocytes; however, the role of epithelial cells in the etiopathogenesis OLP is not completely understood. There is however a growing body of evidence regarding the involvement of epithelial-derived cytokines, immune receptors, and costimulatory molecules in the pathobiological processes that promote and sustain OLP. In the present study, we used a reverse transcriptase-polymerase chain reaction assay to assess whether CD40-a receptor found mainly on antigen presenting cells-and the costimulatory molecule CD86 were expressed in oral keratinocytes (three strains of primary normal oral keratinocytes and the H357 cell line) in the presence or absence of IFN-γ. To further characterize the involvement of CD40 in OLP, expression and distribution of receptor and ligand (CD40/CD154) in tissues from OLP were evaluated by immunohistochemistry. The present results are the first to show that both CD40 and CD86 are constitutively expressed at low levels in oral keratinocytes and that their expression was enhanced by IFN-γ stimulation. The intensity of CD40 staining in OLP tissues was strong. Taken together, the results strongly suggest that CD40 and CD86 play a role in the pathophysiology of oral inflammatory diseases such as OLP.