Covid-19 and oral diseases: Crosstalk, synergy or association?

The coronavirus disease 2019 (Covid-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that clinically affects multiple organs of the human body. Cells in the oral cavity express viral entry receptor angiotensin-converting enzyme 2 that allows viral replication and may cause tissue inflammation and destruction. Recent studies have reported that Covid-19 patients present oral manifestations with multiple clinical aspects. In this review, we aim to summarise main signs and symptoms of Covid-19 in the oral cavity, its possible association with oral diseases, and the plausible underlying mechanisms of hyperinflammation reflecting crosstalk between Covid-19 and oral diseases. Ulcers, blisters, necrotising gingivitis, opportunistic coinfections, salivary gland alterations, white and erythematous plaques and gustatory dysfunction were the most reported clinical oral manifestations in patients with Covid-19. In general, the lesions appear concomitant with the loss of smell and taste. Multiple reports show evidences of necrotic/ulcerative gingiva, oral blisters and hypergrowth of opportunistic oral pathogens. SARS-CoV-2 exhibits tropism for endothelial cells and Covid-19-mediated endotheliitis can not only promote inflammation in oral tissues but can also facilitate virus spread. In addition, elevated levels of proinflammatory mediators in patients with Covid-19 and oral infectious disease can impair tissue homeostasis and cause delayed disease resolution. This suggests potential crosstalk of immune-mediated pathways underlying pathogenesis. Interestingly, few reports suggest recurrent herpetic lesions and higher bacterial growth in Covid-19 subjects, indicating SARS-CoV-2 and oral virus/bacteria interaction. Larger cohort studies comparing SARS-CoV-2 negative and positive subjects will reveal oral manifestation of the virus on oral health and its role in exacerbating oral infection.

Clinicopathological analysis of 34 Japanese patients with EBV-positive mucocutaneous ulcer.

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) is a unifocal mucosal or cutaneous ulcer that is histologically characterized by proliferating EBV-positive atypical B cells. While EBVMCU demonstrates a histology similar to that of EBV-positive diffuse large B-cell lymphoma (DLBCL), their clinical behavior differs. Thus, characterizing distinguishing features of EBVMCU and EBV-positive DLBCL is critical. To identify unique characteristics between EBVMCU and lymphoma, we analyzed the clinicopathological and genetic features of 34 Japanese patients with EBVMCU and compared them to those of 24 EBV-positive DLBCL patients and 25 EBV-negative DLBCL patients. All patients with EBVMCU had localized ulcerative lesions, and 31 patients (91%) were using immunosuppressants, such as methotrexate (MTX) or hydroxycarbamide. All patients that were followed up with exhibited good prognosis following immunosuppressant reduction or chemotherapy. In addition, 17 EBV-positive DLBCL patients, and 15 EBV-negative DLBCL patients, received chemotherapy (P < 0.001, P < 0.001, respectively). Our data showed that EBVMCU did not increase indicators associated with lymphoma prognosis, such as soluble interleukin 2 receptor (sIL-2R) and lactate dehydrogenase (LDH) compared to those in the EBV-positive DLBCL or EBV-negative DLBCL groups (sIL-2R, P < 0.001, P = 0.025; LDH, P = 0.018, P = 0.038, respectively). However, histologically, EBVMCU exhibited EBV-positive, variable-sized, atypical B-cell proliferation. Thus, EBVMCU was histologically classified as: (1) polymorphous; (2) large cell-rich; (3) classic Hodgkin lymphoma-like; and (4) mucosa-associated lymphoid tissue lymphoma-like. Moreover, genetic analysis showed that immunoglobin heavy chain (IGH) gene rearrangement did not differ significantly between EBVMCU and EBV-positive DLBCL (44% vs. 32%; P = 0.377), or between EBVMCU and EBV-negative DLBCL (44% vs. 58%; P = 0.280). Therefore, it is difficult to distinguish EBVMCU from EBV-positive DLBCL using only pathological and genetic findings, suggesting that clinical information is important in accurately distinguishing between EBVMCU and EBV-positive DLBCL.

Regulatory T Cells and Their Association with Serum Markers and Symptoms in Systemic Lupus Erythematosus and Rheumatoid Arthritis.

PURPOSE: Impairment in number and functions of regulatory T cells (Treg) has been found to be associated with many autoimmune diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This study was conducted to identify and compare Treg by flow cytometry using two different staining approaches. METHODS: Treg were identified by using CD4+CD25+high and CD4+CD25+CD127dim staining approaches in SLE and RA patients and healthy controls. Association of both identified Treg levels with various serum markers and clinical presentation was also examined. RESULTS: Blood CD4+CD25+CD127dim cells levels were 11.4+3.57 %, 9.76+2.37 % and 6.95+1.16 %; while CD4+CD25+high cells were 1.46+1.09 %, 0.95+0.59 % and 1.87+1.14 % in SLE patients, RA patients and healthy controls respectively. Number of CD4+CD25+CD127dim cells was higher than CD4+CD25+high cells in blood samples of all three study groups. Levels of CD4+CD25+CD127dim cells were significantly higher in SLE and RA patients, compared to healthy controls, but this difference was not observed for CD4+CD25+high Treg. CD4+CD25+high levels showed significant correlation with serum C4, IFN-γ and IL-10 levels in healthy subjects and with C4 levels and fever in SLE patients. CD4+CD25+CD127dim levels showed significant association with alopecia and oral ulcers in SLE patients only, but no correlation with measured serum markers. CONCLUSION: Results suggest that both staining approaches detect Treg differently and also that Treg play different role in pathogenesis of SLE and RA.

Serum levels of IgG antibodies against alpha-enolase are increased in patients with Behçet's disease and are associated with the severity of oral ulcer, erythrocyte sedimentation rates, and C-reactive protein.

OBJECTIVES: Behçet's disease (BD) is a chronic inflammatory disease of unknown etiology, characterised by recurrent oral and genital ulcers, skin lesions, uveitis, and arthritis. It is regarded as vasculitis and anti-endothelial cell antibodies (AECA) are found in patients with BD. One of the endothelial cell antibodies was reported to recognise alpha-enolase. This study aimed to investigate expression of alpha-enolase in the surface of peripheral blood cells and serum anti-alpha-enolase antibody (AEA), and their association with clinical manifestations or disease activity of BD. METHODS: Cell surface alpha-enolase expression was examined from several cell types of peripheral blood, including lymphocytes, monocytes, and neutrophils using flow cytometry in patients with BD and healthy controls (HCs). IgG AEA levels were measured by enzyme-linked immunosorbent assay (ELISA) in sera from 110 patients with BD, and age/sex matched 110 HCs. Association of alpha-enolase or AEA with clinical manifestation was analysed. RESULTS: The frequency of surface alpha-enolase-expressing cells was increased in BD in lymphocytes and monocytes. Serum AEA levels were in- creased in BD patients (median [IQR], 0.360 [0.268-0.482], p < 0.0001), particularly with mucocutaneous involvement (0.367 [0.273-0.490], p < 0.0001) compared to HCs (0.274 [0.231-0.357]). The levels of AEA were correlated with the number of oral ulcer, ESR, and CRP. There was no association between serum levels of AEA and other clinical manifestations. CONCLUSIONS: Serum AEA was increased in BD patients and correlated with oral ulcer, ESR and CRP.

Natural Killer Cell Subsets and Their Functional Activity in Behçet's Disease.

BACKGROUND: Behçet's disease (BD) is a rare, chronic autoinflammatory disorder of unknown origin. Natural killer (NK) cells are one of the major immunoregulatory cell groups of the innate immune system, but their role in BD pathogenesis is not well documented. OBJECTIVES: We aimed to investigate the role of NK cell subsets and their cytokine secretion and cytotoxic activity in patients with BD. PATIENTS AND METHODS: The study group consisted of BD patients who had only mucocutaneous involvement, and they were compared with healthy subjects. BD patients were divided into two groups according to their frequencies of oral ulcerations. NK cell cytotoxicity was determined using CD107a expression and a CFSE-based cytotoxicity test. Expression of NK cell receptors and surface markers and the intracellular IL-5, IL-10, IL-17, and IFN-γ levels in CD16+ NK cells were assessed by flow cytometry. RESULTS: Although the cytokine secretion pattern was different, no difference was obtained in cytotoxic activity, expression of activatory receptors, or degranulation of NK cells. CONCLUSION: Increases in NK1/NK2 ratio and CD16+IFN-γ+ NK1 cells might support the idea of a biased IFN-γ dominant immune response in the mucocutaneous involvement of BD pathogenesis. Although the cytokine secretion pattern was different, no difference was obtained in cytotoxic activity, expression of activatory receptors, or degranulation of NK cells.

Chronic granulomatous disease as a risk factor for cutaneous lupus in childhood.

Chronic granulomatous disease (CGD) is a primaryimmunodeficiency disorder that affects the phagocyticcells of the innate immune system. It is characterizedby recurrent or persistent infections with granulomaformation. Lupus-like lesions have been reported incarriers of CGD and less frequently, in patients withCGD. Immunological study in these patients areusually negative. We describe the case of an 8-yearoldboy with CGD who developed chronic and acutecutaneous lupus erythematous with angular cheilitis,oral ulcers, Raynaud phenomenon, and positiveserologies for antinuclear, anticentromere, and anti-Saccharomyces cerevisiae antibodies.

Mucosal Lesions in an Allergy Practice.

The diagnosis and treatment of mucosal disease with an allergic pathogenesis are challenging. Oral allergy is often a hypersensitivity reaction with variable symptoms and physical exam findings. Clinical diagnosis requires a history of prior allergen exposure, a delay from exposure to clinical findings, and improvement following allergen removal. The past decades have seen great contributions to the field of oral allergy. The aim of this review is to provide an approach to the diagnosis and treatment of oral dermatologic disease with a focus on diseases with an investigated allergic pathogenesis.

Multiple mucocutaneous ulcers associated with cocaine-induced midline destructive lesions.

Cocaine-induced midline destructive lesions (CIMDL) occur in a small subset of cocaine users, who clinically present with inflammation and necrosis of facial midline structures such as the palate, nasal septum, turbinates, and sinuses. We present a patient with CIMDL occurring concomitantly with ulcers on the cheek and upper trunk. Multiple biopsy specimens from the cutaneous and mucosal lesions consistently showed a dense dermal/submucosal infiltrate of neutrophils and plasma cells, without vasculitis or thrombosis. The ulcers resolved following cessation of cocaine use.

HLA-B51 subtypes in Turkish patients with Behçet's disease and their correlation with clinical manifestations.

Behçet's disease (BD) is a multisystemic inflammatory disease believed to be triggered by microbial or environmental factors on a genetic platform. Clinically, it may have an impact on many body systems, including the mucocutaneous, ocular, articular, vascular, and neurological systems. In this study, we aimed to determine the HLA-B51 subtypes and their correlations with the clinical findings of BD. Fifty-one patients with BD and 44 gender- and age-matched healthy subjects were included in this study. The HLA-B51 subtypes of all participants were determined, and the correlations of the clinical manifestations of the disease with the HLA-B51 subtypes were analyzed. HLA-B51 positivity was found to be significantly higher in the patient group (P < 0.001, RR = 15.20), which had significantly more frequent HLA-B5101, HLA-B5102(01), HLA-B5109, and HLA-B5122 subtypes than the healthy subjects (all P < 0.05). Furthermore, considering the correlation between the genetic makeup and clinical findings, the HLA-B5109 subtype was found to be less frequent in patients with papulopustular skin lesions (P = 0.042). The frequency of HLA-B5103 was significantly higher in patients with central nervous system involvement (P = 0.015). There may be a relationship between HLA-B5102(01), HLA-B5109, and HLA-B5122 in addition to HLA-B51 and HLA-B5101(01) in Turkish patients with BD. The HLA-B5109 subtype can be protective against papulopustular lesion development; however, the HLA-B5103 subtype may pose a risk for neuro-Behçet development in BD.

Common and specific associations of anti-SSA/Ro60 and anti-Ro52/TRIM21 antibodies in systemic lupus erythematosus.

Little information exists about the association of anti-SSA/Ro60 and anti-Ro52/TRIM21 with systemic lupus erytematosus (SLE) features. In this work, we analysed the associations of both anti-Ro reactivities with clinical and immunological manifestations in 141 SLE patients. Photosensitivity and xerophtalmia/xerostomia were found to be positively associated with both anti-SSA/Ro60 (P = 0.024 and P = 0.019, resp.) and anti-Ro52/TRIM21 (P = 0.026 and P = 0.022, resp.). In contrast, a negative association was detected regarding anti-phospholipid antibodies, anti-SSA/Ro60 having a stronger effect (P = 0.014) than anti-Ro52/TRIM21. Anti-SSA/Ro60 showed a specific positive association with hypocomplementemia (P = 0.041), mainly with low C4 levels (P = 0.008), whereas anti-Ro52/TRIM21 was found to be positively associated with Raynaud's phenomenon (P = 0.026) and cytopenia (P = 0.048) and negatively associated with anti-dsDNA (P = 0.013). Lymphocytes are involved in the relationship between anti-Ro52/TRIM21 and cytopenia since positive patients showed lower cell levels than negative patients (P = 0.036). In conclusion, anti-SSA/Ro60 and anti-Ro52/TRIM21 showed both common and specific associations in SLE. These data thus increase evidence of the different associations of the two anti-Ro specificities even in a particular disease.

[Lymphadenopathy: demarcation to malignant lymphomas]. / Lymphadenopathie: Grenzziehung zu malignen Lymphomen.

Recognition of the differential diagnosis between lymphadenitis and malignant lymphoma requires good knowledge of the basic forms of the disease as well in depth knowledge of the structure of the individual compartments. There are defined forms of lymphadenitis where the differential diagnosis to certain lymphoma entities is known. Other reactive structural alterations show indistinct limits so that a decision is only possible after using additional techniques, such as immunohistochemistry and molecular analyses. Finally, there are marginal areas which can only be clarified by including clinical data.

[Local immunomodulating agents in complex treatment of oral lichen planus].

The paper presents the results of local immunity status assessment in patients with erosive-ulcerous form of oral lichen planus by etiopatogenetic treatment including imudone and derinate. The positive dynamics of immunological parameters under imudone and derinate is demonstrated.

Long-term remission of ocular and extraocular manifestations in Behçet's disease using infliximab.

OBJECTIVES: To investigate the long-term effect of infliximab on ocular and extraocular manifestations in patients with Behçet's disease. METHODS: Seven patients with active Behçet's disease and treated with infliximab at Aichi Medical University Hospital for more than 18 months were included in the study. We evaluated visual acuity, the average number of uveitis attacks involving the posterior segment, and general disease activity every 2 months. The Behçet's Disease Current Activity Form (BDCAF) was used for an overall index of disease activity. Anti-infliximab antibody levels were examined in the patients' sera. RESULTS: The follow-up period after initial introduction of infliximab ranged from 19 to 40 months (mean ± SD, 32 ± 8.7 months). The number of infliximab infusions ranged from 12 to 24 (19 ± 4.4). By the 2-month follow-up, the frequency of uveitis attacks involving the posterior segment and the BDCAF scores were significantly improved compared to the 2 months before introducing infliximab. Anti-infliximab antibodies were detected in the sera of all examined patients. CONCLUSIONS: Significant long-term improvement in both the frequency of uveitis attacks involving the posterior segment and overall disease activity was provided by the administration of infliximab to patients suffering from Behçet's disease, despite the presence of anti-infliximab antibodies.

Oral eosinophilic ulcer, an Epstein-Barr virus-associated CD30+ lymphoproliferation?

Eosinophilic ulcer of the oral mucosa is a benign lesion of unclear pathogenesis mostly affecting the tongue. It has been suggested to represent a reactive pattern to several stimuli. We report on a 12-year-old boy who presented with a painless infiltrating ulcer on the gingiva of the lower jaw, which was covered by necrotic yellowish slough. There were no pathologic features of the jawbones or regional lymph nodes. Histopathological, immunohistochemical and gene rearrangement studies were in agreement with eosinophilic ulcer with predominant oligoclonal CD3+ and CD30+ T lymphocytes expressing the Epstein-Barr virus membrane protein. The ulcer resolved within 4 weeks and follow-up for 3 years revealed no evidence of recurrence. Epstein-Barr virus may have played a role in triggering this reactive lymphoproliferative disorder.

MAGE-A antigens in lesions of the oral mucosa.

Oral squamous cell carcinoma develops continuously out of predamaged oral mucosa. For the physician and pathologist, difficulties arise in distinguishing precancerous from cancerous lesions. MAGE-A antigens are tumor antigens that are found solely in malignant transformed cells. These antigens might be useful in distinguishing precancerous from cancerous lesions. The aim of this study was to verify this assumption by comparing MAGE-A expression in benign, precancerous, and cancerous lesions of the oral mucosa. Retrospectively, biopsies of different oral lesions were randomly selected. The lesions that were included are 64 benign oral lesions (25 traumatic lesions (oral ulcers), 13 dental follicles, and 26 epulis), 26 oral lichen planus, 123 epithelial precursor lesions (32 epithelial hyperplasia found in leukoplakias, 24 epithelial dysplasia found in leukoplakias, 26 erythroplasia with oral epithelial dysplasia, and 41 carcinomas in situ in erythroleukoplakias). The lesions were immunohistochemically stained with the poly-MAGE-A antibody 57B, and the results were compared. Biopsies of oral lichen planus, oral ulcers, dental follicles, epulis, and leukoplakia without dysplasia showed no positive staining for MAGE-A antigens. Leukoplakia with dysplasia, dysplasia, and carcinomata in situ displayed positive staining in 33%, 65%, and 56% of the cases, respectively. MAGE-A antigens were not detectable via immunohistochemistry in benign lesions of the oral mucosa. The staining rate of dysplastic precancerous lesions or malignant lesions ranged from 33% to 65%. The MAGE-A antigens might facilitate better differentiation between precancerous and cancerous lesions of the oral mucosa.

A Novel RELA Truncating Mutation in a Familial Behçet's Disease-like Mucocutaneous Ulcerative Condition.

OBJECTIVE: Monogenic Behçet's disease (BD)-like conditions are increasingly recognized and to date have been found to predominantly involve loss-of-function variants in TNFAIP3. This study was undertaken to identify genetic and pathobiologic mechanisms associated with a BD-like mucocutaneous ulcerative syndrome and neuromyelitis optica (NMO) occurring in 3 generations of an Irish family (n = 5 cases and 5 familial controls). METHODS: Whole-exome sequencing was used to identify potential pathogenic variants in affected family members and determine segregation between affected and unaffected individuals. Relative v-rel reticuloendotheliosis viral oncogene homolog A (RELA) expression in peripheral blood mononuclear cells was compared by Western blotting. Human epithelial and RelA-/- mouse fibroblast experimental systems were used to determine the molecular impact of the RELA truncation in response to tumor necrosis factor (TNF). NF-κB signaling, transcriptional activation, apoptosis, and cytokine production were compared between wild-type and truncated RELA in experimental systems and patient samples. RESULTS: A heterozygous cytosine deletion at position c.1459 in RELA was detected in affected family members. This mutation resulted in a frameshift p.His487ThrfsTer7, producing a truncated protein disrupting 2 transactivation domains. The truncated RELA protein lacks a full transactivation domain. The RELA protein variants were expressed at equal levels in peripheral mononuclear cells. RelA-/- mouse embryonic fibroblasts (MEFs) expressing recombinant human RELAp.His487ThrfsTer7 were compared to those expressing wild-type RELA; however, there was no difference in RELA nuclear translocation. In RelA-/- MEFs, expression of RELAp.His487ThrfsTer7 resulted in a 1.98-fold higher ratio of cleaved caspase 3 to caspase 3 induced by TNF compared to wild-type RELA (P = 0.036). CONCLUSION: Our data indicate that RELA loss-of-function mutations cause BD-like autoinflammation and NMO via impaired NF-κB signaling and increased apoptosis.