Immune system and zinc are associated with recurrent aphthous stomatitis: an assessment using a network-based approach

OBJECTIVE: The aim of this research was to identify genes, proteins and processes from the biomedical information published on recurrent aphthous stomatitis (RAS) using network-based foci. METHODS: The clinical context was defined using MeSH terms for RAS and biomarkers, combined with words associated with risk. A set of protein coding genes was prioritized using the Génie web server and classified with PANTHER. For defining biologically relevant proteins, protein-protein interaction networks were constructed using Reactome database and Cytoscape. Top 20 proteins were then subjected to functional enrichment using STRING. RESULTS: From 1,075,576 gene-abstract links, 1,491 genes were prioritized. Proteins were related to signaling molecule proteins (n=221), receptor proteins (n=221) and nucleic acid binding proteins (n=169). The network constructed with these proteins included 3,963 nodes and functional analysis showed that main processes involved immune system and zinc ion binding function. CONCLUSIONS: For the first time, bioinformatics tools were used for integrating pathways and networks associated with RAS. Molecules and processes associated with immune system recur robustly in all analyzed information. The molecular zinc ion binding function could be an area for exploring more specific and effective therapeutic interventions

Oxidative stress and cellular immunity in patients with recurrent aphthous ulcers

Recurrent aphthous ulcer (RAU) is an inflammatory condition of the oral mucosa characterized by painful, well-circumscribed, single or multiple round or ovoid ulcerations. The exact etiologic factor(s) of these ulcerations are not yet understood. The objective of this study was to evaluate inflammatory processes and free radical metabolism of 25 patients with RAUs compared to 25 healthy controls. The levels of malondialdehyde (MDA) and glutathione (GSH) were determined by high-performance liquid chromatography. Tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), IL-10, and IL-12 were determined by ELISA. Nitric oxide (NO), myeloperoxidase (MPO), total antioxidant status (TAS), and total oxidant status (TOS) levels were measured spectroscopically in serum. The levels of MDA, GSH, TNF-α, IL-2, IL-12, MPO, and TOS, and oxidative stress index (OSI) were higher, and the levels of NO, IL-10, and TAS were lower in patients with RAU than in controls. Statistical analysis showed that GSH, TNF-α, IL-2, IL-10, and OSI differed significantly in patients with RAU compared to controls. These parameters have important roles in oxidant/antioxidant defense.

Correlation between histocompatibility antigens and recurrent aphthous stomatitis in the brazilian population / Estudo da associação entre antígenos de histocompatibilidade e estomatite aftoide recorrente em população brasileira

Recurrent aphthous stomatitis is a common oral mucosa disorder that affects 20 percent of the world's population, characterized by recurring painful ulcers in the mouth. The diagnosis is primarily based on the patient's clinical history. Inheritance may pose as a risk factor for the disease; however, the studies available are inconclusive as to the results attained, and they vary according to the population studied. AIM: to typify class I and class II HLA molecules and to assess how frequent these molecules are present in the Brazilian population with Recurrent Aphthous Stomatitis, compared to healthy controls. MATERIALS AND METHODS: In this prospective, cross-sectional and investigative study, thirty one patients with diagnostic hypothesis of recurrent aphthous stomatitis were seen from February of 2004 to May of 2006. We obtained the DNA from those patients who matched the inclusion criteria and typified their HLA by PCR. RESULTS: In those patients with Recurrent Minor Aphthous Stomatitis we found statistically significant occurrences of HLA-A33 and HLA-B35. CONCLUSION: HLA-A33 and HLA-B35 may be associated with recurrent minor aphthous stomatitis in the Brazilian's population.

A Estomatite Aftoide Recorrente é uma doença oral com incidência em 20 por cento da população mundial, caracterizada por úlceras mucosas de caráter recidivante. O diagnóstico baseiase principalmente na história clínica do paciente. Hereditariedade pode ser um fator de risco para doença, entretanto, os estudos disponíveis não são conclusivos quanto aos resultados obtidos, variando segundo a população estudada. OBJETIVO: Tipificar moléculas HLA de classe I e de classe II e avaliar a frequência destas moléculas em pacientes brasileiros, portadores de Estomatite Aftoide Recorrente, comparando com grupo controle. MATERIAL E MÉTODO: Este trabalho possui um desenho prospectivo, transverso e investigativo. Foram estudados 31 pacientes com suspeita diagnóstica de Estomatite Aftoide Recorrente no período de fevereiro de 2004 a maio de 2006. Os pacientes foram submetidos a protocolo de exames e, daqueles que obedeceram aos critérios de inclusão, foi extraído o DNA e realizada a tipificação HLA por Reação de Polimerização em Cadeia. RESULTADO: Nos pacientes portadores de Estomatite Aftoide Recorrente do tipo minor encontramos as frequências HLA A33 e B35 estatisticamente significantes. CONCLUSÃO: As frequências HLA-A33 e HLA-B35 podem estar associadas à Estomatite Aftoide Recorrente minor na população brasileira.

O papel da imunofluorescência direta na fisiopatologia e no diagnóstico diferencial da estomatite aftóide recorrente / The role of immunoflorescence in the physiopathology and differential diagnosis of recurrent aphthous stomatitis

A estomatite aftóide recorrente é doença caracterizada por aparecimento periódico de aftas na mucosa oral, cuja etiologia e fisiopatologia não estão bem explicadas. Estudos recentes com imunofluorescência direta mostram resultados controversos. Alguns revelam que o distúrbio básico está relacionado à imunidade humoral, enquanto outros apontam alterações da imunidade celular. Formas atípicas de estomatite aftóide podem fazer diagnóstico diferencial com doenças vésico-bolhosas como pênfigo vulgar. OBJETIVO: Verificar a presença de imunecomplexos na mucosa de pacientes com estomatite aftóide e utilidade do método no diagnóstico diferencial com dermatopatias bolhosas. CASUÍSTICA E MÉTODO: 23 pacientes portadores de estomatite aftóide, de modo prospectivo, foram incluídos no estudo. Todos foram submetidos à biópsia de mucosa sob anestesia local para retirada de dois fragmentos. Um deles foi enviado para exame histológico e, outro, para ser realizada a imunofluorescência direta. RESULTADOS: As 23 amostras no exame histológico revelaram processo inflamatório inespecífico ulcerado. As amostras enviadas para imunofluorescência resultaram negativas e apenas uma revelou presença de complemento em membrana basal. CONCLUSÃO: Baseado em nossos resultados, concluímos que pacientes portadores de EAR não apresentam depósitos de imunecomplexos na mucosa da cavidade bucal e a imunofluorescência é útil no diagnóstico diferencial entre a doença e dermatopatias bolhosas.

Recurrent aphthous stomatitis (RAS) is a disease characterized by the periodic appearance of aphthous lesions on the oral mucosa, of which etiology and physiopathology are not well explained. Recent studies with direct immunofluorescence show controversial results. Some reveal that the basic disorder is associated with humoral immunity, while others point to changes in cellular immunity. Atypical forms of aphthous stomatitis may have its differential diagnosis carried out with vesicobullous diseases, such as pemphigus vulgaris. AIM: Check the presence of immunocomplexes in the mucosa of patients with aphthous stomatitis and the usefulness of the differential diagnosis method with bullous skin diseases. MATERIALS AND METHODS: 23 patients with aphthous stomatitis were prospectively included in the study. There were all submitted to mucosa biopsy under local anesthesia for the removal of two fragments. One of these was sent to histology and, the other to direct immunofluorescence. RESULTS: The 23 samples from the histology exam revealed an ulcerated inflammatory process. The samples referred to immunofluorescence resulted negative and only one showed the presence of complement in the basal membrane. CONCLUSION: Based on our results, we conclude that the patients with RAS do not show deposits of immunocomplexes in their oral cavity mucosa and immunofluorescence is useful in the differential diagnosis between this disease and bullous skin diseases.

Factores inmunológicos y microbiológicos asociados con la etiología de la estomatitis aftosa recurrente / Microbiological and immunological factors associated with the etiology of recurrent aphthous stomatitis

La Estomatitis Aftosa Recurrente (EAR) es una enfermedad ulcerativa, dolorosa y muy común de la cavidad bucal, cuya etiología es desconocida. Algunos reportes han señalado que los pacientes afectados con esta condición presentan una respuesta inmunológica defectuosa. Adicionalmente, existe atención en destacar la importancia y participación de las moléculas de adhesión en el reclutamiento del infiltrado inflamatorio en esta condición. Las moléculas de adhesión VCAM-1 (molécula de adhesión vascular-1) e ICAM-1 (molécula de adhesión intercelular-1), son esenciales para la unión de las células inflamatorias a las células endoteliales. Formas circulantes de estas moléculas han sido detectadas en un número de enfermedades vasculíticas, y EAR tiene características similares a esta entidad. Por otra parte Helicobacter pylori ha sido demostrado como el agente causal de la úlcera gástrica que presenta gran similitud histológica con la EAR. El objetivo del presente trabajo es realizar una revisión de los principales factores inmunológicos y microbiológicos, asociados con la EAR

Recurrent aphtous stomatitis (RAS) is a common, painful and ulcerative disorder of the oral cavity of unknown etiology. Several reports have suggested that the patients affected with this condition have a defectous celular immune response. Aditionally, adhesion molecules are known to play a crucial role in the recruitment of immflamatory cells to sites of inflammation. Adhesion molecules VCAM-1 (vascular cell adhesion molecule-1), and ICAM-1 (intercellular adhesion molecule-1) are essential for the binding of inflammatory cells to Endothelial cells. Circulating forms of these molecules have been detected in a number of vasculitic disease. RAS has some features of a vasculitic disease process. Helicobacter pylori has been shown to be the causative factor in peptic ulcers, which is very similar with RAS The aim of this study was to review the inmmunological and microbiological factors associated with the etiology of RAS

Imunoglobulina A secretora, proteínas totais e fluxo de saliva nas ulcerações aftosas recorrentes / Secretory A immunoglobulin, total proteins and salivary flow in Recurrent Aphthous Ulceration

De etiologia discutível, as ulcerações aftosas recorrentes (UAR) são, na maioria das vezes, consideradas em um quadro de deficiência imunológica. OBJETIVOS: Este trabalho baseia-se na revisão de literatura e em investigações clínico-laboratoriais dos títulos salivares de imunoglobulina A secretora (IgA-s), proteínas totais e fluxo de saliva (em repouso) de pacientes nos períodos de atividade e quiescência das Ulcerações aftosas recorrentes. Forma de Estudo: Estudo clínico e experimental. MATERIAL E MÉTODOS: Empregou-se a Nefelometria na quantificação das IgA-s salivares, o vermelho de Pirogalol para as proteínas totais salivares e a análise gravimétrica para a determinação do fluxo de saliva. RESULTADOS: Os resultados demonstraram aumento estatisticamente significativo das IgA-s salivares nos períodos de lesão ativa em relação aos de quiescência. Não houve diferença estatística nas concentrações de proteínas totais e no fluxo de saliva. CONCLUSÃO: Sugere-se que a IgA-s pode ser usada como parâmetro do status imune da mucosa oral.

Clinical and experimental study. Introduction. Of debatable etiology, Recurrent Aphthous Ulcerations (R.A.U), is most of the time considered an immunological deficiency. AIM: The aim of this paper is to review the literature and clinical investigations regarding IgA-s, total proteins salivary concentration and basal salivary flow of patients with R.A.U. during activity and quiescence. METHODOLOGY: Nephelometry was used to measure salivary IgA-s; Pyrogallol red was used for total salivary proteins and the gravimetrical analysis for salivary flow measurement. RESULTS: Results demonstrated a significant increase in salivary IgA-s in active lesions in relation to quiescence. On the other hand, protein concentration rates were similar in both periods. CONCLUSION: Salivary IgA-s can be used as a parameter to study the immune status of the oral mucosa.

Aids e estomatite aftóide recidivante / AIDS and recurrent aphtous stomatitis

O estado de imunodeficiência em pacientes HIV positivos tem sido causa de episódios severos de Estomatite Aftóide Recidivante (EAR). OBJETIVO: Este estudo objetiva estabelecer evidências da relação entre o surgimento (ou agravamento) de EAR com o estado de imunossupressão causado pelo vírus HIV, por meio da contagem de células CD4+, CD8+ e da carga viral infectante. FORMA DE ESTUDO: estudo de série. MATERIAL E MÉTODO: Noventa e quatro pacientes HIV (1)-positivos (25 mulheres e 69 homens) com EAR foram acompanhados no ambulatório de Aids da Divisão de Clínica ORL do Hospital das Clínicas da FMUSP no período de janeiro de 1998 a dezembro de 2003. A idade dos pacientes variou de 19 a 63 anos (média = 35,3 anos). RESULTADO: Os pacientes com Aids e soropositivos apresentaram, respectivamente, oito aftas e duas aftas por surto. Da mesma maneira, os pacientes portadores de úlceras do tipo major apresentaram menor contagem de células CD8+, CD4+ e relação CD4+/CD8+ e maior valor médio da carga viral do que os pacientes portadores de aftas herpetiformes e minor. Entre os portadores de aftas minor e herpetiforme não houve diferença estatística. CONCLUSÕES O aparecimento das lesões, principalmente as do tipo major, está diretamente relacionado ao estado imunitário do paciente soropositivo, acarretando déficits nutricionais e piora na qualidade de vida. Desta forma, o diagnóstico e tratamento da EAR é um desafio que não deve ser desprezado.

Estomatitis aftosa recurrente. Determinación de marcadores de inmunidad celular / Recurrent aphthous stomatitis. Determination of cell immunity markers

La estomatitis aftosa recurrente, aftosis oral o aftas, es la enfermedad más frecuente de todas las lesiones de la mucosa oral. Su etiopatogenia no es completamente conocida, pero se citan factores genéticos, alimentarios, infecciosos, alérgicos, medicamentosos, traumáticos e inmunológicos. Estudiamos 51 pacientes atendidos en el Servicio de Cirugía Maxilofacial del Hospital Pediátrico " William Soler", que padecen de esta enfermedad para valorar el estado de inmunocompetencia celular mediante la determinación del porcentaje de células formadoras de rosetas activas y espontáneas. La edad promedio en nuestro grupo fue de 12 años, ambos sexos se afectaron por igual, y se encontró un predominio franco de los enfermos de raza blanca sobre los de raza negra. El 73 por ciento de los enfermos mostró afectación al menos de un marcador de inmunorrespuesta, 25 pacientes tuvieron ambos marcadores por debajo de lo normal y 12 casos presentaron alteración en uno de los dos. Se concluye que la enfermedad se asocia con defectos de la inmunidad celular, lo cual debe considerarse al indicar tratamiento, teniendo en cuenta que hasta el momento no disponemos de ninguna droga curativa(AU)

Recurrent aphthous stomatitis, oral aphthosis or aphthae is the most frequent of all oral mucosal membrane diseases. Its etiology and pathogenesis are not totally known but genetic, food, infectious, allergic, drug, trauma and immunological factors are involved. We studied 51 patients who suffered from this disease and were seen at the Maxillofacial Surgery Department of "William Soler" Pediatric Hospital. Our objective was to assess the cell immunocompetence by determining the percentage of active and spontaneous rosette-forming cells. The average age of the group was 12 years, both sexes were equally affected but white patients greatly prevailed over black patients. At least one immunoresponse marker of 73 percent of the patients was affected; 25 patients had both markers under the normal parameters and 12 cases presented with disturbances in one of the two markers. It was concluded that the disease is linked to cell immunity defects, which should be considered in the treatment, taking into account that no curative drug is so far available(AU)

Nuevo enfoque etiopatogénico en úlceras aftosas recidivantes (RAU) de la mucosa bucal: se trata de un proceso vasculítico?, estudio inmunohistoquímico en lesiones orales de pacientes inmunocompetentes, VIH (-) e inmunodeficientes, VIH (+) / New etiopathogenic approach in recurrent aphtous ulcers (RAU) of oral mucose: is this a vasculitis process?, immunohistochemical study in oral lesions of immunocompetent, HIV (-) and immunodeficient, HIV (+), patients

La úlcera aftosa recurrente (RAU), es una lesión muy dolorosa de la mucosa oral, que afecta entre el 6 y el 20 por ciento de la población mundial. En personas inmunocompetentes es una enfermedad complicada de tratamiento muy difícil. En inmunodeficiencia humana (VIH), RAU es más persistente y severamente debilitante. Las últimas comunicaciones están interesadas en estudios inmunológicos. Objetivos: 1) Investigar en pacientes con úlceras RAU+: la expresión de moléculas de adhesión (MA), en especial los marcadores de activación endotelial y sus ligandos, subpoblaciones leucocitarias, gen anti-apoptosis, células Natural Killer (NK), y macrófagos. 2) Establecer las diferencias entre poblaciones con úlceras, RAU+ (VIH+/VIH-) y sin úlceras, RAU- (VIH+/VIH-). 3) Establecer las diferencias entre las subpoblaciones RAU+, VIH+ y VIH-. Población y métodos: pacientes mayores de 15 años de edad, VIH- y VIH+ (estadío III según CDC). Se obtuvieron biopsias de pacientes RAU+: 8 VIH+ y 15 VIH-, y de pacientes RAU: 2 VIH+ y 8 VIH- (grupo control). La tinción por inmunoperoxidasa fue realizada usando anticuerpos monoclonales primarios para los siguientes antígenos: ICAM-1 (CD54), CD11-CD18, CD56 (NK), CD15 (PMN), CD62 E-selectina, CD31, BM-1 (Lewys Y), BCL-2, CD8, CD68. La intensidad de la inmunotinción fue evaluada semicuantitativamente: Pd: positiva débil, P: positivo (marrón moderado), PP: positiva (marrón intenso), PPP: positiva (marrón muy intenso), E/P: positiva intraepitelial, N: negativa, L: leucocitos, V: vasos, E: epitelio. Se realizó estudio estadístico (test de Fisher), y también registro fotográfico clínico e histológico de las lesiones de mucosa oral...

Decreased CD4+/CD8+ ratio in major type of recurrent aphthous ulcers: comparing major to minor types of ulcers.

The etiology of recurrent aphthous ulcers (RAU) has not been clearly defined. However, the results of several studies indicated the evidence of the role of immunological factors. The association between the regulator and effector component of the immune system in RAU needs clarifying by comparing major and minor type of RAU patients. The proportion of peripheral blood lymphocyte subsets were enumerated during active ulcer phase and analyzed in relation to ulcer types. Nineteen patients with RAU (12 minor type and 7 major type) and 8 healthy volunteers, of both sexes, aged 24-54 years old were tested. CD3+ (T cell), CD4+ (helper T cell), CD8+ (suppressor/cytotoxic T cell), CD19+ (B cell), and CD16+/CD56+ (NK cell) were determined by using appropriate monoclonal antibodies in double colored flow cytometry. The results showed that CD4+ was lower in RAU than control (P < 0.01). Comparing both types of RAU, it appeared that CD8+ was higher in the major type than the minor type (p < 0.01); CD4+/CD8+ ratio in the major type was lower than the minor type (P < 0.01). There was no difference in CD19+ and CD16+/CD56+ between any groups compared. The finding indicated that RAU was associated with abnormal proportions of CD4+ and CD8+ cells which was dependent on the severity of the lesion.