RESUMO
OBJECTIVES/HYPOTHESIS: To explore the clinically feasible diagnosis criteria and treatment outcomes of allergy-related sialodochitis (ARS). STUDY DESIGN: Prospective Cohort Study. METHODS: Ninety-six consecutive patients were enrolled by the following criteria: 1) recurrent swelling of ≥2 large salivary glands that lasted for ≥3 months; 2) with mucus plug exudations; 3) with atopic diseases; 4) ductal stenosis and/or ectasia. Sixty-four patients with elevation of peripheral blood eosinophil (PBE) and/or serum IgE level comprised group A (highly-suspected ARS group), while the remaining 32 comprised group B (patients without confirmed evidence of ARS). These patients were treated with interventional endoscopy. A chronic obstructive sialadenitis symptom (COSS) questionnaire was used to quantify the treatment outcomes. RESULTS: In group A, Serum IgE was elevated in 84.4% of patients and PBE was elevated in 34.4% of patients. Percentage of submandibular gland involvement was higher in group A than group B (48.4% vs. 18.8%). On sialograms, the snowflake changes of branch ducts were seen in higher percentage of group A compared with group B (59% vs. 35% for parotid glands, 27% vs. 8% for submandibular glands, respectively). Mucus plug smears showed abundant eosinophils in 14 group A patients. Biopsy of five group A patients revealed significant eosinophil infiltration around the main and interlobular ducts. During follow-up, the COSS scores were significantly decreased in both groups, and group B was improved better than group A. CONCLUSION: PBE and serum IgE are important diagnostic indexes of ARS. Mucus plug smear or histopathology verifies the diagnosis. Interventional endoscopy is helpful for ARS cases. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:2030-2035, 2021.
Assuntos
Eosinofilia/sangue , Hipersensibilidade/complicações , Imunoglobulina E/sangue , Ductos Salivares/imunologia , Sialadenite/etiologia , Adulto , Idoso , Biópsia , Estudos de Casos e Controles , Doença Crônica , Estudos de Coortes , Endoscopia/métodos , Eosinofilia/patologia , Feminino , Humanos , Hipersensibilidade/diagnóstico , Hipersensibilidade/imunologia , Masculino , Pessoa de Meia-Idade , Muco/imunologia , Estudos Prospectivos , Ductos Salivares/patologia , Sialadenite/diagnóstico , Sialadenite/imunologia , Sialadenite/cirurgia , Sialografia/métodos , Inquéritos e Questionários , Resultado do TratamentoRESUMO
A major complication of primary Sjögren's syndrome (pSS) is development of mucosa associated lymphoid tissue (MALT) B-cell lymphoma, particularly in salivary glands. These lymphomas express FcRL4 and are characteristically associated with lymphoepithelial lesions. Neoplastic B-cells may be derived from non-neoplastic glandular intraductal B-cells, also virtually all expressing FcRL4. A characteristic feature of MALT lymphomas is the production of rheumatoid factors (RFs), which are largely encoded by stereotypic immunoglobulin variable heavy chain (IGHV) sequences. The aim of this study was to examine whether there is a relationship between the intraductal and periductal B-cells and whether the intraductal B-cells are selected for RF. RNA was extracted from laser-microdissected infiltrated ductal areas and periductal infiltrates from frozen parotid gland tissue sections of 5 pSS patients. PCR amplified IGHV transcripts were cloned into pCR™4-TOPO vector and subsequently sequenced. Microdissected ducts yielded 96 unique IGHV sequences derived from intraductal B-cells, while 119 unique IGHV sequences were obtained from periductal infiltrates. No major difference in VH-gene usage was observed between intraductal and periductal B-cells. Nearly all (>90%) IGHV sequences derived from both intraductal and periductal B-cells were mutated. Clonal expansions as defined by shared VDJ rearrangements were also present among both intraductal and periductal B-cells: in total 32 clones were found, from which 12 were located within ducts, 15 in periductal areas, and five clones shared members in both areas. We observed 12 IGHV rearrangements encoding for RF sequences from which two were derived from intraductal B-cells and 10 from periductal B-cells. Nine RF sequences were part of a clone. Together these findings indicate that intraductal and periductal B-cells are closely related to each other. Intraductal B-cells are most likely derived from periductal B-cells. We did not obtain evidence that RF-specific B-cells are enriched within the striated ducts. We speculate that in principle any activated B-cell can enter the striated ducts from the periductal infiltrate, irrespective of its antigenic specificity. Within the ducts, these B-cells may receive additional activation and proliferation signals, to further expand at these sites and by acquisition of driver-mutations develop toward lymphoma.
Assuntos
Linfócitos B/fisiologia , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma de Zona Marginal Tipo Células B/imunologia , Fator Reumatoide/genética , Ductos Salivares/imunologia , Glândulas Salivares/imunologia , Síndrome de Sjogren/imunologia , Adulto , Idoso , Células Clonais , Feminino , Rearranjo Gênico do Linfócito B , Humanos , Ativação Linfocitária , Pessoa de Meia-Idade , Receptores Fc/metabolismoRESUMO
Purpose: Salivary duct carcinoma (SDC) is a rare and aggressive salivary gland cancer subtype with poor prognosis. The mutational landscape of SDC has already been the object of several studies, however little is known regarding the functional genomics and the tumor microenvironment despite their importance in oncology. Our investigation aimed at describing both the functional genomics of SDC and the SDC microenvironment, along with their clinical relevance. Methods: RNA-sequencing (24 tumors), proteomics (17 tumors), immunohistochemistry (22 tumors), and multiplexed immunofluorescence (3 tumors) data were obtained from three different patient cohorts and analyzed by digital imaging and bioinformatics. Adjacent non-tumoral tissue from patients in two cohorts were used in transcriptomic and proteomic analyses. Results: Transcriptomic and proteomic data revealed the importance of Notch, TGF-ß, and interferon-γ signaling for all SDCs. We confirmed an overall strong desmoplastic reaction by measuring α-SMA abundance, the level of which was associated with recurrence-free survival (RFS). Two distinct immune phenotypes were observed: immune-poor SDCs (36%) and immune-infiltrated SDCs (64%). Advanced bioinformatics analysis of the transcriptomic data suggested 72 ligand-receptor interactions occurred in the microenvironment and correlated with the immune phenotype. Among these interactions, three immune checkpoints were validated by immunofluorescence, including CTLA-4/DC86 and TIM-3/galectin-9 interactions, previously unidentified in SDC. Immunofluorescence analysis also confirmed an important immunosuppressive role of macrophages and NK cells, also supported by the transcriptomic data. Conclusions: Together our data significantly increase the understanding of SDC biology and open new perspectives for SDC tumor treatment. Before applying immunotherapy, patient stratification according to the immune infiltrate should be taken into account. Immune-infiltrated SDC could benefit from immune checkpoint-targeting therapy, with novel options such as anti-CTLA-4. Macrophages or NK cells could also be targeted. The dense stroma, i.e., fibroblasts or hyaluronic acid, may also be the focus for immune-poor SDC therapies, e.g. in combination with Notch or TGF-ß inhibitors, or molecules targeting SDC mutations.
Assuntos
Carcinoma Ductal , Ductos Salivares/imunologia , Neoplasias das Glândulas Salivares , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Carcinoma Ductal/genética , Carcinoma Ductal/imunologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteoma , Ductos Salivares/patologia , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/imunologia , Transcriptoma , Adulto JovemRESUMO
Salivary glands are a major component of the mucosal immune system that confer adaptive immunity to mucosal pathogens. As previously demonstrated, immunization of the submandibular gland with tissue culture-derived murine cytomegalovirus (tcMCMV) or replication-deficient adenoviruses expressing individual murine cytomegalovirus (MCMV) genes protected mice against a lethal MCMV challenge. Here, we report that salivary gland inoculation of BALB/cByJ mice with tcMCMV or recombinant adenoviruses differentially activates T helper (Th)1, -2, and -17 cells in the salivary glands vs. the associated lymph nodes. After inoculation with tcMCMV, lymphocytes from the submandibular gland preferentially express the transcription factor T-cell-specific T-box transcription factor (T-bet), which controls the expression of the hallmark Th1 cytokine, IFN-γ. Lymphocytes from the periglandular lymph nodes (PGLNs) express both T-bet and GATA-binding protein 3 (GATA3), which promotes the secretion of IL-4, -5, and -10 from Th2 cells. In contrast, after inoculation with replication-deficient adenoviruses, lymphocytes from the submandibular gland express T-bet, GATA3, and RAR-related orphan receptor γ, thymus-specific isoform (RORγt) (required for differentiation of Th17 cells) and forkhead box P3 (Foxp3) (required for the differentiation of regulatory T cells). Lymphocytes from the PGLNs were not activated. The differential induction of Th responses in the salivary gland vs. the PGLNs after inoculation with attenuated virus vs. a nominal protein antigen supports the use of the salivary as an alternative mucosal route for administering vaccines.-Liu, G., Zhang, F., Wang, R., London, S. D., London, L. Salivary gland immunization via Wharton's duct activates differential T-cell responses within the salivary gland immune system.
Assuntos
Imunidade nas Mucosas , Ductos Salivares/imunologia , Glândulas Salivares/imunologia , Linfócitos T Reguladores/imunologia , Adenoviridae/genética , Animais , Citocinas/metabolismo , Feminino , Fator de Transcrição GATA3/metabolismo , Interferon gama/metabolismo , Linfonodos/patologia , Linfócitos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Muromegalovirus , Proteínas com Domínio T/metabolismo , VacinaçãoRESUMO
Guanylate-binding protein-1 (GBP-1) is an interferon-inducible large GTPase involved in the epithelial barrier at tight junctions. To investigate the role of GBP-1 in the epithelial barrier, primary human salivary gland duct epithelial cells were treated with the the proinflammatory cytokines IFNγ, IL-1ß, TNFα and the growth factor TGF-ß. Treatment with IFNγ, IL-1ß, or TNFα markedly enhanced GBP-1 and the epithelial barrier function, and induced not only CLDN-7 but also the tricellular tight junction molecule lipolysis-stimulated lipoprotein receptor (LSR). Knockdown of GBP-1 by its siRNA induced endocytosis of tight junction molecules, and prevented the increases of CLDN-7 and LSR with the upregulation of the epithelial barrier function induced by treatment with IFNγ or TNFα. Treatment with a PKCα inhibitor induced expression of GBP-1, CLDN-7 and LSR and enhanced the epithelial barrier function. In almost intact salivary gland ducts from patients with IgG4-related disease (IgG4-RD) indicated significant infiltration of IgG-positive plasma cells, expression of GBP-1, CLDN-7 and LSR was increased. These findings indicated that GBP-1 might play a crucial role in barrier function of normal human salivary gland duct epithelium and perform a preventive role in the duct epithelium of IgG4-RD disease.
Assuntos
Claudinas/genética , Células Epiteliais/metabolismo , Proteínas de Ligação ao GTP/genética , Doença Relacionada a Imunoglobulina G4/genética , Imunoglobulina G/genética , Receptores de Lipoproteínas/genética , Junções Íntimas/metabolismo , Transporte Biológico , Claudinas/imunologia , Endocitose , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/patologia , Epitélio/efeitos dos fármacos , Epitélio/imunologia , Epitélio/patologia , Epitélio/cirurgia , Proteínas de Ligação ao GTP/antagonistas & inibidores , Proteínas de Ligação ao GTP/imunologia , Regulação da Expressão Gênica , Humanos , Imunoglobulina G/metabolismo , Doença Relacionada a Imunoglobulina G4/imunologia , Doença Relacionada a Imunoglobulina G4/patologia , Doença Relacionada a Imunoglobulina G4/cirurgia , Interferon gama/farmacologia , Ocludina/genética , Ocludina/imunologia , Permeabilidade/efeitos dos fármacos , Plasmócitos/imunologia , Plasmócitos/patologia , Cultura Primária de Células , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/imunologia , Receptores de Lipoproteínas/imunologia , Ductos Salivares/imunologia , Ductos Salivares/patologia , Ductos Salivares/cirurgia , Transdução de Sinais , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/imunologia , Junções Íntimas/ultraestrutura , Fatores de Transcrição , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
BACKGROUND: Sublingual immunotherapy (SLIT) has proven to be safe and efficient for the treatment of type I allergies. However, the mechanisms underlying allergen transportation within the sublingual compartment, the localization of antigens, and the identities of the cells responsible for this immunization remain incompletely understood. OBJECTIVE: In this study, we focused on the sublingual ductal system and analysed the localization and transportation of antigens after their sublingual application. METHODS: In mice given adjuvant-free antigens sublingually, tissues were removed at 0, 0.5, 1, or 2 h after the application and subjected to immunohistochemistry. Cells isolated from the sublingual duct and mucosa were analysed by flow cytometry. RESULTS: Substantial immunoreactivity to ovalbumin (OVA) was evident in sublingual ductal epithelial cells at 30 min and 1 h after sublingual administration of OVA, but it had disappeared at 2 h. The ductal epithelial cells incorporated not only OVA, but also particulate antigens such as latex or silica beads and microbes. MHC class II (MHCII)(+) antigen-presenting cells (APCs) were located around the sublingual ductal system, and MHCII(+) cells were co-localized with, and around, antigen-incorporated sublingual duct cells. CD11b(+) CD11c(-) cells were present among CD45(+) MHCII(+) cells at greater frequency in the sublingual duct than in the sublingual mucosa, and they were the main contributors to the incorporation of OVA in vitro. CONCLUSIONS AND CLINICAL RELEVANCE: This study reveals that sublingual antigens can be transported across sublingual ductal epithelial cells to the ductal APCs. If the system is the same in humans as in mice, the ductal APCs may prove to be important target cells for SLIT.
Assuntos
Alérgenos/imunologia , Alérgenos/metabolismo , Células Apresentadoras de Antígenos/imunologia , Absorção pela Mucosa Oral , Ductos Salivares/imunologia , Ductos Salivares/metabolismo , Administração Sublingual , Alérgenos/administração & dosagem , Animais , Apresentação de Antígeno , Células Apresentadoras de Antígenos/metabolismo , Transporte Biológico , Dessensibilização Imunológica , Feminino , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Camundongos , Ductos Salivares/citologiaRESUMO
Salivary glands, a major component of the mucosal immune system, confer antigen-specific immunity to mucosally acquired pathogens. We investigated whether a physiological route of inoculation and a subunit vaccine approach elicited MCMV-specific and protective immunity. Mice were inoculated by retrograde perfusion of the submandibular salivary glands via Wharton's duct with tcMCMV or MCMV proteins focused to the salivary gland via replication-deficient adenovirus expressing individual MCMV genes (gB, gH, IE1; controls: saline and replication deficient adenovirus without MCMV inserts). Mice were evaluated for MCMV-specific antibodies, T-cell responses, germinal center formation, and protection against a lethal MCMV challenge. Retrograde perfusion with tcMCMV or adenovirus expressed MCMV proteins induced a 2- to 6-fold increase in systemic and mucosal MCMV-specific antibodies, a 3- to 6-fold increase in GC marker expression, and protection against a lethal systemic challenge, as evidenced by up to 80% increased survival, decreased splenic pathology, and decreased viral titers from 10(6) pfu to undetectable levels. Thus, a focused salivary gland immunization via a physiological route with a protein antigen induced systemic and mucosal protective immune responses. Therefore, salivary gland immunization can serve as an alternative mucosal route for administering vaccines, which is directly applicable for use in humans.
Assuntos
Imunidade/imunologia , Muromegalovirus/imunologia , Ductos Salivares/imunologia , Glândulas Salivares/imunologia , Adenoviridae/genética , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , DNA Recombinante , Feminino , Imunofluorescência , Expressão Gênica/imunologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/prevenção & controle , Infecções por Herpesviridae/virologia , Humanos , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/imunologia , Proteínas Imediatamente Precoces/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Muromegalovirus/genética , Muromegalovirus/metabolismo , Fator de Transcrição PAX5/genética , Fator de Transcrição PAX5/imunologia , Fator de Transcrição PAX5/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ductos Salivares/metabolismo , Glândulas Salivares/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Vacinação/métodos , Proteínas Virais/genética , Proteínas Virais/imunologia , Proteínas Virais/metabolismo , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia , Replicação Viral/genéticaRESUMO
Sjögren's Syndrome (SS) is a chronic inflammatory disorder affecting exocrine glands, in particular the lacrimal and salivary glands. The disease can be primary (pSS) or secondary to other systemic autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and others. The systemic autoimmune character of pSS is also apparent from the occurrence of (non-organ specific) autoantibodies in this disease. Histopathologically, glandular involvement is characterized by focal accumulation of lymphocytes, particularly around epithelial ducts, with, sometimes, germinal center-like structures. The infiltrates largely consist of T-cells, with a preponderance of CD4-positive T-cells. As a result, the pathology in SS was primarily attributed to T cells. However, a break with the fixation on the role of T cells in pSS came when therapeutic B-cell depletion strategies proved remarkably efficacious in this disease, thereby indicating a major role for B-cells in the immunopathogenesis of pSS. In this regard, a closer look at the composition of B-cells and B-cell sub-populations, both in the peripheral blood and in target tissues, is worthwhile. In this review, we discuss current data on B-cells in pSS. B-cell depletion offers a unique possibility to study the recurrence of (pathogenic) B-cells and their characteristics in pSS patients treated with rituximab. Data on B-cell sub-populations in the peripheral blood and B-cell repertoire in the target tissues following rituximab treatment are discussed as well. We also address their state of activation, repertoire, and relation to B-cell activating factor (BAFF).
Assuntos
Linfócitos B/imunologia , Subpopulações de Linfócitos/imunologia , Síndrome de Sjogren/imunologia , Anticorpos Monoclonais Murinos/uso terapêutico , Antígenos CD20/uso terapêutico , Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Fator Ativador de Células B/imunologia , Linfócitos T CD4-Positivos/imunologia , Humanos , Depleção Linfocítica , Rituximab , Ductos Salivares/imunologia , Glândulas Salivares/imunologiaRESUMO
A case of bilateral carcinoma in situ of Wharton's duct after chronic sialadenitis is reported. The patient, a 54-year-old man, complained of recurrent pain and swelling in the left lower submandibular region. Computed tomography showed large stones in the hilar area of both submandibular glands. The patient underwent bilateral submandibular excision. Histologic and immunohistochemical examination revealed squamous metaplasia with areas of carcinoma in situ in both right and left ducts adjacent to the calculus. To the best of our knowledge, this is the first case report in the literature describing an association between obstructive sialadenitis and carcinoma in situ of Wharton's duct. We discuss etiologic factors and chronic inflammation as a possible cause of malignancy.
Assuntos
Carcinoma in Situ/imunologia , Inflamação/imunologia , Lesões Pré-Cancerosas/imunologia , Cálculos dos Ductos Salivares/cirurgia , Ductos Salivares/patologia , Sialadenite/imunologia , Neoplasias da Glândula Submandibular/imunologia , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/cirurgia , Transformação Celular Neoplásica , Humanos , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/patologia , Ductos Salivares/imunologia , Ductos Salivares/cirurgia , Sialadenite/patologia , Neoplasias da Glândula Submandibular/diagnóstico , Neoplasias da Glândula Submandibular/cirurgia , Resultado do TratamentoRESUMO
OBJECTIVES: Chronic infiltration of lymphocytes into the salivary and lacrimal glands of patients with Sjögren's syndrome (SS) leads to destruction of acinar cells and loss of exocrine function. Protein kinase C-delta (PKCδ) is known to play a critical role in B-cell maintenance. Mice in which the PKCδ gene has been disrupted have a loss of B-cell tolerance, multiple organ lymphocytic infiltration, and altered apoptosis. To determine whether PKCδ contributes to the pathogenesis of SS, we quantified changes in indicators of SS in PKCδ-/- mice as a function of age. Salivary gland histology, function, the presence of autoantibodies, and cytokine expression were examined. MATERIALS AND METHODS: Submandibular glands were examined for the presence of lymphocytic infiltrates, and the type of infiltrating lymphocyte and cytokine deposition was evaluated by immunohistochemistry. Serum samples were tested by autoantibody screening, which was graded by its staining pattern and intensity. Salivary gland function was determined by saliva collection at various ages. RESULTS: PKCδ-/- mice have reduced salivary gland function, B220+ B-cell infiltration, anti-nuclear antibody production, and elevated IFN-γ in the salivary glands as compared to PKCδ+/+ littermates. CONCLUSIONS: PKCδ-/- mice have exocrine gland tissue damage indicative of a SS-like phenotype.
Assuntos
Proteína Quinase C-delta/imunologia , Síndrome de Sjogren/imunologia , Doenças da Glândula Submandibular/imunologia , Animais , Anticorpos Antinucleares/análise , Apoptose/genética , Autoanticorpos/análise , Autoanticorpos/sangue , Linfócitos B/imunologia , Movimento Celular/imunologia , Proliferação de Células , Modelos Animais de Doenças , Feminino , Centro Germinativo/patologia , Interferon gama/análise , Interleucina-4/análise , Antígeno Ki-67/análise , Antígenos Comuns de Leucócito/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Proteína Quinase C-delta/genética , Ductos Salivares/imunologia , Ductos Salivares/patologia , Taxa Secretória/fisiologia , Tolerância a Antígenos Próprios/imunologia , Glândula Submandibular/metabolismo , Glândula Submandibular/patologia , Doenças da Glândula Submandibular/fisiopatologiaRESUMO
The purpose of this study was to investigate the expression pattern of extracellular matrix metalloproteinase inducer (EMMPRIN) as well as the correlation between EMMPRIN and microvessel density (MVD) in salivary gland tumors. Extracellular matrix metalloproteinase inducer expression and MVD were examined immunohistochemically on paraffin-embedded tissue specimens from 95 patients with salivary gland tumors, who underwent surgical resection from 1998 to 2006. Reverse transcription-polymerase chain reaction was used to monitor EMMPRIN mRNA expression in frozen samples. Extracellular matrix metalloproteinase inducer expression in mucoepidermoid carcinomas and adenoid cystic carcinomas was significantly higher than in normal salivary gland tissues and pleomorphic adenomas (P < 0.05). The MVD of mucoepidermoid carcinomas and adenoid cystic carcinomas was significantly higher compared with pleomorphic adenomas (P < 0.05). The MVD of the EMMPRIN-positive expression group was significantly higher than the MVD of the EMMPRIN-negative expression group (P < 0.05). Extracellular matrix metalloproteinase inducer mRNA expression in malignant salivary gland tumors was higher than that in pleomorphic adenomas (P < 0.05). This study suggests that EMMPRIN expression is an important feature of malignant salivary gland tumors and can be used as a biologic marker to characterize salivary gland tumors. Extracellular matrix metalloproteinase inducer is also a positive angiogenic factor in salivary gland tumors.
Assuntos
Antígenos de Neoplasias/análise , Basigina/análise , Microvasos/patologia , Neoplasias das Glândulas Salivares/imunologia , Adenoma Pleomorfo/irrigação sanguínea , Adenoma Pleomorfo/imunologia , Indutores da Angiogênese/análise , Antígenos CD34/análise , Biomarcadores Tumorais/análise , Carcinoma Adenoide Cístico/irrigação sanguínea , Carcinoma Adenoide Cístico/imunologia , Carcinoma Mucoepidermoide/irrigação sanguínea , Carcinoma Mucoepidermoide/imunologia , Epitélio/irrigação sanguínea , Epitélio/imunologia , Humanos , Imuno-Histoquímica , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ductos Salivares/irrigação sanguínea , Ductos Salivares/imunologia , Neoplasias das Glândulas Salivares/irrigação sanguínea , Glândulas Salivares/irrigação sanguínea , Glândulas Salivares/imunologiaRESUMO
BACKGROUND: Recent studies have demonstrated the expression of Toll-like receptor 3 (TLR3) in salivary glands and epithelial cell lines derived from Sjögren's syndrome (SS) patients. As viral infections are considered to be a trigger for SS, in this study we investigated whether in vivo engagement of TLR3 affects salivary gland function. METHODS: Female New Zealand Black/WF1 mice were repeatedly injected with polyinosinic:polycytidylic acid [poly(I:C)]. TLR3 expression within submandibular glands was studied using immunohistochemistry. RNA levels of inflammatory cytokines in the submandibular glands were determined by real time polymerase chain reaction. Pilocarpine induced saliva volume was used as an index of glandular function. RESULTS: Immunohistochemical analysis of submandibular glands showed TLR3 expression in epithelium of serous and mucous acini, granular convoluted tubules, and ducts. Poly(I:C) treatment rapidly up-regulated the mRNA levels of type I interferon (IFN) and inflammatory cytokines in the submandibular glands. One week after treatment, the saliva volumes in poly(I:C) treated mice were significantly reduced in comparison with the phosphate-buffered saline (PBS) treated mice. Hematoxylin and eosin staining showed that salivary gland histology was normal and lymphocytic foci were not detected. Glandular function recovered after poly(I:C) treatment was stopped. CONCLUSIONS: Our results demonstrate that engagement of TLR3 within the salivary glands results in a rapid loss of glandular function. This phenomenon is associated with the production of type I IFN and inflammatory cytokines in the salivary glands. Restoration of glandular function suggests that for viral etiology of SS, a chronic infection of salivary glands might be necessary.
Assuntos
Imunidade Inata/imunologia , Glândula Submandibular/fisiopatologia , Receptor 3 Toll-Like/imunologia , Animais , Quimiocina CCL5/efeitos dos fármacos , Quimiocina CCL5/imunologia , Feminino , Imunidade Inata/efeitos dos fármacos , Imuno-Histoquímica , Indutores de Interferon/farmacologia , Interferon Tipo I/efeitos dos fármacos , Interferon Tipo I/imunologia , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/imunologia , Interleucina-6/análise , Interleucina-6/imunologia , Camundongos , Camundongos Endogâmicos NZB , Agonistas Muscarínicos/farmacologia , Pilocarpina/farmacologia , Poli I-C/farmacologia , Reação em Cadeia da Polimerase/métodos , Saliva/efeitos dos fármacos , Saliva/metabolismo , Ductos Salivares/efeitos dos fármacos , Ductos Salivares/imunologia , Taxa Secretória/efeitos dos fármacos , Glândula Submandibular/efeitos dos fármacos , Glândula Submandibular/imunologia , Receptor 3 Toll-Like/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologia , Regulação para CimaRESUMO
OBJECTIVE: The mechanism underlying the onset and development of autoimmune diseases such as Sjogren's syndrome is not well understood. Here, we examined the effects of preceding inflammation of the salivary gland at the onset of autoimmunity against the salivary gland. MATERIALS AND METHODS: One side of the submandibular gland duct was ligated in mice and the effect on the contralateral gland was investigated. After histological evaluation with hematoxylin and eosin staining, the presence of autoantibodies and immune compounds was examined. RESULTS: In all five strains of mice that were used, the salivary gland of the ligated side showed severe inflammation and atrophic change. In two mouse strains (SJL/J and PL/J), mild sialadenitis was observed on the non-ligated side 8 weeks after ligation. Autoantibodies reacting to the salivary gland were detected in three mouse strains (C3H/He, SJL/J, and PL/J). Immune complex was also detected in the duct basement membrane. CONCLUSION: The results indicate that the autoimmune mechanism is activated by the transient inflammation in the salivary gland under a specific genetic background.
Assuntos
Autoimunidade/imunologia , Sialadenite/imunologia , Glândula Submandibular/imunologia , Animais , Complexo Antígeno-Anticorpo/análise , Atrofia , Autoanticorpos/análise , Membrana Basal/imunologia , Corantes , Complemento C3/análise , Feminino , Fibrose , Corantes Fluorescentes , Imunoglobulina G/análise , Ligadura , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos , Ductos Salivares/imunologia , Glândula Submandibular/patologia , Fatores de TempoRESUMO
Salivary duct carcinoma (SDC) is an uncommon malignant tumor, characterized by aggressive behavior and poor prognosis. SDC usually arises from ductal epithelium of the major salivary glands, and it is quite infrequent elsewhere. We present a rare case of a 73-year-old man with SDC, which is possibly originated from the paranasal sinuses or the lacrimal system. Microscopic evaluation revealed that the tumor cells, with pleomorphic nuclei and abundant eosinophilic cytoplasm, formed cell nests and duct-like structure. A cribriform growth pattern was also seen. Immunohistochemical staining was positive for cytokeratins (CAM 5.2 and 34betaE12), gross cystic disease fluid protein 15 (GCDFP-15), and androgen receptor protein, while p63 and involucrin were negative. The patient already had multiple metastasis of the tumor in the lung at diagnosis, and he could not undergo definitive surgical procedures, because of severe restrictive lung disease. Although SDC in the sinonasal tract is quite rare, SDC should be in the differential diagnosis in these regions, due to its aggressive behavior and poor prognosis.
Assuntos
Carcinoma/secundário , Segunda Neoplasia Primária/patologia , Neoplasias dos Seios Paranasais/patologia , Ductos Salivares/patologia , Neoplasias das Glândulas Salivares/secundário , Idoso , Biomarcadores , Carcinoma/diagnóstico por imagem , Carcinoma/imunologia , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Queratinas/imunologia , Masculino , Segunda Neoplasia Primária/diagnóstico por imagem , Segunda Neoplasia Primária/imunologia , Neoplasias dos Seios Paranasais/diagnóstico por imagem , Neoplasias dos Seios Paranasais/imunologia , Prognóstico , Ductos Salivares/imunologia , Neoplasias das Glândulas Salivares/diagnóstico por imagem , Neoplasias das Glândulas Salivares/imunologia , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: Immunoglobulin A (IgA) is transported across glandular epithelial cells by polymeric immunoglobulin receptor (plgR), with each receptor molecule participating in only one round of transcytosis. Nerve-related stimuli rapidly increase salivary secretion of IgA, while concentrations are increased in the autoimmune disease Sjögren's syndrome. Our aim here was to determine whether autonomic agonists and cytokines present in Sjögren's-affected glands can up-regulate salivary cell plgR expression. METHODS: Cultures of rat parotid acinar cells (PAR C5) and human submandibular gland ductal cells (HSG) were exposed to carbachol or adrenaline for 24 h and to interleukin-4 and/or interferon-gamma for 48 h. The human colonic cell line HT-29 served as a positive control for cytokine response. plgR mRNA was quantified by reverse transcription and real-time PCR and protein expression was examined by immunoblotting. RESULTS: Carbachol increased plgR mRNA levels significantly in all cells but adrenaline did so only with PAR cells (P<0.05). HSG and HT-29 cells both up-regulated plgR gene transcription on exposure to interleukin-4 and interferon-gamma either alone or in combination (P<0.05). By contrast, production of plgR mRNA in PAR cells tended to decrease in response to all cytokine treatments. plgR protein levels rose in line with mRNA expression in cytokine-treated HT-29 cultures (P<0.05). CONCLUSIONS: Autonomimetics can up-regulate plgR transcription in transformed and neoplastic salivary and colonic cells, although intracellular coupling mechanisms require further investigation. Immunomodulatory cytokines increased plgR expression in one of the salivary cell lines, but additional work is needed to establish whether this occurs in Sjögren's patients.
Assuntos
Fármacos do Sistema Nervoso Autônomo/agonistas , Citocinas/farmacologia , Glândula Parótida/efeitos dos fármacos , Receptores de Imunoglobulina Polimérica/efeitos dos fármacos , Síndrome de Sjogren/imunologia , Glândula Submandibular/efeitos dos fármacos , Agonistas Adrenérgicos/farmacologia , Animais , Carbacol/farmacologia , Linhagem Celular , Agonistas Colinérgicos/farmacologia , Epinefrina/farmacologia , Células HT29 , Humanos , Interferon gama/farmacologia , Interleucina-4/farmacologia , Glândula Parótida/citologia , Glândula Parótida/imunologia , RNA Mensageiro/análise , Ratos , Receptores de Imunoglobulina Polimérica/análise , Ductos Salivares/citologia , Ductos Salivares/efeitos dos fármacos , Ductos Salivares/imunologia , Glândula Submandibular/citologia , Glândula Submandibular/imunologia , Fatores de Tempo , Transcrição Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
Transduction of salivary glands with antimicrobial peptide genes has great potential for oral infection control. Our ultimate goal is to introduce antimicrobial peptide genes into salivary glands that secrete these peptides into saliva to control bacterial/fungal infection in the oral cavity. However, an animal study model to test this potential has not been established. Therefore, we determined to test (i) whether the potent antimicrobial peptide human beta-defensin-2 (hBD-2) can be overexpressed in saliva after transduction of salivary glands and (ii) whether oral fungal infection can be developed in a NOD/SCID murine model. Lentiviral vector SIN18cPPTRhMLV bearing hBD-2 cDNA was introduced into SCID mouse submandibular glands via cannulation. Reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry or enzyme-linked immunosorbent assay (ELISA) were performed to detect hBD-2 expression in glands or in saliva. Candida albicans 613p was inoculated orally into SCID mice to establish oral candidiasis. Whilst expression of hBD-2 was detected in mouse salivary glands by RT-PCR and immunohistochemistry 1 day or 1 week following delivery of lentivirus, hBD-2 was not detected in saliva. There was recoverable C. albicans from the oral cavity and gastrointestinal tract 4 days to 4 weeks after infection, but there was no establishment of observable oral candidiasis in SCID mice under a stereomicroscope. Our data indicate that lentiviral vectors transduce mouse salivary glands, but not at a sufficient level to allow hBD-2 detection in saliva. Other vectors for gene transduction and additional treatment of SCID mice to establish oral candidiasis are needed in order to utilise mouse salivary glands to test antimicrobial gene therapy.
Assuntos
Anti-Infecciosos/farmacologia , Candida albicans/efeitos dos fármacos , Retroviridae/efeitos dos fármacos , Saliva/metabolismo , Ductos Salivares/metabolismo , beta-Defensinas/farmacologia , Animais , Anti-Infecciosos/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Regulação da Expressão Gênica/fisiologia , Terapia Genética , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mucosa Bucal/metabolismo , Retroviridae/genética , Saliva/química , Ductos Salivares/química , Ductos Salivares/imunologia , Ductos Salivares/patologia , beta-Defensinas/genética , beta-Defensinas/uso terapêuticoRESUMO
The parotid duct transports saliva from the gland into the oral cavity. However, its immune response properties, along with the secretion and moistening principles of the duct, have not yet been fully investigated. These properties may play an important role in protecting the parotid gland from infection and also prevent development of sialodocholithiasis, as the parotid duct -- in contrast to the submandibular salivary duct -- is often free of duct concrements. Up to now, only the parotid gland has been investigated, without regard to its duct. The present study analyses the structures of the parotid duct in their relations to antimicrobial defence mechanisms and rheological properties. Investigations were performed on 23 parotid ducts using histological, histochemical and immunohistochemical methods. Epithelial and goblet cells of the parotid duct synthesize a complex mucous layer that covers the epithelium. The viscosity is influenced by secreted mucins and TFF peptides. This layer contains carbohydrates including N-acetyl-glucosamine, N-acetyl-galactosamine, galactose, mannose, fucose and sialic acids. The lamina propria contains granulocytes, T lymphocytes and macrophages. IgA, produced by plasma cells in the subepithelial layer, is frequently integrated in the secretory product. Synthesized mucins, TFF peptides, carbohydrates and immunoglobulins form a complex layer that can be expected to prohibit infection and enables salivary flow. Our study demonstrates that the steady secretion of the parotid gland, together with the ductal cellular and biochemical immune protection system, is likely to thwart ascending infections in the parotid duct and gland.
Assuntos
Glândula Parótida/imunologia , Parotidite/imunologia , Ductos Salivares/imunologia , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/análise , Biomarcadores/análise , Feminino , Células Caliciformes/imunologia , Histocitoquímica/métodos , Humanos , Imunoglobulina A/análise , Imunoglobulina G/análise , Imuno-Histoquímica/métodos , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Mucina-1 , Mucinas/análise , Neutrófilos/imunologia , Glândula Parótida/anatomia & histologia , Peptídeos/análise , Ductos Salivares/anatomia & histologia , Fator Trefoil-3RESUMO
A case of chronic graft-versus-host disease (chronic GvHD) mimicking symptoms associated with idiopathic Sjögren's syndrome is presented. Hypotheses on the pathophysiological origin of clinical syndromes associated with graft-versus-host disease are discussed.
Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Autoanticorpos/classificação , Doenças Autoimunes/imunologia , Transplante de Medula Óssea/imunologia , Quimerismo , Diagnóstico Diferencial , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Humanos , Aparelho Lacrimal/imunologia , Aparelho Lacrimal/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ductos Salivares/imunologia , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/fisiopatologia , Sialadenite/imunologia , Síndrome de Sjogren/diagnósticoRESUMO
OBJECTIVE: To study the expression of laminin and type IV collagen as biomarkers of the organisation of the basal lamina of acini and ducts in labial salivary glands from patients with Sjögren's syndrome, and to relate this organisation to inflammatory cell invasion of acini and ducts. METHODS: Immunohistochemistry for laminin and type IV collagen was undertaken on sections of labial salivary glands from 30 patients with Sjögren's syndrome, 10 control subjects, and 24 controls with chronic sialoadenitis. Immunohistochemistry reaction, alterations to cell morphology, and the presence of inflammatory cells in acini and ducts were evaluated and scored using a semiquantitative method. RESULTS: Changes in the expression of laminin and type IV collagen in the basal lamina of acini and ducts of labial salivary glands from patients with Sjögren's syndrome were more pronounced than in labial salivary glands from control groups. A remarkable characteristic was the disorganisation of the basal lamina in the labial salivary glands in Sjögren's syndrome. The pattern of immunoreactivity of the basal lamina of other structures (for example, blood vessels) did not change. In Sjögren's syndrome, invasion of cytotoxic T lymphocytes was only observed in acini and ducts which had a disorganised basal lamina. CONCLUSIONS: The high state of disorganisation of the basal lamina of acini and ducts could allow invasion of cytotoxic T lymphocytes in Sjögren's syndrome, contributing to cell death and ductal hyperplasia.
Assuntos
Membrana Basal/patologia , Lábio , Glândulas Salivares Menores/patologia , Síndrome de Sjogren/patologia , Adulto , Membrana Basal/imunologia , Biomarcadores/análise , Estudos de Casos e Controles , Doença Crônica , Colágeno Tipo IV/análise , Feminino , Humanos , Imuno-Histoquímica/métodos , Laminina/análise , Masculino , Pessoa de Meia-Idade , Ductos Salivares/imunologia , Ductos Salivares/patologia , Glândulas Salivares Menores/imunologia , Sialadenite/imunologia , Sialadenite/patologia , Síndrome de Sjogren/imunologia , Linfócitos T Citotóxicos/imunologiaRESUMO
The purpose of this study was to evaluate morphologically the tongue of individuals with chronic Chagas disease (CD) in comparison to the non-chagasic ones. Twenty-four protocol cases of autopsies were selected. They were subdivided into CD patients (10 cases) and non-chagasic ones (14 cases). The morphometric analysis was accomplished for the tongue muscle and salivary glands duct lumen area. In three CD patients, perineuritis was found, and two of them showed megaesophagus and megacolon. The intensity of the inflammation in the von Ebner's glands, the tongue muscles, and the salivary glands duct lumen area was significantly higher in the CD patients. We concluded that the CD patients show salivary glands duct dilatation, which probably would have a relation with alterations in the autonomic nervous system. The inflammation found in CD patients is in accordance with that described in comparative studies on the digestive tract and heart. These morphological findings suggest that the histopathological analysis of the tongue associated with other organs, or even in an isolated manner, can add in the diagnosis and pathogenesis of the CD chronic phase.