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1.
Arthritis Rheumatol ; 73(7): 1189-1199, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33452867

RESUMO

OBJECTIVE: We undertook this study to evaluate the activation and functional relevance of inflammasome pathways in ankylosing spondylitis (AS) patients and rodent models and their relationship to dysbiosis. METHODS: An inflammasome pathway was evaluated in the gut and peripheral blood from 40 AS patients using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), flow cytometry, and confocal microscopy, and was compared to that of 20 healthy controls and 10 patients with Crohn's disease. Bacteria was visualized using silver stain in human samples, and antibiotics were administered to HLA-B27-transgenic rats. The NLRP3 inhibitor MCC950 was administered to SKG mice, and ileal and joint tissues were assessed by IHC analysis and real-time qRT-PCR. The role of inflammasome in modulating the interleukin-23 (IL-23)/IL-17 axis was studied ex vivo. RESULTS: Expression levels of Nlrp3, Nlrc4, and Aim2 were increased in the gut of HLA-B27-transgenic rats and reduced by antibiotic treatment (P < 0.05). In curdlan-treated SKG mice, NLRP3 blockade prevented ileitis and delayed arthritis onset (P < 0.05). Compared to healthy controls, AS patients demonstrated overexpression of NLRP3 (fold induction 2.33 versus 22.2; P < 0.001), NLRC4 (fold induction 1.90 versus 6.47; P < 0.001), AIM2 (fold induction 2.40 versus 20.8; P < 0.001), CASP1 (fold induction 2.53 versus 24.8; P < 0.001), IL1B (fold induction 1.07 versus 10.93; P < 0.001), and IL18 (fold induction 2.56 versus 15.67; P < 0.001) in the ileum, and caspase 1 activity was increased (P < 0.01). The score of adherent and invasive mucosa-associated bacteria was higher in AS (P < 0.01) and correlated with the expression of inflammasome components in peripheral blood mononuclear cells (P < 0.001). NLRP3 expression was associated with disease activity (the Ankylosing Spondylitis Disease Activity Score using the C-reactive protein level) (r2 = 0.28, P < 0.01) and with IL23A expression (r2 = 0.34, P < 0.001). In vitro, inflammasome activation in AS monocytes was paralleled by increased serum levels of IL-1ß and IL-18. Induction of IL23A, IL17A, and IL22 was IL-1ß-dependent. CONCLUSION: Inflammasome activation occurs in rodent models of AS and in AS patients, is associated with dysbiosis, and is involved in triggering ileitis in SKG mice. Inflammasomes drive type III cytokine production with an IL-1ß-dependent mechanism in AS patients.


Assuntos
Doença de Crohn/imunologia , Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Íleo/imunologia , Inflamassomos/imunologia , Articulações/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Espondilite Anquilosante/imunologia , Adolescente , Adulto , Animais , Antibacterianos/farmacologia , Proteínas Adaptadoras de Sinalização CARD/imunologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/imunologia , Proteínas de Ligação ao Cálcio/metabolismo , Estudos de Casos e Controles , Caspase 1/imunologia , Caspase 1/metabolismo , Doença de Crohn/microbiologia , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Furanos/farmacologia , Antígeno HLA-B27/genética , Humanos , Ileíte/imunologia , Ileíte/metabolismo , Ileíte/patologia , Íleo/efeitos dos fármacos , Íleo/metabolismo , Íleo/patologia , Imuno-Histoquímica , Indenos/farmacologia , Interleucina-17/imunologia , Interleucina-18/imunologia , Interleucina-18/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-23/imunologia , Articulações/efeitos dos fármacos , Articulações/metabolismo , Articulações/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Ratos Transgênicos , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espondilite Anquilosante/microbiologia , Sulfonamidas/farmacologia , Adulto Jovem
3.
Ann Surg Oncol ; 28(2): 1167-1177, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32761330

RESUMO

BACKGROUND: Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer. PATIENTS AND METHODS: In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability. RESULTS: We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status. CONCLUSIONS: Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.


Assuntos
Adenocarcinoma , Neoplasias Colorretais , Adenocarcinoma/genética , Reparo de Erro de Pareamento de DNA/genética , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Prognóstico
4.
Rheumatology (Oxford) ; 60(1): 92-102, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-32442267

RESUMO

OBJECTIVES: Gut microbiota has been widely reported to be involved in systemic inflammation through microbial translocation and T cell activation in several diseases. In this work we aimed to investigate bacterial infiltration and epithelial impairment in the gut of patients with IBD-associated SpA (SpA-IBD), as well as the relationship of microbial translocation with immune system activation and their putative role in the pathogenesis of joint inflammation in IBD patients. METHODS: Tight-junction proteins (TJPs) occludin and claudin-1/-4 and bacteria were assessed by real-time PCR analysis and immunohistochemical staining of the ileum. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharides (LPS), soluble CD14 (sCD14), sclerostin and anti-sclerostin antibodies (anti-sclerostin-IgG) were assayed with ELISAs and peripheral mononuclear blood cells with flow cytometry. LPS and sCD14 were used in vitro to stimulate a human osteoblast cell line. RESULTS: Compared with IBD, ileal samples from SpA-IBD patients showed bacterial infiltration, epithelial damage and downregulation of TJPs. In sera, they showed higher serum levels of I-FABP, LPS, sCD14 (the latter correlating with sclerostin and anti-sclerostin-IgG) and higher CD80+/CD163+ and lower CD14+ mononuclear cells. In vitro experiments demonstrated that only the LPS and sCD14 synergic action downregulates sclerostin expression in osteoblast cells. CONCLUSION: SpA-IBD patients are characterized by gut epithelium impairment with consequent translocation of microbial products into the bloodstream, immune system activation and an increase of specific soluble biomarkers. These findings suggest that gut dysbiosis could be involved in the pathogenesis of SpA-IBD and it could hopefully prompt the use of these biomarkers in the follow-up and management of IBD patients.


Assuntos
Translocação Bacteriana , Íleo/imunologia , Doenças Inflamatórias Intestinais/complicações , Mucosa Intestinal/imunologia , Espondilartrite/microbiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos de Coortes , Proteínas de Ligação a Ácido Graxo/sangue , Humanos , Íleo/metabolismo , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Mucosa Intestinal/metabolismo , Receptores de Lipopolissacarídeos/sangue , Lipopolissacarídeos/sangue , Monócitos/metabolismo , Osteoblastos/metabolismo , Espondilartrite/sangue , Espondilartrite/imunologia
5.
Nat Commun ; 11(1): 1995, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332732

RESUMO

Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.


Assuntos
Artrite Reumatoide/prevenção & controle , Permeabilidade da Membrana Celular/efeitos dos fármacos , Disbiose/complicações , Haptoglobinas/antagonistas & inibidores , Mucosa Intestinal/efeitos dos fármacos , Oligopeptídeos/administração & dosagem , Precursores de Proteínas/antagonistas & inibidores , Adulto , Animais , Artrite Experimental/sangue , Artrite Experimental/imunologia , Artrite Experimental/microbiologia , Artrite Experimental/prevenção & controle , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Artrite Reumatoide/microbiologia , Translocação Bacteriana/efeitos dos fármacos , Translocação Bacteriana/imunologia , Células CACO-2 , Permeabilidade da Membrana Celular/imunologia , Estudos de Coortes , Estudos Transversais , Disbiose/imunologia , Disbiose/microbiologia , Feminino , Microbioma Gastrointestinal/imunologia , Haptoglobinas/metabolismo , Voluntários Saudáveis , Humanos , Íleo/citologia , Íleo/efeitos dos fármacos , Íleo/microbiologia , Íleo/patologia , Mucosa Intestinal/citologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Precursores de Proteínas/sangue , Precursores de Proteínas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo
7.
Mod Pathol ; 33(7): 1398-1409, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32066859

RESUMO

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1+ immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1+ cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.


Assuntos
Adenocarcinoma/patologia , Antígeno B7-H1/metabolismo , Neoplasias Intestinais/patologia , Intestino Delgado/patologia , Adenocarcinoma/etiologia , Adenocarcinoma/imunologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Doença Celíaca/complicações , Doença de Crohn/complicações , Feminino , Humanos , Neoplasias Intestinais/etiologia , Neoplasias Intestinais/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estudos Retrospectivos
8.
Clin J Gastroenterol ; 13(3): 377-381, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31728918

RESUMO

JC virus is a member of the Polyomavirus family, infects humans worldwide, and 90% of the population carry antibodies to the virus by adult life. The initial infection is asymptomatic, but it may become persistent. JC virus DNA is frequently present in the upper and lower gastrointestinal tracts of healthy adults. Chronic idiopathic intestinal pseudo-obstruction, one of the most severe gastrointestinal motility disorders, is a condition characterized by a clinical picture mimicking small bowel occlusion with related symptoms and signs in the absence of demonstrable mechanical obstruction. Because of the known neuropathic capability of this virus, and its frequent presence in the gut, it has been proposed that JCV might be detectable in tissues of patients with chronic idiopathic intestinal pseudo-obstruction, and possibly be involved in the pathogenesis of this disease, because the virus may actively infect the enteroglial cells of the myenteric plexuses of the patients with chronic idiopathic intestinal pseudo-obstruction. We report two cases of upper idiopathic intestinal pseudo-obstruction associated with JCV infection.


Assuntos
Duodenopatias/etiologia , Pseudo-Obstrução Intestinal/etiologia , Vírus JC , Infecções por Polyomavirus/complicações , Infecções Tumorais por Vírus/complicações , Duodenopatias/diagnóstico , Duodenopatias/patologia , Duodenopatias/virologia , Duodenoscopia , Feminino , Humanos , Pseudo-Obstrução Intestinal/diagnóstico , Pseudo-Obstrução Intestinal/patologia , Pseudo-Obstrução Intestinal/virologia , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/virologia , Infecções Tumorais por Vírus/virologia
9.
J Crohns Colitis ; 14(3): 295-302, 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-31418007

RESUMO

BACKGROUND AND AIMS: Crohn's disease-associated small bowel carcinoma is a rare event, usually reported to have a severe prognosis. However, in previous investigations we have found a minority of cases displaying a relatively favourable behaviour, thus outlining the need to improve the histopathological prediction of Crohn's disease-associated small bowel carcinoma prognosis. METHODS: As in recent studies on colorectal cancer, a substantial improvement in prognostic evaluations has been provided by the histological analysis of the tumour invasive front; we therefore systematically analysed the tumour budding and poorly differentiated clusters in the invasive front of 47 Crohn's disease-associated small bowel carcinomas collected through the Small Bowel Cancer Italian Consortium. RESULTS: Both tumour budding and poorly differentiated cluster analyses proved highly effective in prognostic evaluation of Crohn's disease-associated small bowel carcinomas. In addition, they retained prognostic value when combined with two other parameters, i.e. glandular histology and stage I/II, both known to predict a relatively favourable small bowel carcinoma behaviour. In particular, association of tumour budding and poorly differentiated clusters in a combined invasive front score allowed identification of a minor subset of cancers [12/47, 25%] characterised by combined invasive front low grade coupled with a glandular histology and a low stage [I or II] and showing no cancer-related death during a median follow-up of 73.5 months. CONCLUSIONS: The improved distinction of lower- from higher-grade Crohn's disease-associated small bowel carcinomas provided by invasive front analysis should be of potential help in choosing appropriate therapy for these rare and frequently ominous neoplasms.


Assuntos
Adenocarcinoma , Doença de Crohn , Neoplasias Intestinais , Intestino Delgado/patologia , Gradação de Tumores/métodos , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Doença de Crohn/diagnóstico , Doença de Crohn/epidemiologia , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Intestinais/epidemiologia , Neoplasias Intestinais/patologia , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Seleção de Pacientes , Prevalência , Prognóstico , Estudos Retrospectivos
10.
Oncogene ; 39(5): 987-1003, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31591478

RESUMO

Despite intense research and clinical efforts, patients affected by advanced colorectal cancer (CRC) have still a poor prognosis. The discovery of colorectal (CR) cancer stem cell (CSC) as the cell compartment responsible for tumor initiation and propagation may provide new opportunities for the development of new therapeutic strategies. Given the reduced sensitivity of CR-CSCs to chemotherapy and the ability of bone morphogenetic proteins (BMP) to promote colonic stem cell differentiation, we aimed to investigate whether an enhanced variant of BMP7 (BMP7v) could sensitize to chemotherapy-resistant CRC cells and tumors. Thirty-five primary human cultures enriched in CR-CSCs, including four from chemoresistant metastatic lesions, were used for in vitro studies and to generate CR-CSC-based mouse avatars to evaluate tumor growth and progression upon treatment with BMP7v alone or in combination with standard therapy or PI3K inhibitors. BMP7v treatment promotes CR-CSC differentiation and recapitulates the cell differentiation-related gene expression profile by suppressing Wnt pathway activity and reducing mesenchymal traits and survival of CR-CSCs. Moreover, in CR-CSC-based mouse avatars, BMP7v exerts an antiangiogenic effect and sensitizes tumor cells to standard chemotherapy regardless of the mutational, MSI, and CMS profiles. Of note, tumor harboring PIK3CA mutations were affected to a lower extent by the combination of BMP7v and chemotherapy. However, the addition of a PI3K inhibitor to the BMP7v-based combination potentiates PIK3CA-mutant tumor drug response and reduces the metastatic lesion size. These data suggest that BMP7v treatment may represent a useful antiangiogenic and prodifferentiation agent, which renders CSCs sensitive to both standard and targeted therapies.


Assuntos
Proteína Morfogenética Óssea 7/genética , Proteína Morfogenética Óssea 7/farmacologia , Neoplasias Colorretais/patologia , Mutação , Animais , Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Humanos , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cancer Immunol Res ; 7(5): 841-852, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30940644

RESUMO

Immune checkpoint blockade therapy has changed prognoses for many melanoma patients. However, immune responses that correlate with clinical progression of the disease are still poorly understood. To identify immune responses correlating with melanoma clinical evolution, we analyzed serum cytokines as well as circulating NK and T-cell subpopulations from melanoma patients. The patients' immune profiles suggested that melanoma progression leads to changes in peripheral blood NK and T-cell subsets. Stage IV melanoma was characterized by an increased frequency of CCR7+CD56bright NK cells as well as high serum concentrations of the CCR7 ligand CCL19. CCR7 expression and CCL19 secretion were also observed in melanoma cell lines. The CCR7+ melanoma cell subpopulation coexpressed PD-L1 and Galectin-9 and had stemness properties. Analysis of melanoma-derived cancer stem cells (CSC) showed high CCR7 expression; these CSCs were efficiently recognized and killed by NK cells. An accumulation of CCR7+, PD-L1+, and Galectin-9+ melanoma cells in melanoma metastases was demonstrated ex vivo Altogether, our data identify biomarkers that may mark a CCR7-driven metastatic melanoma pathway.


Assuntos
Células Matadoras Naturais/imunologia , Melanoma/imunologia , Antígeno B7-H1/imunologia , Linhagem Celular , Quimiocina CCL19/imunologia , Técnicas de Cocultura , Citocinas/sangue , Feminino , Galectinas/imunologia , Humanos , Masculino , Melanoma/sangue , Melanoma/patologia , Células-Tronco Neoplásicas/imunologia , Receptores CCR7/imunologia
13.
Oncotarget ; 9(78): 34699-34707, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30410670

RESUMO

Background: Cerebral Amyloid Angiopathy has been indicated as an important cause of spontaneous non-hypertensive intracerebral haemorrhage (ICH). Aims: to analyze the presence of ß-amyloid deposit in the temporal artery of consecutive patients with ICH in comparison to control subjects and its relation to APO-E haplotype frequency. Methods: We enrolled consecutive patients admitted to Neurosurgery Ward of University Hospital "P. Giaccone" of Palermo with a diagnosis of spontaneous non hypertensive ICH and as control 12 subjects without brain haemorrhage. Biopsy of superficial temporal artery has been performed and ß-amyloid deposit was quantified. Results: Among 25 subjects with ICH, 10 (40%) had APOE epsilon 2 allele and among these subjects 7 (70%) showed amyloid accumulation on temporal artery specimens, 8 (32%) subjects had APOE epsilon 3 allele and among these subjects only 2 (25%) showed amyloid accumulation on temporal artery specimens, whereas 7 (28%) had APOE epsilon 4 allele and of these, 7 (100%) showed amyloid accumulation on temporal artery specimens. At multivariable logistic regression analysis for the presence of amyloid, predictive factors for the presence of amyloid in temporal artery biopsies were: age, hypertension, intralobar site of haemorrhage, APOE epsilon 2 and APOE epsilon 4 alleles. Discussion: Our findings of a higher frequency of amyloid deposition in temporal artery specimens in subjects with spontaneous intracerebral haemorrhage indicate a possible role of temporal artery as a possible diagnostic site of biopsy in subjects at high risk to develop intracranial haemorrhage related to Cerebral Amyloid Angiopathy.

14.
Arthritis Rheumatol ; 70(12): 2003-2013, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29869839

RESUMO

OBJECTIVE: Gut-derived innate lymphoid cell 3 (ILC3) has been shown to participate in the pathogenesis of ankylosing spondylitis (AS). CX3 CR1+ mononuclear phagocytes (MNPs) have been demonstrated to modulate ILC3 function in the gut. This study was undertaken to investigate the role of proinflammatory CX3 CR1+CD59+ MNPs in modulating ILC3 function in AS patients. METHODS: MNP subsets in the blood of AS patients and controls were analyzed by flow cytometry. The presence of CX3 CR1+CD59+ cells in tissue was confirmed by confocal microscopy. Expression of the proinflammatory chemokines CX3 CL1 and CCL2 and decoy receptor 6 (DcR-6) was analyzed. Peripheral CX3 CR1+CD59+ cells were cocultured with ILC3, and changes in their frequency were evaluated by flow cytometry. Transcriptome analysis of circulating CX3 CR1+ monocytes was also performed. RESULTS: DcR-6 deficiency and CCL2 overexpression were observed in inflamed tissues from AS patients. In the gut, the proinflammatory CX3 CR1+CD59+ MNP population was expanded, correlated with the presence of bacteria, and produced high levels of tumor necrosis factor-like molecule 1A (TL1A) and interleukin-23 (IL-23). MNPs positive for CD11b, CD11c, and major histocompatibility complex class II, predominantly expressing CX3 CR1, were also expanded in the small intestines of treatment-naive SKG relative to BALB/c mice. The frequency of gut-derived CX3 CR1+CD59+CCR9+TL1A+IL-23+ MNPs was significantly higher in the peripheral blood and synovial fluid of AS patients than controls. CCR9+CX3 CR1+CD59+ monocytes were also expanded in AS synovial and bone marrow samples. Transcriptome analysis of isolated CX3 CR1+CD59+ monocytes demonstrated a specific proinflammatory profile in AS. Isolated proinflammatory CX3 CR1+CD59+ MNPs from AS patients induced the expansion and activation of ILC3. CONCLUSION: Proinflammatory CX3 CR1+CD59+TL1A+IL-23+ MNPs are expanded in AS patients and display a specific proinflammatory transcriptome profile. Given the ability of these cells to support ILC3 expansion, they may promote a sustained proinflammatory status in AS.


Assuntos
Imunidade Inata , Linfócitos/imunologia , Monócitos/imunologia , Sistema Fagocitário Mononuclear/imunologia , Espondilite Anquilosante/imunologia , Adulto , Antígenos CD59/imunologia , Receptor 1 de Quimiocina CX3C/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Interleucina-23/imunologia , Masculino , Pessoa de Meia-Idade , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia
15.
Front Med (Lausanne) ; 5: 63, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29780803

RESUMO

Subclinical gut inflammation occurring in patients affected by spondyloarthritis (SpA) is correlated with the severity of spine inflammation. Several evidences indicate that dysbiosis occurs in SpA, and that may modulate intestinal permeability and intestinal immune responses. The presence of intestinal dysbiosis is accompanied in SpA patients with the presence of zonulin-dependent alterations of gut-epithelial and gut-vascular barriers. The leakage of epithelial and endothelial surface layers is followed by the translocation of bacterial products, such as lipopolysaccharide and intestinal fatty acid binding protein, in the systemic circulation. These bacterial products may downregulate the expression of CD14 on circulating monocytes leading to an "anergic" phenotype. In the gut, IL-23 may induce the expansion of innate immune cells such as mucosal-associated invariant T cells, γδ T cells, and innate lymphoid cells of group 3 that through the interaction with MAdCAM1 may recirculate form the gut to the sites of SpA active inflammation. On the basis of these findings, gut inflammation observed in SpA patient seems to be not only an epiphenomenon of the on going systemic inflammatory process but may also represent the base camp in which inflammatory cells are activated and from whom they shuttle.

17.
Rheumatology (Oxford) ; 57(8): 1377-1380, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29697809

RESUMO

Objective: To evaluate whether CD3 staining performed routinely on temporal artery biopsy specimens might improve the sensitivity of temporal artery biopsy in patients with biopsy-negative GCA. Methods: Two hundred and seventy biopsies were considered for this study, stained with haematoxylin and eosin and with an anti-CD3 antibody. Results: The addition of CD3 staining modified the sensibility and the specificity of the histologic examination in 89.47 and 95.00%, respectively, with a positive and negative predictive values of 97.00 and 79.78% . Conclusion: The addition of CD3 immunostaining to the classic histologic evaluation is accompanied by a significant increase in the sensibility with a comparable specificity.


Assuntos
Complexo CD3/metabolismo , Arterite de Células Gigantes/diagnóstico , Imuno-Histoquímica/métodos , Artérias Temporais/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Biópsia , Complexo CD3/imunologia , Feminino , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fotomicrografia , Curva ROC , Estudos Retrospectivos , Artérias Temporais/metabolismo
18.
Arthritis Rheumatol ; 70(8): 1265-1275, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29569854

RESUMO

OBJECTIVE: To investigate the role of the interleukin-25 (IL-25)/IL-17 receptor B (IL-17RB) axis in experimental Sjögren's syndrome (SS) and in patients with primary SS and primary SS-associated lymphoma. METHODS: Expression of IL-25, IL-17RB, IL-17B, and tumor necrosis factor receptor-associated factor 6 (TRAF6) was analyzed on minor salivary gland (SG) samples from patients with primary SS and on parotid gland samples from patients with primary SS-associated B cell non-Hodgkin's lymphoma (NHL). IL-17RB expression and the frequencies of natural group 2 innate lymphoid cells (ILC2s), inflammatory ILC2s, and M2-polarized macrophages were assessed by flow cytometry in SG mononuclear cells and peripheral blood mononuclear cells (PBMCs). Tissue distribution of ILC2s was studied by confocal microscopy. The role of recombinant IL-25 and of rituximab in modulating IL-25 expression was investigated in in vitro studies. IL-25/IL-17RB and TRAF6 expression and the role of IL-25 inhibition were also studied in the experimental murine model of SS. RESULTS: Activation of the IL-25/IL-17RB/TRAF6 axis correlated with the focus score and was observed in patients with primary SS and in patients with primary SS-associated NHL. A significant increase in the frequency of inflammatory ILC2s was observed both in SG mononuclear cells and in PBMCs. IL-25 stimulation of isolated SG mononuclear cells and PBMCs from patients and controls resulted both in inflammatory ILC2 expansion and in increased autoantibody production. Rituximab modulated expression of inflammatory ILC2s and IL-25 in primary SS. SG protein-immunized mice developed overt SS symptoms with increased IL-25 expression and increased frequency of CD4+IL-17RB+TRAF6+ cells. IL-25 neutralization attenuated disease progression and tissue pathology in mice with experimental SS. CONCLUSION: IL-25 may promote the inflammatory state in primary SS and may be a potential target for novel disease-modifying therapeutic strategies in patients with primary SS.


Assuntos
Interleucina-17/metabolismo , Linfoma/imunologia , Receptores de Interleucina-17/metabolismo , Síndrome de Sjogren/imunologia , Idoso , Animais , Feminino , Humanos , Imunidade Inata , Leucócitos Mononucleares/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Glândulas Salivares/imunologia
20.
Rheumatology (Oxford) ; 57(1): 64-72, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28968695

RESUMO

Objectives: GCA is characterized by arterial remodelling driven by inflammation. IL-22 is an attractive cytokine which acts at the crosstalk between immune and stromal cells. We hypothesized that IL-22 might be induced in GCA and might be involved in disease pathogenesis. Methods: Patients subjected to temporal artery biopsies (TABs) naïve from therapy were enrolled: 27 biopsy-proven GCA, 8 biopsy-negative GCA, 21 biopsy-negative non-GCA patients. Expression of IL-22 was determined in TABs by immunohystochemistry, in plasma by ELISA, in peripheral blood mononuclear cells by real-time PCR and flow cytometry. Effects of IL-22 on viability and gene expression of primary cultures obtained from TABs were also evaluated. Results: Inflamed TABs from GCA patients showed a higher expression of IL-22 and IL-22 specific receptor subunit (IL-22R1) than non-inflamed TABs. IL-22 was expressed in infiltrating immune cells and spindle shaped cells, IL-22R1 was expressed in endothelial cells. Patients with biopsy-proven GCA showed increased levels of IL-22 in plasma than patients with biopsy-negative GCA, without GCA and healthy subjects. Peripheral blood mononuclear cells from GCA patients expressed higher IL-22 transcript than healthy subjects. After stimulation in vitro with phorbol 12-myristate 13-acetate and ionomycin, the frequencies of Th22 and IL-22+ CD4+ lymphocytes were similar between patients with and without GCA. Treatment with IL-22 of primary cultures obtained from TABs increased cell viability under stress conditions and expression of B-cell activating factor. Conclusion: IL-22 is increased in patients with GCA and affects viability and gene expression of arterial cells, supporting a potential role in disease pathogenesis.


Assuntos
Arterite de Células Gigantes/metabolismo , Interleucinas/metabolismo , Artérias Temporais/metabolismo , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos , Ionóforos de Cálcio/farmacologia , Carcinógenos/farmacologia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Arterite de Células Gigantes/genética , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Interleucinas/sangue , Interleucinas/genética , Ionomicina/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Acetato de Tetradecanoilforbol/farmacologia
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