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1.
Medicine (Baltimore) ; 99(44): e22894, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126341

RESUMO

BACKGROUND: Positioning infliximab (IFX), cyclosporine and tacrolimus (TAC) for treating ulcerative colitis (UC) is in great debate. METHODS: A literature search identified studies that investigated IFX vs. cyclosporine or IFX vs TAC in UC patients. Short-term remission, short-term, 1-year and 3-year colectomy rate were employed as primary end-points to assess efficacy. Odds ratios (ORs) with 95% confidence intervals (CIs) were analyzed. RESULTS: Overall, 15 studies comprised 596 patients in IFX group and 866 in calcineurin inhibitors group (644 received cyclosporine and 222 received TAC). No significant difference was seen between IFX and calcineurin inhibitors with regard to short-term remission. IFX led to a lower short-term (OR: 0.59, 95% CI: 0.43-0.82, P:.001), 1-year (OR: 0.53, 95% CI: 0.38-0.73, P < .001), 3-year colectomy (OR: 0.41, 95% CI: 0.20-0.84, P:.02) than calcineurin inhibitors. IFX led to a lower short-term (OR: 0.51, 95% CI: 0.36-0.71, P < .001), 1-year (OR: 0.53, 95% CI: 0.37-0.74, P:.003) colectomy and a trend of lower 3-year colectomy (OR: 0.49, 95% CI: 0.22-1.06, P:.07) than cyclosporine while no significant difference was seen between IFX and TAC. Results of network meta-analysis showed that the order was cyclosporine, TAC and IFX from high rate to low with regard to short-term and 1-year colectomy. CONCLUSION: IFX treatment leads to a lower short-term, 1-year colectomy rate and a trend of lower 3-year colectomy rate in UC patients than cyclosporine while no significant difference is seen between IFX and TAC. TAC may be superior than cyclosporine with regard to efficacy based on indirect comparisons. Randomized trials with fixed protocol are warranted to identify the optimal medical strategy in patients with UC.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Ciclosporina/farmacologia , Infliximab/farmacologia , Tacrolimo/farmacologia , Colectomia/estatística & dados numéricos , Colite Ulcerativa/imunologia , Colite Ulcerativa/cirurgia , Humanos , Imunossupressores/farmacologia , Indução de Remissão/métodos , Resultado do Tratamento
3.
Medicine (Baltimore) ; 99(35): e21997, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871953

RESUMO

BACKGROUND: Ulcerative colitis (UC) was a type of inflammatory bowel diseases, which was difficult to cure and even would malignant turn into colon cancer. The specific etiology and molecular mechanism of UC were unclear to date. The purpose of this study was to search for new targets for the diagnosis and treatment of UC. METHODS: Firstly, we downloaded the gene expression data of UC from the gene expression omnibus database database (GSE107499), and used multiple bioinformatics methods to find differently expressed genes (DEGs) in UC. Subsequently, we evaluated the lymphocyte infiltration in UC inflamed colon tissue by using the cell type identification by estimating relative subset of known RNA transcripts method. RESULTS: We obtained 1175 DEGs and 8 hub genes (IL6, TNF, PTPRC, CXCL8, FN1, CD44, IL1B, and MMP9) in this study. Among them, 903 DEGs were up-regulated and 272 DEGs were down-regulated. Compared with non-inflamed colon tissues, the inflamed colon tissues had higher levels of memory B cells, activated memory CD4 T cells, follicular helper T cells, M1 macrophages, resting dendritic cells, activated dendritic cells, activated mast cells, and neutrophils, whereas the proportions of plasma cells, resting memory CD4 T cells, gamma delta T cells, activated NK cells, M2 macrophages and resting mast cells were relatively lower. CONCLUSIONS: The DEGs, hub genes and different lymphatic infiltration conditions can provide new targets for diagnosis and treatment of UC. However, these were just predictions through some theoretical methods, and more basic experiments will be needed to prove in the future.


Assuntos
Colite Ulcerativa/metabolismo , Linfócitos/fisiologia , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Biologia Computacional , Humanos , Mapas de Interação de Proteínas , Transcriptoma
4.
J Environ Pathol Toxicol Oncol ; 39(3): 235-245, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865915

RESUMO

Ulcerative colitis (UC) is an intractable ailment, in which may chronic inflammations/ulcerations may develop in the mucosal lining of the colon with multiple recurrences. Various drugs such as steroids, immunosuppressants, and antibiotics are extensively used to treat UC. The patients suffer from adverse effects of these advanced drugs. So, they need a harmless therapeutic agent from natural sources. The therapeutic D-carvone has an anti-inflammatory action against the investigational colon cancer models. Therefore, we analyzed the effect of D-carvone on dextran sulfate sodium (DSS) provoked colitis model in mice as follows: Group I: noncolitis healthy control mice; Group II: ulcerative colitis mice models; Group III: D-carvone (40 mg/kg) + ulcerative colitis models; Group IV: sulfasalazine (50 mg/kg) + ulcerative colitis models. On the 8th day, the experimental study was terminated and serum samples and colon tissues were processed for further analysis. The effect of D-carvone at different concentration was studied on the LPS challenged RAW 264.7 cell lines. The D-carvone (40 mg/kg) treatment maintained the colon length and decreased disease activity index (DAI) score in UC animals. The increased antioxidant enzymes status and decreased oxidative stress and pro-inflammatory markers were noted in the D-carvone (40 mg/ kg) + UC mice. Histopathological study of colon tissue of D-carvone (40 mg/kg) treated UC mice displayed less mucosal damage and improved crypt integrity and goblet cells compared with DSS only provoked mice. The im-munohistochemical expression of iNOS and COX-2 was drastically diminished in the D-carvone treated UC mice. D-carvone (40 mg/kg) treatment appreciably diminished the LPS provoked NO production and pro-inflammatory modulators in the RAW 264.7 macrophage cell lines. These findings proved that D-carvone has a potential therapeutic effect to prevent LPS induced inflammation in in vitro cells and chemically induced ulcerative colitis in vivo models.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Monoterpenos Cicloexânicos/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Macrófagos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangue , Animais , Anti-Inflamatórios/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Monoterpenos Cicloexânicos/administração & dosagem , Sulfato de Dextrana , Modelos Animais de Doenças , Lipopolissacarídeos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7
6.
Life Sci ; 258: 118129, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32717271

RESUMO

Ulcerative colitis (UC) is an inflammatory bowel disease with increasing incidence in the world, especially in developing countries. Although knowledge of its pathogenesis has progressed over the last years, some details require clarification. Studies have highlighted the role of microbial dysbiosis and immune dysfunction as essential factors that may initiate the typical high-grade inflammatory outcome. In order to better understand the immunopathophysiological aspects of UC, experimental murine models are valuable tools. Some of the most commonly used chemicals to induce colitis are trinitrobenzene sulfonic acid, oxazolone and dextran sodium sulfate. These may also be used to investigate new ways of preventing or treating UC and therefore improving targeting in human studies. The use of functional foods or bioactive compounds from plants may constitute an innovative direction towards the future of alternative medicine. Considering the above, this review focused on updated information regarding the 1. gut microbiota and immunopathogenesis of UC; 2. the most utilized animal models of the disease and their relevance; and 3. experimental application of natural products, not yet tested in clinical trials.


Assuntos
Produtos Biológicos/uso terapêutico , Colite Ulcerativa/imunologia , Colite Ulcerativa/microbiologia , Microbioma Gastrointestinal , Animais , Produtos Biológicos/farmacologia , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Modelos Biológicos
7.
J Surg Res ; 253: 185-192, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32361613

RESUMO

BACKGROUND: In recent years, microRNA (miRNA) is considered as a potential therapy target. To study the regulatory mechanism and therapeutic effect of miRNAs on inflammatory bowel disease (IBD), we investigated microRNAs that regulate apoptosis-related protein B cell lymphoma-2 (Bcl-2). We examined the role of miR-16 in IBD and the effect of inhibiting the expression of miR-16 on disease progression. MATERIALS AND METHODS: Dextran sulfate sodium was used to induce ulcerative colitis in mice. RNA and protein were extracted from the rectal mucosa of mice. Real-time quantitative polymerase chain reaction and Western blotting were used to detect the expression of miR-16 and Bcl-2. The effects of miR-16 on intestinal mucosal immunity were studied by real-time quantitative polymerase chain reaction, and inflammatory factors such as interleukin-1ß, interleukin-6, and tumor necrosis factor-α were detected. The weight changes, disease activity index, length of the rectal colon, and pathological score of the mice were used to evaluate the effect of inhibiting miR-16 on disease progression. Through the establishment of overexpression and low expression cell lines of miR-16, the regulation of miR-16 on Bcl-2 was studied. RESULTS: MiR-16 was overexpressed in the IBD model, whereas Bcl-2 had lower expression in the mucosa. Inhibiting expression of miR-16 significantly decreased the expression of interleukin-1ß, interleukin-6, and tumor necrosis factor-α. In mice, the weight change, disease activity index, and pathological score decreased in the experimental group, in which miR-16 was inhibited. High expression of miR-16 can inhibit Bcl-2 expression. CONCLUSIONS: MiR-16 plays a critical role in IBD via Bcl-2 and is a promising target in IBD therapy.


Assuntos
Colite Ulcerativa/genética , Colo/imunologia , Mucosa Intestinal/imunologia , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Animais , Células CACO-2 , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Mucosa Intestinal/patologia , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/metabolismo
8.
BMC Public Health ; 20(1): 713, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32429900

RESUMO

BACKGROUND: Patients with inflammatory bowel disease (IBD) have a higher risk of developing opportunistic infections due to either the disease itself or to treatment with immunosuppressants. This risk can be reduced through vaccination. The aim of this study was to determine the prevalence of compliance with the guidelines on recommended immunization schedule in patients with IBD in the health district of Lleida, Spain. METHODS: Descriptive, cross-sectional, retrospective study of data at December 31, 2016. The reference population was formed by adults with a clinical diagnosis of IBD. The dependent variable was "compliance with the guidelines on recommended immunization schedule". Variables were sex, age, residence, diagnosis, vaccination against measles, mumps, rubella, varicella, tetanus-diphtheria, influenza, pneumococcus, meningococcus C, hepatitis B, and hepatitis A. Data were obtained from electronic medical records. For the data analysis, mean (standard deviation), prevalence with 95% confidence intervals, χ2 test and Mann-Whitney test were used. RESULTS: Compliance did not exceed 65% for any of vaccines analysed in the 1722 studied patients with ulcerative colitis or Crohn's disease. Significant differences across age groups were found in compliance for measles, mumps, rubella, varicella, tetanus, diphtheria and influenza in both ulcerative colitis and Crohn's disease and for meningococcus C and hepatitis A exclusively in ulcerative colitis. CONCLUSIONS: Compliance in patients with IBD is low. Thus, prevention of immunopreventable diseases or their complications is not maximized in this kind of patients. Greater awareness of how vaccines can reduce the risk of vaccine-preventable infections is needed among both patients and healthcare professionals.


Assuntos
Doenças Inflamatórias Intestinais/psicologia , Infecções Oportunistas/prevenção & controle , Cooperação do Paciente/estatística & dados numéricos , Vacinação/estatística & dados numéricos , Vacinas/uso terapêutico , Adolescente , Adulto , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Colite Ulcerativa/psicologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Doença de Crohn/psicologia , Estudos Transversais , Feminino , Humanos , Esquemas de Imunização , Imunossupressores/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Masculino , Infecções Oportunistas/imunologia , Prevalência , Estudos Retrospectivos , Adulto Jovem
9.
Arq Gastroenterol ; 57(1): 69-73, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294738

RESUMO

BACKGROUND: Patients with inflammatory bowel disease (IBD) vaccinated for hepatitis B have a low success rate in achieving protective antibody levels. The main factors suggested for this are IBD itself and the use of immunosuppressive drugs. OBJECTIVE: To evaluate the concentration of anti-HBs antibodies and to verify factors associated with the effectiveness of hepatitis B vaccination in patients with IBD. METHODS: This is a prospective, consecutive, observational, descriptive and analytical, non-randomized, qualitative study that evaluated the levels of anti-HBs antibodies in IBD patients at the Interdisciplinary Inflammatory Bowel Disease Clinic of the Family and Community Health Unit of UNIVALI - Itajaí, Santa Catarina. RESULTS: Thirty-six patients were vaccinated against hepatitis B virus (HBV), of which 29 were female. The average age was 46.2 years. Regarding the type of IBD, twenty-four patients had Crohn's disease and the duration of inflammatory bowel disease was 74 months. Fifteen patients were on concomitant immunosuppressive therapy. The effective response rate to HBV vaccine was 72.2%, verified by anti-HBs titration ≥10 UI/L. Statistical analysis revealed a negative response to vaccination in patients with Crohn's disease and immunosuppressive drugs. CONCLUSION: The success rate of HBV immunization in IBD patients is low compared to the general population. Type of disease and use of immunosuppressive drugs appear to influence the vaccine response.


Assuntos
Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Anticorpos Anti-Hepatite B/sangue , Vacinas contra Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite B/diagnóstico , Hepatite B/prevenção & controle , Adulto , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Feminino , Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vacinas contra Hepatite B/administração & dosagem , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pesquisa Qualitativa , Soroconversão
10.
Int Arch Allergy Immunol ; 181(6): 456-461, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32316004

RESUMO

BACKGROUND: The etiology of ulcerative colitis (UC) remains elusive even though many genetic and environmental pathogenic factors have been reported. Aberrant inflammatory responses mediated by specific subsets of T cells have been observed in ulcerative lesions of UC patients. OBJECTIVES: To elucidate the involvement of a delayed-type hypersensitivity reaction in UC, we focused on dental metal hypersensitivity, a T cell-mediated, delayed-type allergic reaction that causes oral contact mucositis and systemic cutaneous inflammation. METHOD: We recruited 65 Japanese UC patients and 22 healthy controls (HC) and used the in vitro lymphocyte stimulation test to quantify their sensitivity to zinc, gold, nickel, and palladium - the metals that have been widely used in dentistry. All subjects were users of metallic dental implants and/or prostheses containing zinc, gold, nickel, and/or palladium as major constituents. RESULTS: Sixty percent of the UC patients were hypersensitive to at least one metal species, whereas 32% of the HC were hypersensitive to only a single metal species. The overall incidence of metal hypersensitivity was significantly higher for UC patients than for HC. Furthermore, a significantly greater proportion of UC patients were hypersensitive to nickel or palladium. The severity of the sensitivity to nickel and palladium was also significantly greater for UC patients than for HC. CONCLUSIONS: This pilot study demonstrates that UC patients have a significantly higher incidence of hypersensitivity to nickel and palladium, suggesting the possible involvement of dental metal hypersensitivity in UC pathogenesis.


Assuntos
Colite Ulcerativa/imunologia , Materiais Dentários/efeitos adversos , Hipersensibilidade Tardia/complicações , Níquel/imunologia , Paládio/imunologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Feminino , Ouro/efeitos adversos , Ouro/imunologia , Humanos , Hipersensibilidade Tardia/induzido quimicamente , Hipersensibilidade Tardia/diagnóstico , Hipersensibilidade Tardia/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Níquel/efeitos adversos , Paládio/efeitos adversos , Projetos Piloto , Prevalência , Adulto Jovem , Zinco/efeitos adversos , Zinco/imunologia
11.
Arch Immunol Ther Exp (Warsz) ; 68(2): 12, 2020 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-32248339

RESUMO

The effect of TNF-blockers on T-lymphocyte subsets is largely unknown in inflammatory bowel diseases (IBDs). The aim of the present study was to analyze the prevalence of T-cell subtypes and their correlation to therapeutic response. Sixty-eight patients with Crohn's disease (CD), 46 with ulcerative colitis (UC) were enrolled. (1) The clinical course was followed after the initiation of TNF-blockers (prospective study). (2) The immunophenotype was also compared between long-term anti-TNF treated-responders and non-responders (cross-sectional study). The results were compared with those of therapy-naïve patients with active disease and those in remission with non-biological immunosuppressive therapy, and with healthy controls. Fourteen subtypes of peripheral blood T cells were measured with flow cytometry. The prevalence of Th2 and Th17 cells, of HLA-DR- and CD69-positive CD4 and CD8 cells, was higher, whereas the percentage of CD45RA-positive CD4 and CD8 cells was lower in both IBDs than in controls. CD8CD69 cell frequency was lower in remission, and decreased during anti-TNF therapy in CD responders. CD8CD45RO memory cells had higher prevalence in UC non-responders than in those starting anti-TNF. CD4CD45RO percentage < 49.05 at the initiation of TNF-blockers was predictive of a subsequent therapeutic response in CD, and Th2 and Th17 prevalence correlated with the duration of remission on TNF-blockers in UC. This study provided a detailed description of the T-cell composition in IBDs. CD8CD69 prevalence may be an activity marker in CD, and CD4CD45RO, Th2 and Th17 levels could be predictive for a therapeutic response to anti-TNF.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Subpopulações de Linfócitos T/citologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Idoso , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Subpopulações de Linfócitos T/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Células Th2/citologia , Células Th2/metabolismo , Resultado do Tratamento , Adulto Jovem
12.
Nat Commun ; 11(1): 1512, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32251296

RESUMO

Studies of inflammatory bowel disease (IBD) have been inconclusive in relating microbiota with distribution of inflammation. We report microbiota, host transcriptomics, epigenomics and genetics from matched inflamed and non-inflamed colonic mucosa [50 Crohn's disease (CD); 80 ulcerative colitis (UC); 31 controls]. Changes in community-wide and within-patient microbiota are linked with inflammation, but we find no evidence for a distinct microbial diagnostic signature, probably due to heterogeneous host-microbe interactions, and show only marginal microbiota associations with habitual diet. Epithelial DNA methylation improves disease classification and is associated with both inflammation and microbiota composition. Microbiota sub-groups are driven by dominant Enterbacteriaceae and Bacteroides species, representative strains of which are pro-inflammatory in vitro, are also associated with immune-related epigenetic markers. In conclusion, inflamed and non-inflamed colonic segments in both CD and UC differ in microbiota composition and epigenetic profiles.


Assuntos
Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Epigênese Genética/imunologia , Microbioma Gastrointestinal/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Adulto , Idoso , Bacteroides/genética , Bacteroides/imunologia , Bacteroides/isolamento & purificação , Biópsia , Células CACO-2 , Estudos de Casos e Controles , Estudos de Coortes , Colite Ulcerativa/genética , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia , Colo/diagnóstico por imagem , Colo/imunologia , Colo/microbiologia , Colo/patologia , Colonoscopia , Doença de Crohn/genética , Doença de Crohn/microbiologia , Doença de Crohn/patologia , DNA Bacteriano/isolamento & purificação , Enterobacteriaceae/genética , Enterobacteriaceae/imunologia , Enterobacteriaceae/isolamento & purificação , Epigenômica , Feminino , Microbioma Gastrointestinal/genética , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , RNA-Seq , Adulto Jovem
13.
Mol Immunol ; 121: 92-98, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32193038

RESUMO

Ulcerative colitis (UC) is characterized by a relapsing and remitting pattern. The remission phase may last weeks to years. It remains unclear what specific factors can cause the disease to exist the remission phase and enter an activated state. IL-10 is a cytokine best known for its anti-inflammatory roles. We hypothesized that IL-10 might have a role in suppressing disease flares in UC remission patients. Unexpectedly, we found that UC remission patients with higher serum IL-10 levels presented faster progression to disease flares. Subsequently, we found that exogenous IL-10 could significantly reduce the level of CD4 and CD8 T cell proliferation. On the other hand, IL-10 significantly elevated the viability of activated CD4 and CD8 T cells. Interestingly, it appeared that the IL-10-mediated pro-survival effects were more pronounced in CD8 T cells than in CD4 T cells and were able to promote the survival of activated T cells when administered prior to cell activation. To examine whether IL-10 in the serum of UC patients was able to enhance T cell survival, we separated UC remission patients into Low, Intermediate, and High groups based on the serum IL-10 level. The native serum from High IL-10 patients, but not the native serum from Low IL-10 patients, could significantly increase the viability of activated T cells. In conclusion, we demonstrated that high IL-10 level at the remission phase was associated with shorter duration of remission, possibly due to IL-10-mediated effects on T cell survival.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Sobrevivência Celular/imunologia , Colite Ulcerativa/imunologia , Interleucina-10/metabolismo , Exacerbação dos Sintomas , Adulto , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Colite Ulcerativa/sangue , Humanos , Interleucina-10/sangue , Interleucina-10/imunologia , Ativação Linfocitária
16.
Nat Commun ; 11(1): 1253, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152303

RESUMO

The presence of antiendothelial cell antibodies (AECAs) has been documented in Takayasu arteritis (TAK), a chronic granulomatous vasculitis. Here, we identify cell-surface autoantigens using an expression cloning system. A cDNA library of endothelial cells is retrovirally transfected into a rat myeloma cell line from which AECA-positive clones are sorted with flow cytometry. Four distinct AECA-positive clones are isolated, and endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) are identified as endothelial autoantigens. Autoantibodies against EPCR and SR-BI are detected in 34.6% and 36.5% of cases, respectively, with minimal overlap (3.8%). Autoantibodies against EPCR are also detected in ulcerative colitis, the frequent comorbidity of TAK. In mechanistic studies, EPCR and SR-BI function as negative regulators of endothelial activation. EPCR has also an effect on human T cells and impair Th17 differentiation. Autoantibodies against EPCR and SR-BI block the functions of their targets, thereby promoting pro-inflammatory phenotype.


Assuntos
Autoanticorpos/metabolismo , Autoantígenos/isolamento & purificação , Autoantígenos/metabolismo , Células Endoteliais/imunologia , Arterite de Takayasu/imunologia , Arterite de Takayasu/metabolismo , Animais , Autoanticorpos/isolamento & purificação , Autoantígenos/genética , Autoantígenos/imunologia , Linhagem Celular Tumoral , Membrana Celular/química , Clonagem Molecular , Colite Ulcerativa/imunologia , Modelos Animais de Doenças , Receptor de Proteína C Endotelial , Endotélio Vascular/metabolismo , Biblioteca Gênica , Humanos , Mieloma Múltiplo/metabolismo , Proteína C/metabolismo , Ratos , Receptores de Endotelina/metabolismo , Receptores Depuradores Classe B/metabolismo
17.
Nat Rev Gastroenterol Hepatol ; 17(6): 323-337, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32203403

RESUMO

Cytokines are involved in intestinal homeostasis and pathological processes associated with inflammatory bowel disease (IBD). The biological effects of cytokines, including several involved in the pathology of Crohn's disease and ulcerative colitis, occur as a result of receptor-mediated signalling through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) DNA-binding families of proteins. Although therapies targeting cytokines have revolutionized IBD therapy, they have historically targeted individual cytokines, and an unmet medical need exists for patients who do not respond to or lose response to these treatments. Several small-molecule inhibitors of JAKs that have the potential to affect multiple pro-inflammatory cytokine-dependent pathways are in clinical development for the treatment of IBD, with one agent, tofacitinib, already approved for ulcerative colitis and several other agents with demonstrated efficacy in early phase trials. This Review describes the current understanding of JAK-STAT signalling in intestinal homeostasis and disease and the rationale for targeting this pathway as a treatment for IBD. The available evidence for the efficacy, safety and pharmacokinetics of JAK inhibitors in IBD as well as the potential approaches to optimize treatment with these agents, such as localized delivery or combination therapy, are also discussed.


Assuntos
Citocinas/imunologia , Doenças Inflamatórias Intestinais/imunologia , Janus Quinases/imunologia , Fatores de Transcrição STAT/imunologia , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Intestinos/imunologia , Inibidores de Janus Quinases/uso terapêutico , Transdução de Sinais/imunologia
18.
J Crohns Colitis ; 14(9): 1334-1336, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32215548

RESUMO

Crohn's disease [CD] and ulcerative colitis [UC], the main inflammatory bowel diseases [IBD] in humans, are chronic, immune-inflammatory diseases, the pathogenesis of which suggests a complex interaction between environmental factors and genetic susceptibility. These disabling conditions affect millions of individuals and, together with the drugs used to treat them, can put patients at risk of developing complications and other conditions. This is particularly relevant today, as coronavirus disease [Covid-19] has rapidly spread from China to countries where IBD are more prevalent, and there is convincing evidence that Covid-19-mediated morbidity and mortality are higher in subjects with comorbidities. The primary objectives of this Viewpoint are to provide a focused overview of the factors and mechanisms by which the novel severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infects cells and to illustrate the link between such determinants and intestinal inflammation. We also provide clues about the reasons why the overall IBD population might have no increased risk of developing SARS-CoV-2 infection and highlight the potential of cytokine blockers, used to treat IBD patients, to prevent Covid-driven pneumonia.


Assuntos
Colite Ulcerativa , Infecções por Coronavirus , Doença de Crohn , Pandemias , Pneumonia Viral , Betacoronavirus/fisiologia , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/imunologia , Colite Ulcerativa/terapia , Controle de Doenças Transmissíveis/métodos , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Doença de Crohn/epidemiologia , Doença de Crohn/imunologia , Doença de Crohn/terapia , Humanos , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Prevalência , Medição de Risco , Fatores de Risco
19.
Dig Dis Sci ; 65(5): 1299-1306, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32124197

RESUMO

Intestinal fibrosis is a common outcome of inflammatory bowel diseases (IBDs), becoming clinically apparent in 40% of patients with Crohn's disease and 5% of those with ulcerative colitis. Effective pharmacological treatments aimed at controlling or reversing fibrosis progression are unavailable. Fibrosis is characterized by an excessive local accumulation of extracellular matrix proteins (mainly collagen), as a result of their increased production by activated myofibroblasts and/or their reduced degradation by specific matrix metalloproteinases. Initiation and progression of fibrosis are modulated by several pro- and anti-fibrogenic molecules. In recent years, the cytokine interleukin-17 (IL-17) has been integrated into the pathogenesis of fibrosis, although its precise contribution to IBD, and especially to its related intestinal fibrosis, remains controversial. Several data suggest both a pro-inflammatory and pro-fibrotic action and a protective function of the Th17/IL-17 immune response. A recent study has demonstrated that the treatment with anti-IL-17 antibody significantly alleviated 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colorectal fibrosis in mice by down-regulating the expression of collagen 3 and several pro-fibrogenic cytokines. Here, we describe and discuss the possible involvement of the Th17/IL-17 immune response in the initiation ad progression of intestinal fibrosis.


Assuntos
Imunidade Adaptativa , Doenças Inflamatórias Intestinais/imunologia , Interleucina-17/imunologia , Intestinos/patologia , Células Th17/imunologia , Animais , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colo/patologia , Doença de Crohn/imunologia , Doença de Crohn/patologia , Citocinas/imunologia , Fibrose , Humanos , Doenças Inflamatórias Intestinais/patologia , Intestinos/imunologia , Miofibroblastos/imunologia
20.
PLoS One ; 15(2): e0228615, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32050001

RESUMO

To date, no comprehensive analysis of autoantibodies in sera of patients with ulcerative colitis has been conducted. To analyze the spectrum of autoantibodies and to elucidate their role serum-IgG from UC patients (n = 49) and non-UC donors (n = 23) were screened by using a human protein microarray. Screening yielded a remarkable number of 697 differentially-reactive at the nominal 0·01 significance level (FDR<0·1) of the univariate test between the UC and the non-UC group. CD99 emerged as a biomarker to discriminate between both groups (p = 1e-04, AUC = 0·8). In addition, cytokines, chemokines and growth factors were analyzed by Olink's Proseek® Multiplex Inflammation-I 96×96 immuno-qPCR assay and 31 genes were significant at the nominal 0.05 level of the univariate test to discriminate between UC and non-UC donors. MCP-3, HGF and CXCL-9 were identified as the most significant markers to discriminate between UC patients with clinically active and inactive disease. Levels of CXCL10 (cor = 0.3; p = 0.02), CCL25 (cor = 0.25; p = 0.04) and CCL28 (cor = 0.3; p = 0.02) correlated positively with levels of anti CD99. To assess whether autoantibodies are detectable prior to diagnosis with UC, sera from nine donors at two different time points (T-early, median 21 months and T-late, median 6 months) were analyzed. 1201 features were identified with higher reactivity in samples at time points closer to clinical UC presentation. In vitro, additional challenge of peripheral mononuclear cells with CD99 did not activate CD4+ T cells but induced the secretion of IL-10 (-CD99: 20.21±20.25; +CD99: 130.20±89.55; mean ±sd; p = 0.015). To examine the effect of CD99 in vivo, inflammation and autoantibody levels were examined in NOD/ScidIL2Rγnull mice reconstituted with PBMC from UC donors (NSG-UC). Additional challenge with CD99 aggravated disease symptoms and pathological phenotype as indicated by the elevated clinical score (-CD99: 1·85 ± 1·94; +CD99: 4·25 ± 1·48) and histological score (-CD99: 2·16 ± 0·83; +CD99: 3·15 ± 1·16, p = 0·01). Furthermore, levels of anti-CD99 antibodies increased (Control: 398 ± 323; mean MFI ± sd; Ethanol + PBS: 358 ±316; Ethanol + CD99: 1363 ± 1336; Control versus Ethanol + CD99: p = 0.03). In a highly inflammatory environment, frequencies of pro-inflammatory M1 monocytes (CD14+ CD64+: unchallenged 8.09±4.72; challenged 14.2±8.62; p = 0.07; CD14+ CD1a+: unchallenged 16.29 ±6.97; challenged 43.81±14.4, p = 0.0003) increased and levels of autoantibodies in serum decreased in the NSG-UC mouse model. These results suggest that autoantibodies are potent biomarkers to discriminate between UC and non-UC and indicate risk to develop UC. In an inflammatory environment, auto-antibodies may promote the pathological phenotype by activating M1 monocytes in the NSG-UC animal model and also in patients with UC.


Assuntos
Autoanticorpos/sangue , Colite Ulcerativa/diagnóstico , Adulto , Idoso , Animais , Autoanticorpos/imunologia , Biomarcadores/sangue , Células Cultivadas , Colite Ulcerativa/sangue , Colite Ulcerativa/imunologia , Citocinas/sangue , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade
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