RESUMO
AIM: C-reactive protein (CRP) is both an inflammatory and prognostic marker in various cancers. This study aimed to elucidate the characteristics of CRP and the prognostic factors in patients who were administered with atezolizumab plus bevacizumab (ATZ + BEV) for unresectable hepatocellular carcinoma (HCC). METHODS: A total of 213 patients who received ATZ + BEV for HCC from November 2020 to March 2023 at 15 hospitals were enrolled in this retrospective study. The prognosis was analyzed by subdividing the patients based on baseline characteristics, radiologic response, and treatment lines. Accuracy of survival prediction was assessed using CRP, alpha fetoprotein (AFP), C-reactive protein and alpha fetoprotein in immunotherapy (CRAFITY), and Glasgow Prognostic Score. RESULTS: Compared with patients with baseline CRP <1 mg/dL, those with baseline CRP ≥1 mg/dL (n = 45) had a significantly higher baseline albumin-bilirubin score and AFP levels, significantly lower disease control rate (62.2%), and significantly shorter median overall survival (hazards ratios 2.292; 95% confidence interval 1.313-5.107; log-rank test, p < 0.001). Multivariate analysis identified CRP ≥1 mg/dL, AFP ≥100 ng/mL, and modified albumin-bilirubin grade as the significant prognostic factors. The baseline CRP, AFP, CRAFITY, and Glasgow Prognostic Score demonstrated higher discrimination for 1-year survival prediction after first-line ATZ + BEV administration, compared with beyond second line, with area under the receiver operating characteristic curves of 0.759, 0.761, 0.805, and 0.717, respectively. CONCLUSIONS: CRP was a significant biomarker in patients treated with ATZ + BEV for HCC. Elevated CRP levels may indicate aggressive cancer progression and potential resistance to ATZ + BEV therapy.
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Apelin (APL), an endogenous ligand for APJ, has been reported to be upregulated in a murine model of acute colitis induced by sodium dextran sulfate, as well as inflammatory bowel diseases (IBD) in humans. However, the mechanisms and functions of APL/APJ axis in the pathogenesis of IBD are unclear. We herein analyzed CD4+ T cells to determine the functions of APL in a murine model of chronic colitis induced in Rag deficient mice (Rag-/-). In colonic tissues of wild-type mice (WT), we found that APL was expressed especially in the lamina propria lymphocytes, where CD4+ T cells are dominant, rather than the epithelial cells. Unexpectedly, the APL expression was rather downregulated in the colonic tissue of the chronic colitis group compared to the control groups (Rag-/- before colitis induction and WT). The APL expression was downregulated when naïve T cells were differentiated into effecter T cells. A lack of APL resulted in decreased naïve T cells and increased effecter T cells in secondary lymphoid organs. A synthetic APL peptide, [Pyr1]-APL-13, increased IL-10 and decreased IFN-γ productions by effecter T cells. Administration of [Pyr1]-APL-13 improved survival rate in association with lessened colitis severity and decreased pro-inflammatory cytokine production. This is the first report showing immunological function of APL specifically on T cells, and these results indicate that APL/APJ axis may be a novel therapeutic target for IBD.
Assuntos
Colite , Doenças Inflamatórias Intestinais , Camundongos , Humanos , Animais , Linfócitos T/metabolismo , Apelina/metabolismo , Modelos Animais de Doenças , Colite/patologia , Doenças Inflamatórias Intestinais/metabolismo , Sulfato de Dextrana , Camundongos Endogâmicos C57BL , Linfócitos T CD4-PositivosRESUMO
OBJECTIVE: Although immunoglobulin A (IgA) is abundantly expressed in the gut and known to be an important component of mucosal barriers against luminal pathogens, its precise function remains unclear. Therefore, we tried to elucidate the effect of IgA on gut homeostasis maintenance and its mechanism. DESIGN: We generated various IgA mutant mouse lines using the CRISPR/Cas9 genome editing system. Then, we evaluated the effect on the small intestinal homeostasis, pathology, intestinal microbiota, cytokine production, and immune cell activation using intravital imaging. RESULTS: We obtained two lines, with one that contained a <50 base pair deletion in the cytoplasmic region of the IgA allele (IgA tail-mutant; IgAtm/tm) and the other that lacked the most constant region of the IgH α chain, which resulted in the deficiency of IgA production (IgA-/-). IgA-/- exhibited spontaneous inflammation in the ileum but not the other parts of the gastrointestinal tract. Associated with this, there were significantly increased lamina propria CD4+ T cells, elevated productions of IFN-γ and IL-17, increased ileal segmented filamentous bacteria and skewed intestinal microflora composition. Intravital imaging using Ca2+ biosensor showed that IgA-/- had elevated Ca2+ signalling in Peyer's patch B cells. On the other hand, IgAtm/tm seemed to be normal, suggesting that the IgA cytoplasmic tail is dispensable for the prevention of the intestinal disorder. CONCLUSION: IgA plays an important role in the mucosal homeostasis associated with the regulation of intestinal microbiota and protection against mucosal inflammation especially in the ileum.
Assuntos
Ileíte/etiologia , Íleo/patologia , Imunoglobulina A/fisiologia , Animais , Linfócitos B/fisiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Microbioma Gastrointestinal , Homeostase , Ileíte/metabolismo , Ileíte/patologia , Íleo/metabolismo , Íleo/ultraestrutura , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Microscopia Intravital , Masculino , Camundongos , Camundongos Mutantes , Linfócitos T/fisiologiaRESUMO
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expressed in T cells may regulate immune responses in the gut. In addition to T cells, B cells are also an important population in the gut-associated lymphoid tissues that orchestrate mucosal homeostasis. However, the role of CEACAM1 in B cells has not been elucidated. We herein analyzed mature B cells to determine the functions of CEACAM1. Flow cytometry revealed high expression of CEACAM1 on B cells in secondary lymphoid tissues. Cytokine production induced by activation of B cell receptor (BCR) signaling was suppressed by CEACAM1 signaling in contrast to that associated with either Toll-like receptor 4 or CD40 signaling. Confocal microscopy revealed co-localization of CEACAM1 and BCR when activated with anti-Igµ F(ab')2 fragment. Overexpression of CEACAM1 in a murine B cell line, A20, resulted in reduced expressions of activation surface markers with decreased Ca2+ influx after BCR signal activation. Overexpression of CEACAM1 suppressed BCR signal cascade in A20 cells in association with decreased spontaneous proliferation. Our results suggest that CEACAM1 can regulate BCR-mediated mature B cell activation in lymphoid tissues. Therefore, further studies of this molecule may lead to greater insights into the mechanisms of immune responses within peripheral tissues and the potential treatment of inflammatory diseases.
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Antígenos CD/metabolismo , Moléculas de Adesão Celular/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , Animais , Linfócitos B/metabolismo , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Citocinas/biossíntese , Feminino , Camundongos Endogâmicos C57BLRESUMO
Although previous studies have suggested that appendix seems to be involved in the colitis, the role of this in the pathogenesis remains unclear. In this study, we assessed the importance of appendiceal lymphoid follicles, specifically the cecal patches (CP) in mice, using an experimental colitis model. Treatment with oxazolone resulted in ulcerations particularly at CP with follicular expansion as well as colitis. The colitis was attenuated by either appendectomy or the absence of mature B cells. We therefore established an intravital imaging system accompanied by the fluorescence resonance energy transfer technology to analyze the dynamic immune response of CP B cells. Our observation revealed frequent Ca2+ signaling in CP B cells during the early phase of colitis development. These findings suggested that the CP B cells may be involved in the pathogenesis of colitis including inflammatory bowel diseases in humans.
Assuntos
Apêndice/imunologia , Ceco/imunologia , Colite/imunologia , Colo/imunologia , Estruturas Linfoides Terciárias/imunologia , Animais , Apêndice/diagnóstico por imagem , Apêndice/patologia , Linfócitos B/imunologia , Linfócitos B/patologia , Sinalização do Cálcio , Ceco/diagnóstico por imagem , Ceco/patologia , Colite/induzido quimicamente , Colite/diagnóstico por imagem , Colite/patologia , Colo/diagnóstico por imagem , Colo/patologia , Modelos Animais de Doenças , Humanos , Microscopia Intravital , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Oxazolona , Estruturas Linfoides Terciárias/diagnóstico por imagem , Estruturas Linfoides Terciárias/patologiaRESUMO
Prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). Previous studies had shown that nuclear factor-x03BA;B (NF-x03BA;B) activation in both macrophages and epithelia in inflamed colonic tissue is associated with CAC development. However, the mechanism by which epithelial NF-x03BA;B activation leading to CAC development had not previously been rigorously studied. We and others had observed the increased expression of the type 2 receptor for tumor necrosis factor (TNFR2/TNFRSF1b/p75) in IBD models. Myosin light chain kinase (MLCK) is suggested to be associated with epithelial permeability via TNF signaling. Therefore, the relationship between epithelial MLCK expression and NF-x03BA;B activation via TNFR2 signaling on CAC development was investigated. Pro-tumorigenic cytokines such as interleukin (IL)-1ß, IL-6 and macrophage inflammatory protein-2 at the lamina propria were increased in the setting of colitis and further increased in tumor tissues with upregulated epithelial TNFR2 and MLCK expressions in an animal model of CAC. The upregulated MLCK expression was also observed in TNF-stimulated colonic epithelial cells in vitro in association with the upregulation of TNFR2 but not TNFR1/TNFRSF1a/p55. Gene silencing of tnfrsf1b, but not tnfrsf1a, resulted in restoration of epithelial tight junction (TJ) associated with decreased MLCK expression. The presence of anti-TNF antibody also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results including the suppressed TNFR2 and MLCK expressions were observed by inhibiting MLCK in the epithelial cells. MLCK silencing also led to suppressed TNFR2 expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in reduced CAC development, restored TJ, and decreased pro-tumorigenic cytokines. These imply that TNF-induced NF-x03BA;B activation and MLCK expression may be a potential target for the prevention of IBD-associated carcinogenesis.
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Carcinogênese/imunologia , Carcinoma/imunologia , Colite/imunologia , Neoplasias do Colo/imunologia , Citocinas/imunologia , Células Epiteliais/imunologia , Doenças Inflamatórias Intestinais/imunologia , NF-kappa B/imunologia , Animais , Humanos , Mucosa Intestinal , Quinase de Cadeia Leve de Miosina/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/imunologiaRESUMO
BACKGROUND: The aim of the present study was to examine the usability of procalcitonin (PCT) for severity assessment in patients with acute cholangitis (AC). METHODS: Serum PCT concentrations were measured on admission in patients with AC. Patients were classified with mild, moderate, or severe AC based on severity assessment guidelines. RESULTS: We included 159 treatment-naïve patients with AC (95 males, 64 females) in this study. The median PCT concentrations were 0.08 ng/mL (interquartile range (IQR) 0.04 - 0.18 ng/mL), 0.37 ng/mL (IQR 0.15 - 1.85 ng/mL), and 5.56 ng/mL (IQR 3.59 - 25.89 ng/mL) in patients with mild, moderate and severe AC, respectively. PCT concentrations were significantly higher in patients with severe AC than in patients with moderate AC (p < 0.0001), and in patients with moderate AC than in patients with mild AC (p < 0.0001). The areas under the receiver operating characteristic curves for PCT to discriminate patients with moderate and severe AC were 0.84 (95% CI 0.77 to 0.92, p < 0.001) and 0.86 (95% CI 0.78 to 0.92, p < 0.001), respectively. CONCLUSIONS: Serum PCT concentrations were elevated in patients with AC and may be a useful parameter for the severity assessment of AC.
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Calcitonina/sangue , Colangite/fisiopatologia , Precursores de Proteínas/sangue , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Peptídeo Relacionado com Gene de Calcitonina , Colangite/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
Systemic immune deficiency is a major cause of cytomegalovirus (CMV) esophagitis. We report a case of CMV esophagitis during topical steroid therapy of eosinophilic esophagitis (EoE) in a non-immunodeficient patient. An 85-year-old man with dysphagia was on a 6-year regimen of oral budesonide (1200 mcg daily) for EoE. He underwent right upper lobectomy and postoperative radiotherapy 25 years ago for lung squamous cell carcinoma. Esophageal cicatricial stenosis due to EoE or previous radiation therapy persisted. Esophagogastroduodenoscopy revealed ulcerating mucosa with a thick white coat originating from the fixed stenotic lesion to the oral side. Histopathological examinations revealed CMV esophagitis. All signs of CMV esophagitis rapidly disappeared after reducing the budesonide dose and initiating anti-viral treatment with ganciclovir and valganciclovir for 12 and 2 days, respectively. The patient continued topical budesonide 400 mcg daily after anti-viral therapy. The clinical course was uneventful and without CMV esophagitis recurrence. This suggests that topical steroid therapy, particularly the local stasis of steroids at stenotic lesions, may induce CMV esophagitis. This is the first report of CMV esophagitis complicating the local steroid therapy of EoE with a stenotic lesion. When EoE patients' clinical symptoms worsen with topical steroid therapy, CMV esophagitis should be considered.
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Infecções por Citomegalovirus , Esofagite Eosinofílica , Idoso de 80 Anos ou mais , Citomegalovirus , Infecções por Citomegalovirus/tratamento farmacológico , Humanos , Masculino , Recidiva Local de Neoplasia , EsteroidesRESUMO
Chronic diarrhea is one of the major symptoms in gastroenterology. However, this may be caused by pathologic conditions for which the diagnosis is critical. Villous atrophy, as an endoscopic lesion, accompanied by chronic diarrhea can occasionally be observed in the patients with inflammatory diseases of the gastrointestinal (GI) tract. Herein, we present a case with persistent diarrhea accompanied by intestinal wall thickening without any other significant endoscopic features other than villous atrophy in the jejunum and the ileum, where we diagnosed as an indolent T cell lymphoproliferative disorder (T-LPD) of the GI tract, defined in the 2016-2017 revised World Health Organization classification, via single-balloon enteroscopy (SBE). Interestingly, we found the same lymphocyte infiltration from the distal third portion of the duodenum, where gastroscopy could not reach, via SBE, even though no endoscopic findings were observed such as villous atrophy. Since infiltrating cells in the intestinal tissues were CCR4+, mogamulizumab was administered with resulting durable symptomatic remission for more than 2 years. Patients with persistent diarrhea may have serious small intestinal disorder including not only chronic inflammatory diseases but also lymphoid neoplasmic conditions including T-LPD of GI tract.
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Intestino Delgado/patologia , Transtornos Linfoproliferativos/diagnóstico , Enteroscopia de Balão Único/métodos , Linfócitos T/patologia , Idoso , Atrofia/etiologia , Atrofia/patologia , Biópsia , Diarreia/etiologia , Humanos , Intestino Delgado/imunologia , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Masculino , Tomografia Computadorizada por Raios XRESUMO
Mice deficient in the megakaryoblastic leukaemia 1 (Mkl1) gene experience less severe dextran sulphate sodium (DSS)-induced colitis, implying that Mkl1 plays a pathological role in inflammatory bowel disease (IBD). However, the contribution of Mkl1 to the development of colitis remains to be elucidated. The expression of Mkl1 is higher in the colonic lamina propria macrophages (LPMac) of DSS-treated mice than in those of control mice. Therefore, we established a transgenic mouse line that overexpresses human MKL1 (MKL1-Tg) specifically in cells of the monocyte/macrophage lineage, in order to investigate the potential role of macrophage MKL1 in the pathogenesis of colitis. MKL1-Tg mice displayed spontaneous colon shortening and rectal prolapse. Flow cytometric and quantitative RT-PCR analyses revealed that, in MKL1-Tg mice compared to littermate controls, the population of LPMac was decreased and had an altered inflammatory phenotype indicative of impaired anti-inflammatory properties, whereas bone marrow-derived macrophages from MKL1-Tg mice skewed towards M1 polarisation. In addition, MKL1-Tg mice had higher susceptibility to DSS-induced colitis than their littermate controls. These observations indicated that MKL1 crucially contributes to the development of colitis via the regulation of the function of macrophages, suggesting that it may be a potential therapeutic target for the prevention of IBD.
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Colite/metabolismo , Macrófagos/metabolismo , Transativadores/metabolismo , Animais , Polaridade Celular , Colite/patologia , Colo/metabolismo , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Suscetibilidade a Doenças/metabolismo , Feminino , Expressão Gênica , Humanos , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Prolapso Retal/metabolismo , Prolapso Retal/patologia , Transativadores/genéticaRESUMO
It has been suggested that prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). We previously observed that the NF-κB activation in colonic epithelial cells is associated with increased tumor necrosis factor receptor 2 (TNFR2) expression in CAC development. However, the mechanism by which epithelial NF-κB activation leading to CAC is still unclear. Myosin light chain kinase (MLCK) has been reported to be responsible for the epithelial permeability associated with TNF signaling. Therefore we focused on the role of MLCK expression via TNFR2 signaling on CAC development. Pro-tumorigenic cytokines such as IL-1ß, IL-6 and MIP-2 production as well as INF-γ and TNF production at the lamina propria were increased in the setting of colitis, and further in tumor tissues in associations with up-regulated TNFR2 and MLCK expressions in the epithelial cells of a CAC model. The up-regulated MLCK expression was observed in TNF-stimulated colonic epithelial cells in a dose-dependent fashion in association with up-regulation of TNFR2. Silencing TNFR2, but not TNFR1, resulted in restoration of epithelial tight junction (TJ) associated with decreased MLCK expression. Antibody-mediated blockade of TNF signaling also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results were observed with suppressing TNFR2 and MLCK expressions by inhibiting MLCK in the epithelial cells. Silencing of MLCK also resulted in suppressed TNFR2, but not TNFR1, expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in restored TJ, decreased pro-tumorigenic cytokines and reduced CAC development. These results suggest that MLCK may be a potential target for the prevention of IBD-associated tumor development.