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1.
Artigo em Inglês | MEDLINE | ID: mdl-33618023

RESUMO

BACKGROUND & AIMS: The IM-UNITI study and long-term extension (LTE) evaluated the long-term efficacy, safety, and immunogenicity of subcutaneous ustekinumab maintenance therapy in patients with Crohn's disease. Here, we report the final results of IM-UNITI LTE through 5 years. METHODS: Patients completing safety and efficacy evaluations at week 44 of the maintenance study were eligible to participate in the LTE and continue the treatment they were receiving. Unblinding occurred after completion of maintenance study analyses (August 2015), and patients receiving placebo were discontinued. No dose adjustment occurred in the LTE. Efficacy assessments were conducted every 12 weeks until unblinding and at dosing visits thereafter through week 252. Serum ustekinumab concentrations and antidrug antibodies were evaluated through weeks 252 and 272, respectively. RESULTS: Using an intent-to-treat analysis of all patients randomized to ustekinumab at maintenance baseline, 34.4% of patients in the every-8-weeks group and 28.7% in the every-12-weeks group were in clinical remission at week 252. Corresponding remission rates among patients who entered the LTE were 54.9% and 45.2%. Overall, adverse event rates (per 100 patient-years) from maintenance week 0 through the final visit generally were similar in the placebo and combined ustekinumab groups for all adverse events (440.3 vs 327.6), serious adverse events (19.3 vs 17.5), infections (99.8 vs 93.8), and serious infections (3.9 vs 3.4). Serum ustekinumab concentrations were maintained throughout the LTE. Antidrug antibodies occurred in 5.8% of patients who received ustekinumab during induction and maintenance and continued in the LTE. CONCLUSIONS: Patients receiving subcutaneous ustekinumab maintained clinical remission through 5 years. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.

2.
J Crohns Colitis ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33300546

RESUMO

BACKGROUND AND AIMS: It is unclear whether pre-pouch ileitis heralds an aggressive inflammatory pouch disease in patients with ileal-pouch anal anastomosis (IPAA). We compared outcomes of patients with pouchitis and concomitant pre-pouch ileitis to those with pouchitis alone. METHODS: Patients undergoing IPAA surgery for inflammatory bowel disease who subsequently developed pouchitis with concomitant pre-pouch ileitis (pre-pouch ileitis group) were matched by year of IPAA surgery and pre-operative diagnosis (ulcerative colitis or inflammatory bowel disease-unclassified) with patients who developed pouchitis alone (pouchitis group). Primary outcomes were development of Crohn's disease (CD)-like complications (non-anastomotic strictures or perianal disease >6 months after ileostomy closure) and pouch failure. Secondary outcomes were need for surgical/endoscopic interventions and immunosuppressive therapy. Log-rank test was used to compare outcome-free survival and Cox regression was performed to identify predictors of outcomes. RESULTS: There were 66 patients in each group. CD-like complications and pouch failure developed in 36.4% and 7.6% patients in pre-pouch ileitis group and 10.6% and 1.5% in pouchitis group, respectively. CD-like complications-free survival (log-rank p=0.0002) and pouch failure-free survival (log-rank p=0.046) were significantly lower in the pre-pouch ileitis group. Pre-pouch ileitis group had a higher risk of requiring surgical/endoscopic interventions (log-rank p=0.0005) and immunosuppressive therapy (log-rank p<0.0001). Pre-pouch ileitis was independently associated with an increased risk of CD-like complications (HR 3.8; p=0.0007), need for surgical/endoscopic interventions (HR 4.1; p=0.002) and immunosuppressive therapy (HR 5.0; p=0.0002). CONCLUSIONS: Pre-pouch ileitis is associated with a higher risk of complicated disease and pouch failure than pouchitis. It should be considered a feature of CD.

3.
Inflamm Bowel Dis ; 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33155643

RESUMO

BACKGROUND: Crohn disease (CD) affects the small bowel in 80% of patients. Double balloon endoscopy (DBE) provides the potential for direct and extensive mucosal visualization with the potential for diagnostic monitoring and therapeutic intervention. This study aimed to investigate the safety and effectiveness of DBE in small-bowel CD. METHODS: From our DBE database, patients with CD at the time of index DBE (January 2004-January 2013) were identified. Data collection included demographics, CD phenotype (age at diagnosis, disease location, disease activity), procedural information, adverse events (perforation, pancreatitis, death), therapeutic intervention (stricture dilation), and outcome (escalation or maintenance of existing therapy, referral to surgery). RESULTS: A total of 184 DBEs were performed in patients with inflammatory bowel disease over 162 endoscopic sessions. In this cohort, 115 patients had previously diagnosed CD. A diagnosis of CD was made in 22 patients. Of those with known CD, 140 DBEs were performed in 82 patients; DBE findings led to escalation of medical therapy in 26% of patients, maintenance of therapy in 26% of patients, and surgery in 18% of patients. We considered DBE to have failed in 11% (n = 18) of patients. During 46 endoscopic sessions, in 29 patients, 103 strictures were dilated via balloon dilation. Of patients undergoing dilation with clinical follow-up, 19 of 24 (79%) patients were surgery-free during the study period. Overall, there were 2 perforations. CONCLUSIONS: We found that DBE is a safe and effective procedure in patients with suspected or established CD. Furthermore, patients undergoing dilation of strictures via DBE had an 80% surgery-free rate within the follow-up period.

4.
Gastroenterology ; 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33160965

RESUMO

BACKGROUND AND AIMS: The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) is highly expressed in small bowel (SB). Our aim was to identify factors influencing intestinal ACE2 expression in Crohn's disease (CD), ulcerative colitis (UC) and non-inflammatory bowel disease (non-IBD) controls. METHODS: Using bulk RNA-seq or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; CD=495; UC=387; non-IBD=94), we analyzed the relationship of ACE2 with demographics, disease activity and prognosis. We examined the outcome of anti-TNF and anti-IL12/IL-23 treatment on SB and colonic ACE2 expression in three clinical trials. Univariate and multivariate regression models were fitted. RESULTS: ACE2 levels were consistently reduced in SB CD and elevated in colonic UC, when compared to non-IBD controls. Elevated SB ACE2 was also associated with demographic features (age and elevated BMI) associated with poor COVID-19 outcomes. Within CD, SB ACE2 was reduced in patients subsequently developing complicated disease. Within UC, colonic ACE2 was elevated in active disease and in patients subsequently requiring anti-TNF rescue therapy. SB and colonic ACE2 expression in active CD and UC were restored by anti-cytokine therapy, most notably in responders. CONCLUSIONS: Reduced SB, but elevated colonic ACE2 levels in IBD are associated with inflammation and severe disease but normalized following anti-cytokine therapy suggesting compartmentalization of ACE2-related biology in SB and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy may be important in the context of SARS-CoV-2 infection and potentially explain reports of reduced morbidity from COVID-19 in IBD patients treated with anti-cytokines.

5.
Sci Rep ; 10(1): 18189, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097818

RESUMO

Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease, modulating the location and severity of inflammation and fibrosis. TL1A expression is increased in inflamed mucosa and associated with fibrostenosing Crohn's disease. Tl1a-overexpression in mice causes spontaneous ileitis, and exacerbates induced proximal colitis and fibrosis. Intestinal fibroblasts express Death-receptor 3 (DR3; the only know receptor for TL1A) and stimulation with TL1A induces activation in vitro. However, the contribution of direct TL1A-DR3 activation on fibroblasts to fibrosis in vivo remains unknown. TL1A overexpressing naïve T cells were transferred into Rag-/- , Rag-/- mice lacking DR3 in all cell types (Rag-/-Dr3-/-), or Rag-/- mice lacking DR3 only on fibroblasts (Rag-/-Dr3∆Col1a2) to induce colitis and fibrosis, assessed by clinical disease activity index, intestinal inflammation, and collagen deposition. Rag-/- mice developed overt colitis with intestinal fibrostenosis. In contrast, Rag-/-Dr3-/- demonstrated decreased inflammation and fibrosis. Despite similar clinical disease and inflammation as Rag-/-, Rag-/-Dr3∆Col1a2 exhibited reduced intestinal fibrosis and attenuated fibroblast activation and migration. RNA-Sequencing of TL1A-stimulated fibroblasts identified Rho signal transduction as a major pathway activated by TL1A and inhibition of this pathway modulated TL1A-mediated fibroblast functions. Thus, direct TL1A signaling on fibroblasts promotes intestinal fibrosis in vivo. These results provide novel insight into profibrotic pathways mediated by TL1A paralleling its pro-inflammatory effects.

6.
Aliment Pharmacol Ther ; 52(11-12): 1658-1675, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33086438

RESUMO

BACKGROUND: The ongoing UNIFI long-term extension evaluates subcutaneous ustekinumab for moderate-to-severe ulcerative colitis (UC) from weeks 44 through 220. AIMS: To assess efficacy (through week 92) and safety (through week 96) during the long-term extension METHODS: Overall, 399 responders to intravenous ustekinumab induction and who were randomised to maintenance therapy were treated in the long-term extension (115 received subcutaneous placebo, 141 received ustekinumab 90 mg every 12 weeks [q12w], and 143 received ustekinumab 90 mg q8w). Placebo treatment was discontinued at unblinding after week 44. Partial Mayo scores were collected every 12 weeks and at each dosing visit after unblinding. Safety was evaluated throughout. RESULTS: Among all patients randomised in maintenance, symptomatic remission rates (stool frequency = 0/1; rectal bleeding = 0) at week 92 were, 64.5% and 67.6% in the ustekinumab q12w and q8w groups, respectively. Among randomised patients treated in the long-term extension, 78.7% and 83.2% of patients receiving q12w and q8w, respectively, attained symptomatic remission at week 92; >95% of patients in symptomatic remission at week 92 were corticosteroid-free. Both ustekinumab groups maintained efficacy through week 92. From weeks 44 to 96, adverse events (AEs) per hundred patient-years (PY) of follow-up for combined ustekinumab vs placebo were: 255.68 vs 267.93; serious AEs, 9.34 vs 12.69; malignancies (including non-melanoma skin cancers), 0.93 vs 1.49; and serious infections, 2.33 vs 2.99. One patient with multiple comorbidities who received one ustekinumab dose after dose adjusting from placebo experienced a fatal cardiac arrest. CONCLUSIONS: The efficacy of ustekinumab in patients with UC was sustained through 92 weeks. No new safety signals were observed (ClinicalTrials.gov number, NCT02407236).

7.
Life Sci ; 262: 118220, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781075

RESUMO

AIMS: Tumor necrosis factor-like ligand 1A (TL1A) has been proved to activate adaptive immunity in inflammatory bowel disease (IBD). However, its role in the regulation of intestinal dendritic cells (DCs) has not been fully characterized. This study aims to investigate the modulation of TL1A in DCs activation in murine colitis. MATERIALS AND METHODS: Myeloid TL1A-Transgenic C57BL/6 mice and wild-type (WT) mice were administrated with dextran sulfate sodium (DSS) to explore the effects of TL1A in murine colitis. Bone marrow-derived DCs (BMDCs) were isolated to detect the ability of antigen phagocytosis and presentation. The expression of nuclear factor-κB (NF-κB) pathway and chemokines receptors (CCRs) was assessed by real-time PCR and Western blot. KEY FINDINGS: Myeloid cells with constitutive TL1A expression developed worsened murine colitis with exacerbated TH1/TH17 cytokine responses. Intestinal DCs from TL1A transgenic mice expressed high levels of costimulatory molecules (CD80 and CD86) with increased pro-inflammatory cytokines of IL-1ß, TNF-α and IL-12/23 p40. Mechanistic studies showed that TL1A enhanced the phagocytotic ability of BMDCs. Moreover, TL1A enhanced the capacity of antigen process and presentation in BMDCs. Besides, TL1A induced the phosphorylation of NF-κB(p65) and IκBα. Meanwhile, higher expression of CCR2, CCR5, CCR7, and CX3CR1 was observed both in vivo and in vitro. SIGNIFICANCE: TL1A exacerbated DSS-induced chronic experimental colitis, probably through activation and migration of dendritic cells, and therefore increasing the secretion of pro-inflammatory cytokines.

8.
medRxiv ; 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32511625

RESUMO

Angiotensin-Converting Enzyme 2 ( ACE2 ) has been identified as the host receptor for SARS-coronavirus 2 (SARS-CoV-2) which has infected millions world-wide and likely caused hundreds of thousands of deaths. Utilizing transcriptomic data from four cohorts taken from Crohn's disease (CD) and non-inflammatory bowel disease (IBD) subjects, we observed evidence of increased ACE2 mRNA in ileum with demographic features that have been associated with poor outcomes in COVID-19 including age and raised BMI. ACE2 was downregulated in CD compared to controls in independent cohorts. Within CD, ACE2 expression was reduced in inflamed ileal tissue and also remarkably, from uninvolved tissue in patients with a worse prognosis in both adult and pediatric cohorts. In active CD, small bowel ACE2 expression was restored by anti-TNF therapy particularly in anti-TNF responders. Collectively our data suggest that ACE2 downregulation is associated with inflammation and worse outcomes in CD.

9.
Dig Dis Sci ; 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170473

RESUMO

BACKGROUND AND AIMS: Infliximab rescue therapy is effective in patients with corticosteroid refractory acute severe ulcerative colitis, but predictors of response remain poorly understood. We aimed to identify predictors of colectomy in this high-risk patient population. METHODS: Patients hospitalized with acute severe ulcerative colitis who received infliximab after failing intravenous corticosteroid therapy between July 2012 and June 2017 were retrospectively identified. Stepwise regression with backward elimination was used to identify predictors of colectomy at 90 days and 1 year. Ninety-day and 1-year colectomy rates were compared between the patients who received 5 mg/kg and 10 mg/kg IFX rescue dose. RESULTS: Sixty-three patients met the eligibility criteria. Twenty-nine patients received 5 mg/kg, and 34 received 10 mg/kg infliximab dose. Serum albumin on admission (OR 0.10; p = 0.04) and band neutrophil percentage at the time of infliximab administration (OR 1.21; p = 0.02) were independent predictors of 90-day colectomy. A combination of serum albumin ≤ 2.5 g/dl and band neutrophil count ≥ 13% had a 100% positive predictive value for 90-day colectomy. Unadjusted 90-day and 1-year colectomy rates were similar in the 5 mg/kg and 10 mg/kg infliximab groups. After adjusting for confounding factors, 10 mg/kg infliximab dose was potentially protective for 90-day (OR 0.07; p = 0.06) but not for 1-year colectomy (OR 0.19; p = 0.16). CONCLUSIONS: Bandemia and low serum albumin are independent predictors of failure of infliximab rescue therapy in acute severe ulcerative colitis. Serum albumin ≤ 2.5 g/dl and band neutrophil count ≥ 13% had a 100% positive predictive value for 90-day colectomy.

10.
Int J Mol Sci ; 21(4)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093254

RESUMO

In inflammatory bowel disease (IBD), the intestinal epithelium is characterized by increased permeability both in active disease and remission states. The genetic underpinnings of this increased intestinal permeability are largely unstudied, in part due to a lack of appropriate modelling systems. Our aim is to develop an in vitro model of intestinal permeability using induced pluripotent stem cell (iPSC)-derived human intestinal organoids (HIOs) and human colonic organoids (HCOs) to study barrier dysfunction. iPSCs were generated from healthy controls, adult onset IBD, and very early onset IBD (VEO-IBD) patients and differentiated into HIOs and HCOs. EpCAM+ selected cells were seeded onto Transwell inserts and barrier integrity studies were carried out in the presence or absence of pro-inflammatory cytokines TNFα and IFNγ. Quantitative real-time PCR (qRT-PCR), transmission electron microscopy (TEM), and immunofluorescence were used to determine altered tight and adherens junction protein expression or localization. Differentiation to HCO indicated an increased gene expression of CDX2, CD147, and CA2, and increased basal transepithelial electrical resistance compared to HIO. Permeability studies were carried out in HIO- and HCO-derived epithelium, and permeability of FD4 was significantly increased when exposed to TNFα and IFNγ. TEM and immunofluorescence imaging indicated a mislocalization of E-cadherin and ZO-1 in TNFα and IFNγ challenged organoids with a corresponding decrease in mRNA expression. Comparisons between HIO- and HCO-epithelium show a difference in gene expression, electrophysiology, and morphology: both are responsive to TNFα and IFNγ stimulation resulting in enhanced permeability, and changes in tight and adherens junction architecture. This data indicate that iPSC-derived HIOs and HCOs constitute an appropriate physiologically responsive model to study barrier dysfunction and the role of the epithelium in IBD and VEO-IBD.


Assuntos
Colo/metabolismo , Regulação da Expressão Gênica , Células-Tronco Pluripotentes Induzidas/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Modelos Biológicos , Linhagem Celular , Colo/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/patologia , Organoides/metabolismo , Organoides/patologia
11.
Int J Mol Sci ; 22(1)2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-33396621

RESUMO

Human intestinal organoids (HIOs) are increasingly being used to model intestinal responses to various stimuli, yet few studies have confirmed the fidelity of this modeling system. Given that the interferon-gamma (IFN-γ) response has been well characterized in various other cell types, our goal was to characterize the response to IFN-γ in HIOs derived from induced pluripotent stem cells (iPSCs). To achieve this, iPSCs were directed to form HIOs and subsequently treated with IFN-γ. Our results demonstrate that IFN-γ phosphorylates STAT1 but has little effect on the expression or localization of tight and adherens junction proteins in HIOs. However, transcriptomic profiling by microarray revealed numerous upregulated genes such as IDO1, GBP1, CXCL9, CXCL10 and CXCL11, which have previously been shown to be upregulated in other cell types in response to IFN-γ. Notably, "Response to Interferon Gamma" was determined to be one of the most significantly upregulated gene sets in IFN-γ-treated HIOs using gene set enrichment analysis. Interestingly, similar genes and pathways were upregulated in publicly available datasets contrasting the gene expression of in vivo biopsy tissue from patients with IBD against healthy controls. These data confirm that the iPSC-derived HIO modeling system represents an appropriate platform to evaluate the effects of various stimuli and specific environmental factors responsible for the alterations in the intestinal epithelium seen in various gastrointestinal conditions such as inflammatory bowel disease.

12.
N Engl J Med ; 381(13): 1201-1214, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31553833

RESUMO

BACKGROUND: The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown. METHODS: We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). RESULTS: The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P<0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P<0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo. CONCLUSIONS: Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Ustekinumab/uso terapêutico , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Quimioterapia de Indução , Infusões Intravenosas , Injeções Subcutâneas , Quimioterapia de Manutenção , Masculino , Gravidade do Paciente , Indução de Remissão/métodos , Ustekinumab/administração & dosagem , Ustekinumab/efeitos adversos
14.
J Crohns Colitis ; 13(8): 1055-1066, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30877309

RESUMO

BACKGROUND AND AIMS: Heterogeneity in Crohn's disease [CD] provides a challenge for the development of effective therapies. Our goal was to define a unique molecular signature for severe, refractory CD to enable precision therapy approaches to disease treatment and to facilitate earlier intervention in complicated disease. METHODS: We analysed clinical metadata, genetics, and transcriptomics from uninvolved ileal tissue from CD patients who underwent a single small bowel resection. We determined transcriptional risk scores, cellular signatures, and mechanistic pathways that define patient subsets in refractory CD. RESULTS: Within refractory CD, we found three CD patient subgroups [CD1, CD2, and CD3]. Compared with CD1, CD3 was enriched for subjects with increased disease recurrence after first surgery [OR = 6.78, p = 0.04], enhanced occurrence of second surgery [OR = 5.07, p = 0.016], and presence of perianal CD [OR = 3.61, p = 0.036]. The proportion of patients with recurrence-free survival was smaller in CD3 than in CD1 (p = 0.02, median survival time [months] in CD1 = 10 and CD3 = 6). Overlaying differential gene expression between CD1 and CD3 on CD subgroup-associated genetic polymorphisms identified 174 genes representing both genetic and biological differences between the CD subgroups. Pathway analyses using this unique gene signature indicated eukaryotic initiation factor 2 [eIF2] and cyclic adenosine monophosphate [cAMP] signalling to be dominant pathways associated with CD3. Furthermore, the severe, refractory subset, CD3, was associated with a higher transcriptional risk score and enriched with eosinophil and natural killer T [NKT] cell gene signatures. CONCLUSION: We characterized a subset of severe, refractory CD patients who may need more aggressive treatment after first resection and who are likely to benefit from targeted therapy based on their genotype and tissue gene expression signature.


Assuntos
Anti-Inflamatórios/farmacologia , Doença de Crohn , Íleo , Testes Farmacogenômicos , Transdução de Sinais/genética , Adolescente , Adulto , Criança , Doença de Crohn/diagnóstico , Doença de Crohn/epidemiologia , Doença de Crohn/genética , Doença de Crohn/terapia , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Perfilação da Expressão Gênica/estatística & dados numéricos , Estudo de Associação Genômica Ampla , Humanos , Íleo/metabolismo , Íleo/patologia , Íleo/cirurgia , Masculino , Seleção de Pacientes , Índice de Gravidade de Doença , Estados Unidos
15.
Science ; 363(6430): 993-998, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30819965

RESUMO

Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell-dependent and -independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response.


Assuntos
Estresse do Retículo Endoplasmático , Células Epiteliais/imunologia , Imunidade nas Mucosas , Imunoglobulina A/imunologia , Mucosa Intestinal/imunologia , Animais , Autofagia , Proteínas Relacionadas à Autofagia/genética , Humanos , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmócitos/imunologia , Técnicas de Cultura de Tecidos , Proteína 1 de Ligação a X-Box/genética
16.
Cell Host Microbe ; 25(3): 377-388.e6, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30850233

RESUMO

Inflammatory bowel disease (IBD) is characterized by alterations in the intestinal microbiota and altered immune responses to gut microbiota. Evidence is accumulating that IBD is influenced by not only commensal bacteria but also commensal fungi. We characterized fungi directly associated with the intestinal mucosa in healthy people and Crohn's disease patients and identified fungi specifically abundant in patients. One of these, the common skin resident fungus Malassezia restricta, is also linked to the presence of an IBD-associated polymorphism in the gene for CARD9, a signaling adaptor important for anti-fungal defense. M. restricta elicits innate inflammatory responses largely through CARD9 and is recognized by Crohn's disease patient anti-fungal antibodies. This yeast elicits strong inflammatory cytokine production from innate cells harboring the IBD-linked polymorphism in CARD9 and exacerbates colitis via CARD9 in mouse models of disease. Collectively, these results suggest that targeting specific commensal fungi may be a therapeutic strategy for IBD.


Assuntos
Colite/patologia , Colite/fisiopatologia , Doença de Crohn/patologia , Doença de Crohn/fisiopatologia , Trato Gastrointestinal/microbiologia , Malassezia/crescimento & desenvolvimento , Malassezia/isolamento & purificação , Animais , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Camundongos
17.
Mucosal Immunol ; 12(3): 644-655, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30617301

RESUMO

T helper 9 (TH9) cells are important for the development of inflammatory and allergic diseases. The TH9 transcriptional network converges signals from cytokines and antigen presentation but is incompletely understood. Here, we identified TL1A, a member of the TNF superfamily, as a strong inducer of mouse and human TH9 differentiation. Mechanistically, TL1A induced the expression of the transcription factors BATF and BATF3 and facilitated their binding to the Il9 promoter leading to enhanced secretion of IL-9. BATF- and BATF3-deficiencies impaired IL-9 secretion under TH9 and TH9-TL1A-polarizing conditions. In vivo, using a T-cell transfer model, we demonstrated that TL1A promoted IL-9-dependent, TH9 cell-induced intestinal and lung inflammation. Neutralizing IL-9 antibodies attenuated TL1A-driven mucosal inflammation. Batf3-/- TH9-TL1A cells induced reduced inflammation and cytokine expression in vivo compared to WT cells. Our results demonstrate that TL1A promotes TH9 cell differentiation and function and define a role for BATF3 in T-cell-driven mucosal inflammation.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Interleucina-9/metabolismo , Proteínas Repressoras/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Anticorpos Neutralizantes/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Diferenciação Celular , Células Cultivadas , Humanos , Interleucina-9/genética , Interleucina-9/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas Repressoras/genética , Transdução de Sinais , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo
18.
J Clin Rheumatol ; 25(1): 45-49, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29794876

RESUMO

OBJECTIVES: Avascular necrosis (AVN) is associated with significant morbidity potentially causing severe pain and disability; patients with inflammatory bowel disease (IBD) have a higher prevalence of AVN compared with non-IBD populations. The purpose of our study was to determine the prevalence of AVN in our IBD population and to evaluate these subjects for the presence of clinical characteristics associated with AVN on computed tomography (CT) imaging. METHODS: In 1313 IBD patients with abdomen/pelvis CT scans, we identified 27 patients (2.1%) with CT findings consistent with AVN. Through historical chart review, we confirmed that most patients had prior exposure to steroids, although 2 patients had no documented steroid exposure at all. RESULTS: We found that 59% of the concurrent radiology reports did not comment on the presence of AVN, suggesting that incidental CT findings of AVN among IBD patients are likely underreported. Notably, we found that 63% of these cases had documented complaints of low-back and/or hip pain. Using logistic regression, we found an association between anti-neutrophil cytoplasmic antibody-positive status across IBD (p = 0.007) and a smoking history in Crohn disease (p = 0.03) with the presence of AVN. CONCLUSIONS: We found that a significant proportion of IBD patients with AVN are reported in their records as having hip or low-back pain, and review of CT imaging under dedicated bone windows may identify AVN among this population. Our findings also suggest that additional etiological factors, beyond corticosteroids, contribute to the development of AVN in IBD. Further investigation is warranted regarding the mechanisms associated with AVN in IBD.


Assuntos
Doenças Inflamatórias Intestinais/complicações , Osteonecrose/epidemiologia , Ossos Pélvicos , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Estudos de Coortes , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Osteonecrose/diagnóstico por imagem , Prevalência , Tomografia Computadorizada por Raios X , Adulto Jovem
19.
Immunity ; 49(6): 1077-1089.e5, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30552020

RESUMO

Inflammatory bowel disease (IBD) results from a dysregulated interaction between the microbiota and a genetically susceptible host. Genetic studies have linked TNFSF15 polymorphisms and its protein TNF-like ligand 1A (TL1A) with IBD, but the functional role of TL1A is not known. Here, we found that adherent IBD-associated microbiota induced TL1A release from CX3CR1+ mononuclear phagocytes (MNPs). Using cell-specific genetic deletion models, we identified an essential role for CX3CR1+MNP-derived TL1A in driving group 3 innate lymphoid cell (ILC3) production of interleukin-22 and mucosal healing during acute colitis. In contrast to this protective role in acute colitis, TL1A-dependent expression of co-stimulatory molecule OX40L in MHCII+ ILC3s during colitis led to co-stimulation of antigen-specific T cells that was required for chronic T cell colitis. These results identify a role for ILC3s in activating intestinal T cells and reveal a central role for TL1A in promoting ILC3 barrier immunity during colitis.


Assuntos
Colite/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Microbiota/imunologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Adulto , Idoso , Animais , Colite/genética , Colite/metabolismo , Feminino , Humanos , Imunidade Inata/genética , Interleucinas/genética , Interleucinas/imunologia , Interleucinas/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Linfócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microbiota/fisiologia , Pessoa de Meia-Idade , Fagócitos/citologia , Fagócitos/imunologia , Fagócitos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Adulto Jovem
20.
Mucosal Immunol ; 11(5): 1466-1476, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29988118

RESUMO

Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease (IBD), modulating the location and severity of intestinal inflammation and fibrosis. TL1A expression is increased in inflamed gut mucosa and associated with fibrostenosing Crohn's disease. Tl1a-overexpression in mice lead to spontaneous ileitis, and exacerbated induced proximal colitis and fibrosis. IBD is associated with shifts in the gut microbiome, but the effect of differing microbial populations and their interaction with TL1A on fibrosis has not been investigated. We demonstrate that the pro-fibrotic and inflammatory phenotype resulting from Tl1a-overexpression is abrogated in the absence of resident microbiota. To evaluate if this is due to the absence of a unique bacterial population, as opposed to any bacteria per se, we gavaged germ-free (GF) wild-type and Tl1a-transgenic (Tl1a-Tg) mice with stool from specific pathogen free (SPF) mice and a healthy human donor (Hu). Reconstitution with SPF, but not Hu microbiota, resulted in increased intestinal collagen deposition and fibroblast activation in Tl1a-Tg mice. Notably, there was reduced fibroblast migration and activation under GF conditions compared to native conditions. We then identified several candidate organisms that correlated directly with increased fibrosis in reconstituted mice and showed that these organisms directly impact fibroblast function in vitro. Thus, Tl1a-mediated intestinal fibrosis and fibroblast activation are dependent on specific microbial populations.


Assuntos
Fibrose/metabolismo , Fibrose/microbiologia , Microbioma Gastrointestinal/fisiologia , Inflamação/metabolismo , Intestinos/microbiologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Animais , Colite/metabolismo , Colite/microbiologia , Colágeno/metabolismo , Doença de Crohn/metabolismo , Doença de Crohn/microbiologia , Fibroblastos/metabolismo , Fibroblastos/microbiologia , Humanos , Ileíte/metabolismo , Ileíte/microbiologia , Inflamação/microbiologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
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