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1.
FASEB Bioadv ; 1(10): 624-638, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31803861

RESUMO

Exosomes are nano-sized vesicles that are involved in various biological processes including cell differentiation, proliferation, signaling, and intercellular communication. Urinary exosomes were isolated from a cohort of hereditary α-tryptasemia (HαT) patients and from healthy volunteers. There was a greater number of exosomes isolated from the urine in the HαT group compared to the control volunteers. Here, we investigated the differences in both lipid classes and lipid species within urinary exosomes of the two groups. Lipids were extracted from urinary exosomes and subjected to liquid chromatography mass spectrometry using a targeted approach. Various molecular species of glycerophospholipids, glycerolipids, and sterols were significantly reduced in HαT patients. Out of a possible 1127 lipids, 521 lipid species were detected, and relative quantities were calculated. Sixty-four lipids were significantly reduced in urinary exosomes of HαT patients compared to controls. All significantly reduced sphingolipids and most of the phospholipids were saturated or mono-unsaturated lipids. These results suggest exosome secretion is augmented in HαT patients and the lipids within these exosomes may be involved in various biological processes. The unique lipid composition of urinary exosomes from HαT patients will contribute to our understanding of the biochemistry of this disease.

2.
Inflamm Bowel Dis ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31553433

RESUMO

OBJECTIVE: Mucosal barrier dysfunction plays a crucial role in intestinal inflammation in Crohn's disease (CD). Intestinal epithelial cell (IEC) death resulting from innate immune activation, termed pyroptosis, was recently found to be a cause of this barrier defect. The aim of this study was to determine the predictive value of pretreatment ileal biopsy pyroptosis as a biomarker for clinical response to vedolizumab in CD. DESIGN: Crohn's disease patients ranging 18 to 80 years old from 5 IBD centers with pre-vedolizumab ileal biopsies during colonoscopy were enrolled. Biopsies were stained for activated caspases, and levels of ileal IEC pyroptosis levels were quantified. The primary outcome was clinical response 6 months after therapy, defined as a reduction of Harvey-Bradshaw Index (HBI) of ≥5 points from baseline. Secondary outcomes included clinical remission, defined as HBI <5, and endoscopic improvement, as measured by the Simple Endoscopic Score for Crohn's Disease (SES-CD). RESULTS: One hundred CD patients (45 male, 55 female), median age 47 (19, 78) years, were included; clinical response rate was 60%, and clinical remission was 36%. The response rate in patients with ileal pyroptosis <14 positive cells per 1000 IECs was significantly higher than those above the threshold: 89% (25 of 28) vs 49% (35 of 72), odds ratio (OR) 8.8 (95% CI, 2.3-48.6; P < 0.001). Corresponding remission rates were 54% (15 of 28) vs 29% (21 of 72; OR 2.8 [1.03-7.59; P = 0.036]). For endoscopic improvement, ileal pyroptosis of 22 positive cells per 1000 IECs was the optimal threshold that determines the magnitude SES-CD change. CONCLUSIONS: Ileal biopsy IEC pyroptosis was predictive of clinical response and endoscopic improvement to vedolizmab in CD patients.

3.
J Immunol Res ; 2019: 9406146, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31321245

RESUMO

Crohn's disease (CD) results from dysregulated immune responses to gut microbiota in genetically susceptible individuals, affecting multiple areas of the gastrointestinal tract. Innate lymphoid cells (ILCs) are tissue-resident innate effector lymphocytes which play crucial roles in mucosal immune defense, tissue repair, and maintenance of homeostasis. The accumulation of IFN-γ-producing ILC1s and increased level of proinflammatory cytokines produced by ILCs has been observed in the inflamed terminal ileum of CD patients. To date, the precise mechanisms of ILC plasticity and gene regulatory pathways in ILCs remain unclear. Signal transducer and activator of transcription 3 (STAT3) regulates gene expression in a cell-specific, cytokine-dependent manner, involving multiple immune responses. This study proposes the positive correlation between the prevalence of STAT3 rs744166 risky allele "A" with the severity of disease in a cohort of 94 CD patients. In addition, the results suggest an increased STAT3 activity in the inflamed ileum of CD patients, compared to unaffected ileum sections. Notably, IL-23 triggers the differentiation of CD117+NKp44- ILC3s and induces the activation of STAT3 in both CD117+NKp44- and CD117-NKp44- ILC subsets, implying the involvement of STAT3 in the initiation of ILC plasticity. Moreover, carriage of STAT3 "A" risk allele exhibited a higher basal level of STAT3 tyrosine phosphorylation, and an increased IL-23 triggered the pSTAT3 level. We also demonstrated that there was no delayed dephosphorylation of STAT3 in ILCs of both A/A and G/G donors. Overall, the results of this study suggest that IL-23-induced activation of STAT3 in the CD117-NKp44- ILC1s involves in ILC1-to-ILC3 plasticity and a potential regulatory role of ILC1 function. Those genetically susceptible individuals carried STAT3 rs744166 risky allele appear to have higher basal and cytokine-stimulated activation of STAT3 signal, leading to prolonged inflammation and chronic relapse.


Assuntos
Doença de Crohn/genética , Linfócitos/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Doença de Crohn/imunologia , Doença de Crohn/patologia , Doença de Crohn/cirurgia , Progressão da Doença , Humanos , Íleo/imunologia , Íleo/cirurgia , Imunidade Inata/genética , Inflamação/metabolismo , Interleucina-23/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Receptor 2 Desencadeador da Citotoxicidade Natural/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-kit/metabolismo , Fator de Transcrição STAT3/química , Tirosina/química
4.
Gastroenterology ; 157(4): 1007-1018.e7, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31279871

RESUMO

BACKGROUND & AIMS: Vedolizumab is a gut-selective monoclonal antibody for the treatment of moderately to severely active Crohn's disease (CD). We performed a prospective study of endoscopic, radiologic, and histologic healing in patients with CD who received vedolizumab therapy. METHODS: We performed a phase 3b, open-label, single-group study of 101 patients with at least 3 months of active CD (a CD Activity Index [CDAI] score of 220-450, a simple endoscopic score for CD [SES-CD] of 7 or more, 1 or more mucosal ulcerations [identified by endoscopy], and failure of conventional therapy) from March 2015 through December 2017. Among the patients enrolled, 54.5% had previous failure of 1 or more tumor necrosis factor (TNF) antagonists and 44.6% had severe endoscopic disease activity (SES-CD scores above 15) at baseline. Participants received vedolizumab (300 mg intravenously) at weeks 0, 2, and 6, and then every 8 weeks thereafter, for 26 weeks (primary study) or 52 weeks (substudy, 56 patients). The primary endpoint at week 26 was endoscopic remission (SES-CD score of 4 or less); other endpoints included endoscopic response (50% reduction in SES-CD), radiologic remission (magnetic resonance index of activity score below 7), and histologic response (modified global histologic disease activity score of 4 or less). RESULTS: At week 26, 11.9% of patients were in endoscopic remission (95% confidence interval [CI] 6.3-9.8); at week 52, 17.9% of the patients were in endoscopic remission (95% CI 8.9-30.4). Higher proportions of patients naïve to TNF antagonists achieved endoscopic remission than patients with TNF-antagonist-failure at weeks 26 and 52. Higher proportion of patients with moderate CD (SES-CD scores, 7-15) achieved endoscopic remission at weeks 26 and 52 than patients with severe CD (SES-CD scores above 15). The proportion of patients with complete mucosal healing increased over time, with greater rates of healing in the colon than in the ileum. Remission was detected by magnetic resonance enterography in 21.9% of patients at week 26 (95% CI 9.3-40.0) and in 38.1% at week 52 (95% CI 18.1-61.6). At week 26, 24.4% of patients had a histologic response in the colon (95% CI 15.3-35.4) and 28.3% of patients had a histologic response in the ileum (95% CI 17.5-41.4). At week 52, 20.5% of patients had a histologic response in the colon (95% CI 9.8-35.3) and 34.3% of patients had a histologic response in the ileum (95% CI 19.1-52.2). There were no notable safety issues, including worsening of extraintestinal manifestations. CONCLUSIONS: In a phase 3b trial, we found that 26 and 52 weeks of treatment with vedolizumab (300 mg, at weeks 0, 2, and 6, and then every 8 weeks thereafter) induces endoscopic, radiologic, and histologic healing in patients with moderately to severely active CD. ClinicalTrials.gov no: NCT02425111.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Doença de Crohn/tratamento farmacológico , Endoscopia Gastrointestinal , Fármacos Gastrointestinais/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Imagem por Ressonância Magnética , Cicatrização/efeitos dos fármacos , Adulto , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Biópsia , Doença de Crohn/diagnóstico por imagem , Doença de Crohn/patologia , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Qualidade de Vida , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
5.
Gastroenterol Rep (Oxf) ; 7(2): 107-114, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30976423

RESUMO

Background: Despite major advances in the medical management of Crohn's disease (CD), a significant proportion of patients will require surgery within 5 years of diagnosis. Malnutrition is an independent risk factor for adverse post-operative outcomes following gastrointestinal surgery. Data on the value of pre-operative total parenteral nutrition (TPN) in CD patients are mixed and there is a paucity of data in the biologic era. We aimed to define the role of pre-operative TPN in this population. Methods: This was a retrospective cohort study conducted at a tertiary referral center. CD patients who underwent major abdominal surgery were identified. Patients receiving pre-operative TPN were compared to controls. We compared the incidence of 30-day infectious and non-infectious post-operative complications between the two groups. Results: A total of 144 CD patients who underwent major abdominal surgery between March 2007 and March 2017 were included. Fifty-five patients who received pre-operative TPN were compared to 89 controls. Twenty-one (14.6%) patients developed infectious complications (18.2% in TPN group vs 12.3% in non-TPN group, P = 0.34) and 23 (15.9%) developed non-infectious complications (14.5% in TPN group vs 16.9% in non-TPN group, P = 0.71). In a multivariate analysis, controlling for differences in baseline disease severity and malnutrition between groups, patients receiving pre-operative TPN for ≥60 days had significantly lower odds of developing non-infectious complications (odds ratio 0.07, 95% confidence interval: 0.01-0.80, P = 0.03). Weight loss of >10% in the past 6 months was a significant predictor of post-operative complications. Conclusions: In a subset of malnourished CD patients, TPN is safe and allows comparable operative outcomes to controls. Pre-operative TPN for ≥60 days reduced post-operative non-infectious complications without associated increase in infectious complications.

6.
Inflamm Bowel Dis ; 25(8): 1417-1427, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30839057

RESUMO

BACKGROUND AND AIMS: Medication persistence, defined as the time from drug initiation to discontinuation of therapy, has been suggested as a proxy for real-world therapeutic benefit and safety. This study seeks to compare the persistence of biologic drugs among patients with inflammatory bowel disease (IBD). METHODS: Patients with newly diagnosed IBD were included in a retrospective study using Truven MarketScan database. Treatment persistence and switching was compared among biologic medications including infliximab, adalimumab, certolizumab, golimumab, and vedolizumab. Predictors for discontinuation and switching were evaluated using time-dependent proportional hazard regression. RESULTS: In total, 5612 patients with Crohn's disease (CD) and 3533 patients with ulcerative colitis (UC) were included in this analysis. Less than half of the patients continued using their initial biologic treatment after 1 year (48.48% in CD cohort; 44.78% in UC cohort). In the first year, adalimumab had the highest persistence and lowest switching rates for both CD (median survival time: 1.04 years) and UC (median survival time: 0.84 years). In subsequent years, infliximab users were more likely to persist in the use of biologic. Combination therapy with immunomodulators significantly decreased the risk of discontinuation, especially when immunomodulator therapy was started more than 30 days before the biologic (hazard ratio [HR], 0.22; CI, 0.16, 0.32). The major predictors for noncompliance included infection and hospitalization. CONCLUSION: Overall, the persistence profiles of biologics suggest a high rate of dissatisfaction or adverse disease outcomes resulting in discontinuation and switching to a different agent. Early initiation of immunomodulators will substantially increase the persistence of biologic treatment.

7.
In Vivo ; 33(1): 251-254, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30587632

RESUMO

Pyogenic granuloma (PG) represents a lobular capillary proliferation commonly seen in the skin or oral mucosa. They are rarely reported in the gastrointestinal tract. The mechanism underlying PG pathogenesis is not well understood. Only one case of cutaneous PG associated with cytomegalovirus (CMV) infection has been reported in the English literature. Here, we report such a unique case of PG arising from the small bowel. A 67-year-old male, status post ileocolic resection, presented for follow-up colonoscopy because of Crohn's disease of the terminal ileum and the colon. Colonoscopy revealed inflammation at the ileocolic anastomosis as well as an 8-mm pedunculated lesion with an irregular surface in the neo-terminal ileum. Histological studies of the small bowel mucosa revealed chronic active ileitis with pyloric gland metaplasia, consistent with his clinical history of Crohn's disease. The lesion demonstrated a lobular architecture consisting of clusters of small capillaries of various sizes lined by a single layer of cytologically bland endothelial cells, and accompanied by acute and chronic inflammatory infiltrates and surface erosion/ulceration. The histological features supported the diagnosis of PG. Scattered viral inclusions with positive CMV immunoreactivity were present in the endothelial cells and glandular cells of pyloric gland metaplasia within the PG. To the best of our knowledge, this is the first documented case of PG with local CMV infection in patients with inflammatory bowel disease.


Assuntos
Doença de Crohn/patologia , Infecções por Citomegalovirus/patologia , Granuloma Piogênico/patologia , Doenças Inflamatórias Intestinais/patologia , Idoso , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/virologia , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/virologia , Trato Gastrointestinal/patologia , Trato Gastrointestinal/virologia , Granuloma Piogênico/complicações , Granuloma Piogênico/diagnóstico , Granuloma Piogênico/virologia , Humanos , Íleo/patologia , Íleo/virologia , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/virologia , Mucosa Intestinal/patologia , Mucosa Intestinal/virologia , Intestino Delgado/patologia , Intestino Delgado/virologia , Masculino
8.
Am Surg ; 84(9): 1526-1530, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30268188

RESUMO

Although the effects of biologic agents on postoperative outcomes in Crohn's disease patients have been extensively studied, the effects on intraoperative outcomes, including blood loss, operative time, and length of small bowel resection, remain to be determined. This was a retrospective cohort study at a single tertiary referral center. Crohn's disease (CD) patients who underwent major abdominal surgery were identified. Patients receiving preoperative biologic agents were compared with controls. We compare operative outcomes between groups. A total of 144 patients who underwent major abdominal surgery at the University of Florida between March 2007 and March 2017 were included. One hundred and ten patients (76%) who received preoperative biologic therapy were compared with 34 controls. On univariate analysis, preoperative biologic use was associated with a significantly shorter length of small bowel resection (21.2 cm in biologic group vs 34.5 cm, P = 0.01). There were no significant differences in intraoperative blood loss (100 vs 87.5 mL, P = 0.40) or total operative time (142 vs 154 minutes, P = 0.39) between groups. On multivariate analysis controlling for variables reflecting severity of disease and malnutrition, biologic use remained significantly associated with shorter length of bowel resection (incident rate ratio 0.58, P = 0.04). Preoperative biologic use is associated with a significantly shorter length of bowel resection in CD patients undergoing major abdominal surgery. No negative effects were noted on operative blood loss or total operative time. Our findings allow improved preoperative planning for surgeons and informed decision-making for CD patients undergoing major abdominal surgery.


Assuntos
Fatores Biológicos/uso terapêutico , Doença de Crohn/cirurgia , Complicações Pós-Operatórias/epidemiologia , Cuidados Pré-Operatórios , Adolescente , Adulto , Idoso , Perda Sanguínea Cirúrgica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
9.
Gastroenterol Res Pract ; 2018: 7890161, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30344603

RESUMO

Patients with inflammatory bowel disease (IBD) commonly require surgery despite the availability of an increasingly large repertoire of powerful immunosuppressive medications for the treatment of IBD. Optimizing patients' care preoperatively is crucial to obtaining good surgical outcomes. This review discusses preoperative assessment and management principles including assessing disease location and activity with cross-sectional or endoscopic imaging, addressing modifiable risk factors (i.e., stopping smoking, weaning steroids, and correcting anemia), and properly managing medications. The major focus of our literature review is the evaluation for malnutrition, a common finding that affects up to 70% of patients with IBD and a well-known, independent risk factor for adverse postoperative outcomes. Our review confirms that whenever feasible, oral or enteral nutrition (EN) is the preferred method of nutritional support; parenteral nutrition (PN) should be reserved for nutritionally deficient IBD patients unable to tolerate EN. In selected patients, recent data demonstrated that the use of preoperative PN resulted in improved nutritional status, fewer postoperative complications, and reduced disease severity. Our review highlights the need for well-designed, prospective trials investigating perioperative nutritional support in patients with IBD. Future studies should perform modern nutritional assessment, standardize for diet, and include patients with UC since this subset of patients is underrepresented in existing studies. In addition, relevant outcome of interest specific to Crohn's disease (CD) patients such as length of small bowel resected, number of anastomoses, and need for an ostomy should be included as these patients may require repeated small bowel resections.

10.
Arch Immunol Ther Exp (Warsz) ; 66(6): 415-421, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30155762

RESUMO

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a complex chronic inflammatory condition of the human gut of unknown causes. Traditionally, dysregulated adaptive immune responses are thought to play a major role; however, accumulating evidence suggests that innate immunity also contributes to this process. Innate lymphoid cells (ILCs) are recently identified important components of innate immunity. They have critical roles in immunity, tissue development and remodeling. Numerous researchers have linked ILCs to the pathogenesis of IBD. In this review, we describe recent progress in our understanding about the phenotype and function alterations of ILCs as well as its interactions with other key mucosal cells in the gut of IBD patients. A better delineation of the ILCs' behavior in the human intestine will contribute to our understanding of ILCs biology and provide valuable insights for potential therapeutic target selection for IBD patients.


Assuntos
Imunidade Inata , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Linfócitos/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa , Animais , Humanos
11.
PLoS One ; 13(7): e0200377, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29995938

RESUMO

Inflammatory bowel disease (IBD) continues to increase in prevalence in industrialized countries. Major complications of IBD include formation of fibrotic strictures, fistulas, reduced absorptive function, cancer risk, and the need for surgery. In other chronic gastrointestinal disease models, stiffness has been shown to precede fibrosis; therefore, stiffness may be a reasonable indicator of progression toward stricture formation in IBD patients. Herein, we seek to quantify tissue stiffness and characterize fibrosis in patients with IBD and to compare mechanical properties of unaffected human tissue to common animal species used for IBD studies. Inflamed and unaffected tissue from IBD patients and unaffected tissue from mice, pigs, and cows were indented using a custom device to determine the effective stiffness. Histology was performed on matched tissues, and total RNA was isolated from IBD tissue samples and used for gene expression analysis of pro-fibrotic genes. We observed an increase in the effective stiffness (steady-state modulus, SSM) (p < 0.0001) and increased expression of the collagen type I gene (COL1A1, p = 0.01) in inflamed tissue compared to unaffected areas in our IBD patient cohort. We also found that increased staining of collagen fibers in submucosa positively correlated with SSM (p = 0.093). We determined that unaffected animal bowel stiffness is significantly greater than similar human tissues, suggesting additional limitations on animal models for translational investigations regarding stiffness-related hypotheses. Taken together, our data support development of tools for evaluation of bowel stiffness in IBD patients for prognostic applications that may enable more accurate prediction of those who will develop fibrosis and more precise prescription of aggressive therapies.


Assuntos
Fibrose/complicações , Fibrose/fisiopatologia , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/fisiopatologia , Intestinos/fisiopatologia , Adulto , Idoso , Animais , Bovinos , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Elasticidade , Feminino , Fibrose/patologia , Expressão Gênica , Humanos , Inflamação/complicações , Inflamação/patologia , Inflamação/fisiopatologia , Doenças Inflamatórias Intestinais/patologia , Intestinos/patologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Especificidade da Espécie , Suínos , Adulto Jovem
12.
Inflamm Bowel Dis ; 23(11): 1950-1961, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29023267

RESUMO

BACKGROUND: IL10 receptor (IL10R) deficiency causes severe infantile-onset inflammatory bowel disease. Intact IL10R-dependent signals have been shown to be important for innate and adaptive immune cell functions in mice. We have previously reported a key role of IL10 in the generation and function of human anti-inflammatory macrophages. Independent of innate immune cell defects, the aim of the current study was to determine the role of IL10R signaling in regulating human CD4 T-cell function. METHODS: Peripheral blood mononuclear cells and intestinal biopsies cells were collected from IL10/IL10R-deficient patients and controls. Frequencies of CD4 T-cell subsets, naive T-cell proliferation, regulatory T cell (Treg)-mediated suppression, and Treg and TH17 generation were determined by flow cytometry. Transcriptional profiling was performed by NanoString and quantitative real-time polymerase chain reaction. RNA in situ hybridization was used to determine the quantities of various transcripts in intestinal mucosa. RESULTS: Analysis of 16 IL10- and IL10R-deficient patients demonstrated similar frequencies of peripheral blood and intestinal Tregs, compared with control subjects. In addition, in vitro Treg suppression of CD4 T-cell proliferation and generation of Treg were not dependent on IL10R signaling. However, IL10R-deficient T naive cells exhibited higher proliferative capacity, a strong TH17 signature, and an increase in polarization toward TH17 cells, compared with controls. Moreover, the frequency of TH17 cells was increased in the colon and ileum of IL10R-deficient patients. Finally, we show that stimulation of IL10R-deficient Tregs in the presence of IL1ß leads to enhanced production of IL17A. CONCLUSIONS: IL10R signaling regulates TH17 polarization and T-cell proliferation in humans but is not required for the generation and in vitro suppression of Tregs. Therapies targeting the TH17 axis might be beneficial for IL10- and IL10R-deficient patients as a bridge to allogeneic hematopoietic stem cell transplantation.


Assuntos
Doenças Inflamatórias Intestinais/genética , Interleucina-10/genética , Receptores de Interleucina-10/genética , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adolescente , Adulto , Estudos de Casos e Controles , Proliferação de Células , Criança , Pré-Escolar , Colo/patologia , Feminino , Humanos , Lactente , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Transdução de Sinais/genética , Adulto Jovem
13.
Eur J Haematol ; 99(2): 190-193, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28382662

RESUMO

Mast cell (MC) activation syndrome (MCAS) is a collection of illnesses of inappropriate MC activation with little to no neoplastic MC proliferation, distinguishing it from mastocytosis. MCAS presents as chronic, generally inflammatory multisystem polymorbidity likely driven in most by heterogeneous patterns of constitutively activating mutations in MC regulatory elements, posing challenges for identifying optimal mutation-targeted treatment in individual patients. Targeting commonly affected downstream effectors may yield clinical benefit independent of upstream mutational profile. For example, both activated KIT and numerous cytokine receptors activate the Janus kinases (JAKs). Thus, JAK-inhibiting therapies may be useful against the downstream inflammatory effects of MCAS. The oral JAK1/JAK3 inhibitor, tofacitinib, is currently approved for rheumatoid arthritis and is in clinical trials for other chronic inflammatory disorders. Herein, we report two patients with MCAS who rapidly gained substantial symptomatic response to tofacitinib. Their improvement suggests need for further evaluation of this class of drugs in MCAS treatment.


Assuntos
Mastocitose/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adulto , Biomarcadores , Feminino , Humanos , Mastocitose/metabolismo , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Avaliação de Sintomas , Resultado do Tratamento
16.
Nat Genet ; 48(12): 1564-1569, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27749843

RESUMO

Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase-encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.


Assuntos
Dor Crônica/genética , Doenças do Tecido Conjuntivo/genética , Variações do Número de Cópias de DNA/genética , Disautonomia Familiar/genética , Gastroenteropatias/genética , Prurido/genética , Dermatopatias/genética , Triptases/sangue , Triptases/genética , Adolescente , Adulto , Idoso , Criança , Dor Crônica/sangue , Dor Crônica/enzimologia , Doenças do Tecido Conjuntivo/sangue , Doenças do Tecido Conjuntivo/enzimologia , Disautonomia Familiar/sangue , Disautonomia Familiar/enzimologia , Feminino , Gastroenteropatias/sangue , Gastroenteropatias/enzimologia , Humanos , Masculino , Pessoa de Meia-Idade , Prurido/sangue , Prurido/enzimologia , Dermatopatias/sangue , Dermatopatias/enzimologia , Adulto Jovem
17.
Gastroenterology ; 151(6): 1100-1104, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27693323

RESUMO

Interleukin 10 receptor (IL10R)-deficient mice develop spontaneous colitis and, similarly, patients with loss-of-function mutations in IL10R develop severe infant-onset inflammatory bowel disease. Loss of IL10R signaling in mouse and human macrophages is associated with increased production of interleukin 1ß. We demonstrated that innate immune production of IL1ß mediates colitis in IL10R-deficient mice. Transfer of Il1r1-/- CD4+ T cells into Rag1-/-/Il10rb-/- mice reduced the severity of their colitis (compared to mice that received CD4+ T cells that express IL1R), accompanied by decreased production of interferon gamma, tumor necrosis factor-α, and IL17A. In macrophages from mice without disruption of IL10R signaling or from healthy humans (controls), incubation with IL10 reduced canonical activation of the inflammasome and production of IL1ß through transcriptional and post-translational regulation of NLRP3. Lipopolysaccharide and adenosine triphosphate stimulation of macrophages from Il10rb-/- mice or IL10R-deficient patients resulted in increased production of IL1ß. Moreover, in human IL10R-deficient macrophages, lipopolysaccharide stimulation alone triggered IL1ß secretion via non-canonical, caspase 8-dependent activation of the inflammasome. We treated 2 IL10R-deficient patients with severe and treatment-refractory infant-onset inflammatory bowel disease with the IL1-receptor antagonist anakinra. Both patients had marked clinical, endoscopic, and histologic responses after 4-7 weeks. This treatment served as successful bridge to allogeneic hematopoietic stem cell transplantation in 1 patient. Our findings indicate that loss of IL10 signaling leads to intestinal inflammation, at least in part, through increased production of IL1 by innate immune cells, leading to activation of CD4+ T cells. Agents that block IL1 signaling might be used to treat patients with inflammatory bowel disease resulting from IL10R deficiency.


Assuntos
Colite/imunologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Receptores de Interleucina-10/genética , Trifosfato de Adenosina/farmacologia , Adulto , Animais , Antirreumáticos/uso terapêutico , Linfócitos T CD4-Positivos , Caspase 8/metabolismo , Células Cultivadas , Pré-Escolar , Colite/genética , Colite/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Humanos , Imunidade Inata , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Interferon gama/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-10/farmacologia , Subunidade alfa de Receptor de Interleucina-10/genética , Interleucina-17/metabolismo , Interleucina-1beta/genética , Lipopolissacarídeos/farmacologia , Macrófagos , Camundongos , Camundongos Knockout , Mutação , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Receptores de Interleucina-10/deficiência , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
18.
J Med Case Rep ; 10(1): 264, 2016 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-27663846

RESUMO

BACKGROUND: Esophageal Crohn's disease is reported as a rare manifestation, although its prevalence may be underestimated because upper endoscopies are not routinely performed in asymptomatic adults. Tofacitinib, an oral janus kinase inhibitor, is a new biologic that has shown promise in the treatment of ulcerative colitis and may be effective in the treatment of Crohn's disease according to phase 2 trials. We report the first case of esophageal Crohn's disease successfully treated with tofacitinib in a patient with worsening symptoms despite maintenance therapy with a tumor necrosis factor-α inhibitor. CASE PRESENTATION: A 67-year-old Caucasian woman presented with new dysphagia and had findings of esophageal Crohn's disease on endoscopy. The dosage of her current biologic therapy-adalimumab-was increased in frequency, without improvement. Our patient was started on tofacitinib and demonstrated an improvement in symptoms, with a repeat endoscopy showing resolution of the previous lesions. CONCLUSION: Esophageal Crohn's disease is likely underdiagnosed but is an important consideration in a patient with new symptoms of dysphagia and known Crohn's disease. Tofacitinib, while a novel agent, could have a role in the treatment of esophageal Crohn's disease that does not improve with intensification of the current biologic therapy. It provides a different mechanism in patients who become refractory to maintenance therapy.

19.
Cell Immunol ; 304-305: 63-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27215784

RESUMO

Deregulation of various components of the immune system has been reported in the inflamed gut of Crohn's disease (CD) patients. Innate lymphoid cells (ILCs) are novel innate effector lymphocytes which can rapidly respond to danger signals, from invading pathogens or tissue damage, to maintain homeostasis, especially along the mucosal surfaces. The purpose of this study is to compare composition of the intestinal ILCs subsets of CD patients with differential inflammatory conditions of the terminal ileum, which are marked by distinct histological appearances and mucosal profiles of cytokines. We observed alterations in the frequency of Lineage(-)CRTH2(-)CD45(+)NKp44(-)CD117(-)CD127(+)ILC subset in the inflamed terminal ileum.


Assuntos
Doença de Crohn/imunologia , Íleo/patologia , Imunidade Inata , Inflamação/imunologia , Mucosa Intestinal/imunologia , Subpopulações de Linfócitos/imunologia , Linfócitos/imunologia , Adulto , Linhagem da Célula , Humanos , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Masculino , Pessoa de Meia-Idade , Receptor 2 Desencadeador da Citotoxicidade Natural/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo
20.
Front Immunol ; 7: 679, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28119693

RESUMO

Environmental factors contribute to the initiation, progression, and maintenance of type 1 diabetes (T1D), although a single environmental trigger for disease has not been identified. Studies have documented the contribution of immunity within the gastrointestinal tract (GI) to the expression of autoimmunity at distal sites. Intestinal epithelial cells (IECs) regulate local and systemic immunologic homeostasis through physical and biochemical interactions with innate and adaptive immune populations. We hypothesize that a loss in the tolerance-inducing nature of the GI tract occurs within T1D and is due to altered IECs' innate immune function. As a first step in addressing this hypothesis, we contrasted the global immune microenvironment within the GI tract of individuals with T1D as well as evaluated the IEC-specific effects on adaptive immune cell phenotypes. The soluble and cellular immune microenvironment within the duodenum, the soluble mediator profile of primary IECs derived from the same duodenal tissues, and the effect of the primary IECs' soluble mediator profile on T-cell expansion and polarization were evaluated. Higher levels of IL-17C and beta-defensin 2 (BD-2) mRNA in the T1D-duodenum were observed. Higher frequencies of type 1 innate lymphoid cells (ILC1) and CD8+CXCR3+ T-cells (Tc1) were also observed in T1D-duodenal tissues, concomitant with lower frequencies of type 3 ILC (ILC3) and CD8+CCR6+ T-cells (Tc17). Higher levels of proinflammatory mediators (IL-17C and BD-2) in the absence of similar changes in mediators associated with homeostasis (interleukin 10 and thymic stromal lymphopoietin) were also observed in T1D-derived primary IEC cultures. T1D-derived IEC culture supernatants induced more robust CD8+ T-cell proliferation along with enhanced polarization of Tc1 populations, at the expense of Tc17 polarization, as well as the expansion of CXCR3+CCR6+/- Tregs, indicative of a Th1-like and less regulatory phenotype. These data demonstrate a proinflammatory microenvironment of the T1D-duodenum, whereby IECs have the potential to contribute to the expansion and polarization of innate and adaptive immune cells. Although these data do not discern whether these observations are not simply a consequence of T1D, the data indicate that the T1D-GI tract has the capacity to foster a permissive environment under which autoreactive T-cells could be expanded and polarized.

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