RESUMO
Inflammatory bowel diseases (IBD) are multifactorial diseases which are caused by the combination of genetic predisposition, exposure factors (environmental and dietary), immune status, and dysbiosis. IBD is a disease which presents at any age, ranging from newborns to the elderly. The youngest of the pediatric IBD population have a more unique presentation and clinical course and may have a different etiology. Very early onset IBD (VEOIBD) patients, designated as those diagnosed prior the age of 6, have distinct features which are more frequent in this patient population including increased incidence of monogenetic causes for IBD (0%-33% depending on the study). This proportion is increased in the youngest subsets, which is diagnosed prior to the age of 2. To date, there are approximately 80 monogenic causes of VEOIBD that have been identified and published. Many of these monogenic causes are inborn errors of immunity yet the majority of VEOIBD patients do not have an identifiable genetic cause for their disease. In this review, we will focus on the clinical presentation, evaluation, and monogenic categories which have been associated with VEOIBD including (1) Epithelial cell defects (2) Adaptive immune defects, (3) Innate Immune/Bacterial Clearance and Recognition defects, and (4) Hyperinflammatory and autoinflammatory disorders. We will highlight differential diagnosis of VEOIBD presentations, as well as evaluation and treatment, which will be helpful for those who study and care for VEOIBD patients outside of the pediatric gastroenterology field. This is a fast-moving field of research which has grown significantly based on knowledge that we gain from our patients. These scientific findings have identified novel mucosal biology pathways and will continue to inform our understanding of gastrointestinal biology.
Assuntos
Doenças Inflamatórias Intestinais , Humanos , Criança , Recém-Nascido , Idoso , Idade de Início , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genética , Predisposição Genética para DoençaRESUMO
Crohn disease (CD) is a highly morbid chronic inflammatory disease. Although many patients with CD also develop fibrostenosing complications, there are no medical therapies for intestinal fibrosis. This is due, in part, to a lack of high-fidelity biomimetic models to enhance understanding and drug development, which highlights the need for developing in vivo models of inflammatory bowel disease-related intestinal fibrosis. This study investigates whether the TNFΔARE mouse, a model of ileal inflammation, also develops intestinal fibrosis. Several clinically relevant outcomes were studied, including features of structural fibrosis, histologic fibrosis, and gene expression. These include the use of a new luminal casting technique, traditional histologic outcomes, use of second harmonic imaging, and quantitative PCR. These features were studied in aged TNFΔARE mice as well as in cohorts of numerous ages. At >24 weeks of age, TNFΔARE mice developed structural, histologic, and transcriptional changes of ileal fibrosis. Protein and RNA expression profiles showed changes as early as 6 weeks, coinciding with histologic changes as early as 14 to 15 weeks. Overt structural fibrosis was delayed until at least 16 weeks and was most developed after 24 weeks. This study found that the TNFΔARE mouse is a viable and highly tractable model of ileal fibrosis. This model and the techniques used herein can be leveraged for both mechanistic studies and therapeutic development for the treatment of intestinal fibrosis.
Assuntos
Doença de Crohn , Intestinos , Camundongos , Animais , Intestinos/patologia , Doença de Crohn/patologia , Inflamação/patologia , Íleo/metabolismo , FibroseRESUMO
OBJECTIVES: Pediatric patients diagnosed with inflammatory bowel disease (IBD) are at risk of suboptimal peak bone mass attainment. This study aimed to understand rates of bone health screening adherence, describe factors associated with dual-energy X-ray absorptiometry (DXA) acquisition, and identify factors associated with abnormal DXA. METHODS: We performed a retrospective cohort study of pediatric IBD patients over a 10-year time frame. We included IBD patients (2-20 years of age) enrolled in ImproveCareNow and excluded patients with primary metabolic bone disease. Time-to-event methods and multivariable logistic regression were employed to identify factors associated with DXA acquisition and abnormal DXA. RESULTS: In 676 patients, 464 (68.63%) pediatric patients with IBD had a risk factor for low bone mineral density (BMD); 137 (29.53%) underwent an initial DXA scan. Quiescent disease was significantly associated with a reduced likelihood of DXA (hazard ratio [HR]: 0.48; 95% confidence interval [CI]: 0.24-0.97), while weight z-score <-2 was significantly associated with DXA performance (HR: 2.07; 95% CI: 1.08-3.98). Abnormal DXA results (BMD z-score ≤-1) occurred in 59 (35.54%) individuals. After adjusting for visit diagnosis, delayed puberty, severe disease course, 6 months or greater of steroid exposure, and history of fracture, BMI z-score <-1 (odds ratio: 5.45; 95% CI: 2.41-12.33) was associated with abnormal DXA. CONCLUSIONS: DXA screening occurred in less than one-third of eligible pediatric IBD patients. Compliance was more common in patients with a weight z-score <-2 and less common in those with quiescent disease. BMI strongly predicted abnormal DXA results when adjusting for risk factors for abnormal BMD.
Assuntos
Doenças Ósseas Metabólicas , Doenças Inflamatórias Intestinais , Humanos , Criança , Absorciometria de Fóton/efeitos adversos , Absorciometria de Fóton/métodos , Densidade Óssea , Estudos Retrospectivos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/diagnóstico por imagem , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/diagnósticoRESUMO
BACKGROUND: Internally penetrating Crohn's Disease complications, including abscesses and phlegmon, represent a high-risk Crohn's Disease phenotype. Anti-tumor-necrosis-factor-α (Anti-TNF) therapies are effective in treating penetrating Crohn's Disease and early initiation has shown unique benefits. However, timing of anti-TNF initiation in the setting of internally penetrating Crohn's Disease complications is typically heterogenous due to concern over precipitating serious infections. Recent studies demonstrate such an association may not exist. AIMS: We aimed to describe the multidisciplinary management of pediatric patients with internally penetrating Crohn's Disease complications, focusing on the utilization and timing of anti-TNF therapy relative to complication resolution and adverse events. METHODS: We performed a single-center retrospective cohort study of pediatric patients with internally penetrating Crohn's Disease complications from 2007 to 2021. The safety and effectiveness of anti-TNF therapy initiation prior to complication resolution was assessed by comparing rates of infectious and Crohn's Disease-related adverse events between those who received anti-TNF therapy prior to complication resolution, versus those who did not. RESULTS: Twenty-one patients with internally penetrating Crohn's Disease complications were identified. 7/21 received anti-TNF therapy prior to complication resolution. Infectious adverse events within 90 days of complication occurred in 0/7 patients initiating anti-TNF therapy prior to complication resolution and 10/14 patients who did not (p = 0.004). Crohn's Disease-related surgeries and hospitalizations within 1 year of complication occurred in 12/20 patients, with similar frequency between groups. CONCLUSIONS: Initiating anti-TNF therapy prior to internally penetrating Crohn's Disease complication resolution may be a safe and effective strategy to improve clinical outcomes.
Assuntos
Abscesso Abdominal , Doença de Crohn , Humanos , Doença de Crohn/complicações , Doença de Crohn/tratamento farmacológico , Doença de Crohn/cirurgia , Infliximab/uso terapêutico , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Estudos Retrospectivos , Celulite (Flegmão)/tratamento farmacológico , Celulite (Flegmão)/epidemiologia , Celulite (Flegmão)/complicações , Fator de Necrose Tumoral alfa , Abscesso Abdominal/epidemiologia , Abscesso Abdominal/etiologia , NecroseRESUMO
OBJECTIVES: Celiac disease (CeD) autoimmunity and coexisting inflammatory bowel disease (IBD) present a diagnostic dilemma. Our aims were to describe the phenotype of children with IBD and CeD seropositivity and evaluate provider confidence for diagnosing CeD in this population. METHODS: We performed a single-center retrospective cohort study of subjects ≤18 years old with IBD and CeD seropositivity between 2006 and 2020. Subjects were considered to have IBD-CeD if they met CeD diagnosis by serology and histology per North American Society For Pediatric Gastroenterology, Hepatology and Nutrition guidelines and if providers suspected CeD as evaluated by a survey. The IBD-only cohort included seropositive participants that did not meet criteria for CeD. Demographic, histologic, gross endoscopic, and laboratory features were compared using Fisher exact test. RESULTS: Of 475 children with IBD, 8 had concomitant CeD, 5 had tissue transglutaminase (tTG) immunoglobulin A (IgA) > 10x upper limit of normal (ULN, P = 0.006), and 8 had villous atrophy (VA, P = 0.003) when compared with 17 seropositive participants with IBD-only. No children with IBD-CeD had esophageal eosinophilia, duodenal cryptitis, duodenal ulceration, or fecal calprotectin >250 µg/g. Factors that contributed to provider uncertainty for diagnosing CeD in IBD included the absence of VA and intraepithelial lymphocytes, the presence of neutrophilic and eosinophilic duodenitis, diffuse ulceration, elevated inflammatory markers, and immunosuppression therapy. CONCLUSIONS: Diagnosing CeD in children with IBD continues to be challenging. Although high titers of tTG IgA and VA increased provider confidence for diagnosing CeD in IBD, development of evidence-based guidelines are needed. They should better assess the importance of features atypical of concomitant CeD that contribute to uncertainty.
Assuntos
Doença Celíaca , Doenças Inflamatórias Intestinais , Humanos , Doença Celíaca/complicações , Doença Celíaca/diagnóstico , Estudos Retrospectivos , Duodeno/patologia , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/patologia , Autoanticorpos , Imunoglobulina A , TransglutaminasesRESUMO
OBJECTIVES: Exclusive enteral nutrition (EEN) is infrequently used in the United States but is an effective treatment for pediatric Crohn disease (CD). Limited data exists regarding patient and parent perspectives on this treatment modality. The aim of this study was to determine parent and provider perspectives regarding EEN and understand parent-cited barriers to its use. METHODS: We surveyed the parents/guardians of children ages 1 through 17 with CD in our institution regarding EEN. Healthcare provider perspectives regarding reason for stopping EEN and those cited by survey respondents were compared using retrospective chart review. RESULTS: One hundred fifteen (62.5%) out of 184 recipients responded to the survey. Ninety percentage of respondents had heard of EEN but of these, 26% had not discussed it with their gastroenterologist. Thirty-eight patients (33%) were treated in the past and 15 (13%) were currently on EEN. Common barriers cited by current EEN users were cost/finances and difficult social situations. Of the children who stopped EEN, most did so as parents felt it was not working (nâ=â14, 37%). In these cases, their primary gastroenterologist cited treatment failure for 4 cases and nonadherence for 6. CONCLUSIONS: Despite the efficacy of EEN and interest in dietary treatments by patients with CD, there are many barriers surrounding effective communication and successful implementation of dietary therapies. Future research is needed regarding patient-physician communication, cost mitigation, and coping with the social limitations of dietary therapies.
Assuntos
Doença de Crohn , Nutrição Enteral , Atitude Frente a Saúde , Criança , Doença de Crohn/terapia , Humanos , Lactente , Pais , Indução de Remissão , Estudos RetrospectivosRESUMO
OBJECTIVE: To assess the safety, efficacy, and relative expense of a nurse-led fecal microbiota transplantation (FMT) program for the treatment of recurrent Clostridium difficile infection (CDI). STUDY DESIGN: Retrospective cohort study design in children aged 1-18 years with recurrent CDI. The intervention was an intragastric FMT with stool derived from a donor stool bank. Primary outcome was resolution of diarrhea at 3 months post-transplantation. A secondary analysis compared charge data associated with FMT by intragastric delivery vs administration by colonoscopy or nasoduodenal tube. RESULTS: A total of 47 intragastric FMT procedures were performed in 42 children (median age 9 years) with recurrent CDI. Response to treatment varied by disease status, with 94% success in previously healthy children, 75% in medically complex children, and 54% in children with inflammatory bowel disease (P = .04). FMT via intragastric delivery showed lower facility and professional charges by 85% and 78% compared with delivery via colonoscopy and radiology-placed nasoduodenal tube, respectively. The use of stool derived from a donor stool bank decreased charges by 49% compared with charges associated with the use of a donor who was a relative. CONCLUSION: A nurse-led intragastric FMT procedure using stool derived from a donor stool bank is a relatively inexpensive and efficacious treatment for recurrent CDI in children. Intragastric FMT success in children was attenuated by the presence of underlying disease, particularly inflammatory bowel disease.
Assuntos
Infecções por Clostridium/terapia , Diarreia/terapia , Transplante de Microbiota Fecal/métodos , Adolescente , Criança , Pré-Escolar , Clostridioides difficile , Estudos de Coortes , Colonoscopia/métodos , Diarreia/etiologia , Transplante de Microbiota Fecal/efeitos adversos , Fezes/microbiologia , Feminino , Gastrostomia/métodos , Humanos , Lactente , Intubação Gastrointestinal/métodos , Masculino , Recidiva , Estudos Retrospectivos , Estômago , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate marijuana use by adolescents and young adults with inflammatory bowel disease (IBD). STUDY DESIGN: This descriptive cross-sectional study of patients seen between December 2015 through June 2017 at Children's Hospital Colorado for IBD enrolled patients 13-23 years of age, independent of marijuana use status. Information obtained consisted of chart review, electronic and interview self-report, and serum cannabinoid levels. Marijuana ever-users were compared with never-users for clinical characteristics and perceptions of risk with use; users provided information on routes, patterns, motivations, and perceived benefits and problems with use. RESULTS: Of 99 participants, ever-use was endorsed by 32% (32 of 99) and daily or almost daily use by 9% (9 of 99). Older age was the only characteristic related to endorsing marijuana use. Twenty-nine ever-users completed all questionnaires. After adjusting for age, users were 10.7 times more likely to perceive low risk of harm with regular use (P < .001). At least 1 medical reason for use was endorsed by 57% (17 of 30), most commonly for relief of physical pain (53%, 16 of 30) (2 did not complete all questionnaires). Problems from use were identified by 37% (11 of 30), most commonly craving/strong urge to use. Most common route of use was smoking (83%) followed by edibles (50%), dabbing (40%), and vaping (30%). CONCLUSIONS: Marijuana use by adolescents and young adults with IBD is common and perceived as beneficial. Guidelines for screening, testing, and counseling of marijuana use should be developed for patients with IBD.
Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Fumar Maconha , Uso da Maconha/epidemiologia , Motivação/fisiologia , Adolescente , Colorado/epidemiologia , Estudos Transversais , Feminino , Humanos , Incidência , Masculino , Autorrelato , Inquéritos e Questionários , Adulto JovemRESUMO
OBJECTIVE: Pediatric colonic eosinophilia represents a confounding finding with a wide differential. It is often difficult to determine which children may progress to inflammatory bowel disease (IBD), which have an eosinophilic colitis (EC), and which may have no underlying pathology. There is little guidance for the practitioner on the approach to these patients. To define the clinical presentations of colonic eosinophilia and identify factors which may aid in diagnosis we reviewed patients with colonic eosinophilia and the clinicopathologic factors associated with their diagnoses. METHODS: An 8-year retrospective chart review of children whose histopathology identified colonic eosinophilia (Nâ=â72) compared to controls with normal biopsies (Nâ=â35). RESULTS: Patients with colonic eosinophilia had increased eosinophils/high-power field compared to controls (Pâ<â0.001) and had 3 clinical phenotypes. Thirty-six percent had an inflammatory phenotype with elevated erythrocyte sedimentation rate (Pâ<â.0001), chronic inflammation on colonic biopsies (Pâ<â0.001), and were diagnosed as having IBD. Thirty-seven percent were diagnosed as having EC, associated with male sex (Pâ<â0.005) and peripheral eosinophilia (Pâ=â0.041). Twenty-one percent had no significant colonic pathology. Forty-three percent of patients had >1 colonoscopy and 68% of these had change from initial diagnoses. CONCLUSIONS: There are 3 main phenotypes of children with colonic eosinophilia. Signs of chronic systemic inflammation raise suspicion for IBD. Peripheral eosinophilia and male sex are associated with EC. A significant percent of children with colonic eosinophilia do not have colonic disease. Eosinophils/high-power field is not reliable to differentiate etiologies. Repeat colonoscopies may be required to reach final diagnoses.
Assuntos
Colo/patologia , Doenças do Colo/patologia , Eosinofilia/patologia , Adolescente , Criança , Doenças do Colo/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Fenótipo , Estudos RetrospectivosRESUMO
Dietary influences may affect microbiome composition and host immune responses, thereby modulating propensity toward inflammatory bowel diseases (IBDs): Crohn disease (CD) and ulcerative colitis (UC). Dietary n-6 fatty acids have been associated with UC in prospective studies. However, the critical developmental period when (n-6) consumption may induce UC is not known. We examined the effects of transiently increased n-6 consumption during pediatric development on subsequent dextran-sulfate-sodium (DSS)-induced acute murine colitis. The animals transiently became obese then rapidly lost this phenotype. Interestingly, mice were protected against DSS colitis 40 days after n-6 consumption. The transient high n-6-induced protection against colitis was fat type- and dietary reversal-dependent and could be transferred to germ-free mice by fecal microbiota transplantation. We also detected decreased numbers of chemokine receptor (Cxcr)5(+) CD4(+) T cells in the mesenteric lymph nodes (MLNs) of transiently n-6-fed mice. Further experiments revealed that anti-chemokine ligand (Cxcl)13 (the ligand of Cxcr5) antibody treatment decreased DSS colitis severity, implicating the importance of the Cxcr5-Cxcl13 pathway in mammalian colitis. Consecutively, we found elevated CXCL13 concentrations (CD: 1.8-fold, P = 0.0077; UC: 1.9-fold, P = 0.056) in the serum of untreated pediatric IBD patients. The human serologic observations supported the translational relevance of our findings.
Assuntos
Colite/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Obesidade Infantil/metabolismo , Animais , Colo/metabolismo , Dieta , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estudos ProspectivosRESUMO
Regulatory T cells (Tregs) control autoreactive T cells by inhibiting activation-induced proliferation and cytokine expression. The molecular mechanisms responsible for the inactivation of effector T cells by Tregs remain yet to be fully characterized. We report that T-helper cells stimulated in the presence of Tregs quickly activate NFAT1 and have increased NFAT1-dependent expression of the transcription repressor Ikaros. NFAT1 deficiency or dominant-negative Ikaros compromises Treg-mediated inhibition of T-helper cells in vitro and in vivo. Thus, our results place NFAT-dependent mechanisms as general regulators of T-cell tolerance and show that Treg-mediated suppression of T-helper cells results from the activation of NFAT-regulated gene expression.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Fator de Transcrição Ikaros/biossíntese , Fatores de Transcrição NFATC/imunologia , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Citocinas/biossíntese , Regulação da Expressão Gênica , Fator de Transcrição Ikaros/genética , Ativação Linfocitária/imunologia , Camundongos , Fatores de Transcrição NFATC/biossíntese , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
Recent studies have demonstrated dramatic shifts in metabolic supply-and-demand ratios during inflammation, a process resulting in localized tissue hypoxia within inflammatory lesions ("inflammatory hypoxia"). As part of the adaptive immune response, T cells are recruited to sites of inflammatory hypoxia. Given the profound effects of hypoxia on gene regulation, we hypothesized that T-cell differentiation is controlled by hypoxia. To pursue this hypothesis, we analyzed the transcriptional consequences of ambient hypoxia (1% oxygen) on a broad panel of T-cell differentiation factors. Surprisingly, these studies revealed selective, robust induction of FoxP3, a key transcriptional regulator for regulatory T cells (Tregs). Studies of promoter binding or loss- and gain-of-function implicated hypoxia-inducible factor (HIF)-1α in inducing FoxP3. Similarly, hypoxia enhanced Treg abundance in vitro and in vivo. Finally, Treg-intrinsic HIF-1α was required for optimal Treg function and Hif1a-deficient Tregs failed to control T-cell-mediated colitis. These studies demonstrate that hypoxia is an intrinsic molecular cue that promotes FoxP3 expression, in turn eliciting potent anti-inflammatory mechanisms to limit tissue damage in conditions of reduced oxygen availability.
Assuntos
Fatores de Transcrição Forkhead/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Hipóxia , Inflamação/genética , Mucosa Intestinal/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Hipóxia Celular , Proliferação de Células , Células Cultivadas , Colite/genética , Colite/metabolismo , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/metabolismo , Interleucina-1/farmacologia , Mucosa Intestinal/patologia , Células Jurkat , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Reguladores/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologiaRESUMO
Histone/protein deacetylases (HDACs) regulate chromatin remodeling and gene expression as well as the functions of more than 50 transcription factors and nonhistone proteins. We found that administration of an HDAC inhibitor (HDACi) in vivo increased Foxp3 gene expression, as well as the production and suppressive function of regulatory T cells (T(reg) cells). Although T(reg) cells express multiple HDACs, HDAC9 proved particularly important in regulating Foxp3-dependent suppression. Optimal T(reg) function required acetylation of several lysines in the forkhead domain of Foxp3, and Foxp3 acetylation enhanced binding of Foxp3 to the Il2 promoter and suppressed endogenous IL-2 production. HDACi therapy in vivo enhanced T(reg)-mediated suppression of homeostatic proliferation, decreased inflammatory bowel disease through T(reg)-dependent effects, and, in conjunction with a short course of low-dose rapamycin, induced permanent, T(reg)-dependent cardiac and islet allograft survival and donor-specific allograft tolerance. Our data show that use of HDACi allows the beneficial pharmacologic enhancement of both the numbers and suppressive function of Foxp3(+) T(reg) cells.
Assuntos
Diferenciação Celular/imunologia , Inibidores de Histona Desacetilases , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/enzimologia , Animais , Fatores de Transcrição Forkhead/biossíntese , Histona Desacetilases/biossíntese , Histona Desacetilases/genética , Ácidos Hidroxâmicos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Linfócitos T Reguladores/imunologia , Timo/citologia , Timo/imunologia , Timo/metabolismoAssuntos
Corticosteroides , Integrinas , Anticorpos Monoclonais Humanizados , Enterite , Eosinofilia , Gastrite , Humanos , InflamaçãoRESUMO
The heat shock response is a critical component of the inflammatory cascade that prevents misfolding of new proteins and regulates immune responses. Activation of clusters of differentiation (CD)4+ T cells causes an upregulation of heat shock transcription factor, heat shock factor 1 (HSF1). We hypothesized that HSF1 promotes a pro-regulatory phenotype during inflammation. To validate this hypothesis, we interrogated cell-specific HSF1 knockout mice and HSF1 transgenic mice using in vitro and in vivo techniques. We determined that while HSF1 expression was induced by anti-CD3 stimulation alone, the combination of anti-CD3 and transforming growth factor ß, a vital cytokine for regulatory T cell (Treg) development, resulted in increased activating phosphorylation of HSF1, leading to increased nuclear translocation and binding to heat shock response elements. Using chromatin immunoprecipitation (ChIP), we demonstrate the direct binding of HSF1 to foxp3 in isolated murine CD4+ T cells, which in turn coincided with induction of FoxP3 expression. We defined that conditional knockout of HSF1 decreased development and function of Tregs and overexpression of HSF1 led to increased expression of FoxP3 along with enhanced Treg suppressive function. Adoptive transfer of CD45RBHigh CD4 colitogenic T cells along with HSF1 transgenic CD25+ Tregs prevented intestinal inflammation when wild-type Tregs did not. Finally, overexpression of HSF1 provided enhanced barrier function and protection from murine ileitis. This study demonstrates that HSF1 promotes Treg development and function and may represent both a crucial step in the development of induced regulatory T cells and an exciting target for the treatment of inflammatory diseases with a regulatory T-cell component. SIGNIFICANCE STATEMENT: The heat shock response (HSR) is a canonical stress response triggered by a multitude of stressors, including inflammation. Evidence supports the role of the HSR in regulating inflammation, yet there is a paucity of data on its influence in T cells specifically. Gut homeostasis reflects a balance between regulatory clusters of differentiation (CD)4+ T cells and pro-inflammatory T-helper (Th)17 cells. We show that upon activation within T cells, heat shock factor 1 (HSF1) translocates to the nucleus, and stimulates Treg-specific gene expression. HSF1 deficiency hinders Treg development and function and conversely, HSF1 overexpression enhances Treg development and function. While this work, focuses on HSF1 as a novel therapeutic target for intestinal inflammation, the findings have significance for a broad range of inflammatory conditions.
Assuntos
Inflamação , Linfócitos T Reguladores , Animais , Camundongos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição de Choque Térmico/genética , Resposta ao Choque Térmico , Camundongos Knockout , Camundongos TransgênicosRESUMO
Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract that includes both Crohn disease (CD) and ulcerative colitis. Abdominal pain, rectal bleeding, diarrhea, and weight loss characterize both CD and ulcerative colitis. The incidence of IBD in the United States is 70 to 150 cases per 100,000 individuals and, as with other autoimmune diseases, is on the rise. CD can affect any part of the gastrointestinal tract from the mouth to the anus and frequently will include perianal disease. The first description connecting regional enteritis with perianal disease was by Bissell et al in 1934, and since that time perianal disease has become a recognized entity and an important consideration in the diagnosis and treatment of CD. Perianal Crohn disease (PCD) is defined as inflammation at or near the anus, including tags, fissures, fistulae, abscesses, or stenosis. The symptoms of PCD include pain, itching, bleeding, purulent discharge, and incontinence of stool. In this report, we review and discuss the etiology, diagnosis, evaluation, and treatment of PCD.