RESUMO
The interleukin-23 [IL-23] cytokine, derived predominantly from macrophages and dendritic cells in response to microbial stimulation, has emerged as a critical promoter of chronic intestinal inflammation. Genome-wide association studies linking variants in IL23R to disease protection, bolstered by experimental evidence from colitis models, and the successful application of therapies against the IL-12/IL-23 shared p40 subunit in the treatment of inflammatory bowel disease [IBD] all provide compelling evidence of a crucial role for IL-23 in disease pathogenesis. Moreover, targeting the p19 subunit specific for IL-23 has shown considerable promise in recent phase 2 studies in IBD. The relative importance of the diverse immunological pathways downstream of IL-23 in propagating mucosal inflammation in the gut, however, remains contentious. Here we review current understanding of IL-23 biology and explore its pleiotropic effects on T cells, and innate lymphoid, myeloid and intestinal epithelial cells in the context of the pathogenesis of IBD. We furthermore discuss these pathways in the light of recent evidence from clinical trials and indicate emerging targets amenable to therapeutic intervention and translation into clinical practice.
Assuntos
Doenças Inflamatórias Intestinais , Interleucina-23 , Estudo de Associação Genômica Ampla , Humanos , Imunidade Inata , Inflamação/patologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/terapia , Mucosa Intestinal/patologia , Linfócitos/metabolismoRESUMO
Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still's disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4+ and CD8+ T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which â¼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD+-dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation.
Assuntos
Autoimunidade , Purinas , Linfócitos T CD8-Positivos , Células Dendríticas , Ativação Linfocitária , Purinas/metabolismoRESUMO
Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases the risk for Crohn's disease and leprosy. We developed an unbiased liquid chromatography-mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic orthologs additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence, combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronizes mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Adenina/metabolismo , Adenosina/metabolismo , Adenosina Desaminase/metabolismo , Cromatografia Líquida/métodos , Células HEK293 , Células Hep G2 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Espectrometria de Massas/métodos , Enzimas Multifuncionais/genética , Fosforilação , Proteínas/genética , Nucleotídeos de Purina/metabolismo , Purinas/metabolismoRESUMO
Single-nucleotide variations in C13orf31 (LACC1) that encode p.C284R and p.I254V in a protein of unknown function (called 'FAMIN' here) are associated with increased risk for systemic juvenile idiopathic arthritis, leprosy and Crohn's disease. Here we set out to identify the biological mechanism affected by these coding variations. FAMIN formed a complex with fatty acid synthase (FASN) on peroxisomes and promoted flux through de novo lipogenesis to concomitantly drive high levels of fatty-acid oxidation (FAO) and glycolysis and, consequently, ATP regeneration. FAMIN-dependent FAO controlled inflammasome activation, mitochondrial and NADPH-oxidase-dependent production of reactive oxygen species (ROS), and the bactericidal activity of macrophages. As p.I254V and p.C284R resulted in diminished function and loss of function, respectively, FAMIN determined resilience to endotoxin shock. Thus, we have identified a central regulator of the metabolic function and bioenergetic state of macrophages that is under evolutionary selection and determines the risk of inflammatory and infectious disease.
Assuntos
Artrite Juvenil/genética , Doença de Crohn/genética , Infecções/genética , Hanseníase/genética , Macrófagos/imunologia , Proteínas/genética , Choque Séptico/genética , Trifosfato de Adenosina/metabolismo , Animais , Bacteriólise , Células Cultivadas , Metabolismo Energético , Ácido Graxo Sintase Tipo I/metabolismo , Predisposição Genética para Doença , Humanos , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidases/metabolismo , Oxirredução , Polimorfismo de Nucleotídeo Único , RiscoRESUMO
Crohn's disease (CD) is associated with delayed neutrophil recruitment and bacterial clearance at sites of acute inflammation as a result of impaired secretion of proinflammatory cytokines by macrophages. To investigate the impaired cytokine secretion and confirm our previous findings, we performed transcriptomic analysis in macrophages and identified a subgroup of individuals with CD who had low expression of the autophagy receptor optineurin (OPTN). We then clarified the role of OPTN deficiency in: macrophage cytokine secretion; mouse models of bacteria-driven colitis and peritonitis; and zebrafish Salmonella infection. OPTN-deficient bone-marrow-derived macrophages (BMDMs) stimulated with heat-killed Escherichia coli secreted less proinflammatory TNFα and IL6 cytokines despite similar gene transcription, which normalised with lysosomal and autophagy inhibitors, suggesting that TNFα is mis-trafficked to lysosomes via bafilomycin-A-dependent pathways in the absence of OPTN. OPTN-deficient mice were more susceptible to Citrobacter colitis and E. coli peritonitis, and showed reduced levels of proinflammatory TNFα in serum, diminished neutrophil recruitment to sites of acute inflammation and greater mortality, compared with wild-type mice. Optn-knockdown zebrafish infected with Salmonella also had higher mortality. OPTN plays a role in acute inflammation and neutrophil recruitment, potentially via defective macrophage proinflammatory cytokine secretion, which suggests that diminished OPTN expression in humans might increase the risk of developing CD.
Assuntos
Bactérias/metabolismo , Citocinas/metabolismo , Proteínas do Olho/metabolismo , Infiltração de Neutrófilos , Adulto , Animais , Estudos de Casos e Controles , Proteínas de Ciclo Celular , Citrobacter/fisiologia , Colite/sangue , Colite/microbiologia , Colite/patologia , Doença de Crohn/genética , Doença de Crohn/microbiologia , Citocinas/sangue , Escherichia coli/fisiologia , Infecções por Escherichia coli/prevenção & controle , Feminino , Complexo de Golgi/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Padrões de Herança/genética , Macrófagos/metabolismo , Masculino , Proteínas de Membrana Transportadoras , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Polimorfismo de Nucleotídeo Único/genética , Fator de Transcrição TFIIIA/deficiência , Fator de Transcrição TFIIIA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima , Peixe-ZebraRESUMO
Crohn's disease (CD) is a complex and highly heterogeneous chronic inflammatory disorder, primarily affecting the gastrointestinal tract. Genetic and functional studies have highlighted a key role for innate immunity in its pathogenesis. Profound systemic defects in innate immunity and acute inflammation are understood to result in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes. Macrophages, key orchestrators of acute inflammation, are likely to play an important role in the initial impaired innate immune response. Monocyte-derived macrophages from CD patients stimulated with Escherichia coli were shown to release attenuated levels of tumour necrosis factor and interferon-γ with normal secretion of interleukin-8 (IL-8), IL-10 and IL-6. In controls, the secretion of these cytokines was strongly positively correlated, which was not seen with CD macrophages. The transcriptomes of CD and control macrophages were examined in an attempt to understand the molecular basis of this defect. There were no differentially expressed genes identified between the two groups, consistent with genetic heterogeneity; however, a number of molecules were found to be under-expressed in subgroups of CD patients. The most common of these was optineurin (OPTN) which was under-expressed in approximately 10% of the CD patients. Reduced OPTN expression coincided with lower intracellular protein levels and diminished cytokine secretion after bacterial stimulation both in the patients and with small interfering RNA knockdown in THP-1 cells. Identifying and studying subgroups of patients with shared defective gene expression could aid our understanding of the mechanisms underlying highly heterogeneous diseases such as CD.
Assuntos
Doença de Crohn/imunologia , Citocinas/imunologia , Regulação da Expressão Gênica/imunologia , Macrófagos/imunologia , Fator de Transcrição TFIIIA/imunologia , Adulto , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Doença de Crohn/patologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/patologia , Macrófagos/patologia , Masculino , Proteínas de Membrana Transportadoras , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Mucosal abnormalities are potentially important in the primary pathogenesis of ulcerative colitis (UC). We investigated the mucosal transcriptomic expression profiles of biopsies from patients with UC and healthy controls, taken from macroscopically noninflamed tissue from the terminal ileum and 3 colonic locations with the objective of identifying abnormal molecules that might be involved in disease development. METHODS: Whole-genome transcriptional analysis was performed on intestinal biopsies taken from 24 patients with UC, 26 healthy controls, and 14 patients with Crohn's disease. Differential gene expression analysis was performed at each tissue location separately, and results were then meta-analyzed. Significantly, differentially expressed genes were validated using quantitative polymerase chain reaction. The location of gene expression within the colon was determined using immunohistochemistry, subcellular fractionation, electron and confocal microscopy. DNA methylation was quantified by pyrosequencing. RESULTS: Only 4 probes were abnormally expressed throughout the colon in patients with UC with Bone morphogenetic protein/Retinoic acid Inducible Neural-specific 3 (BRINP3) being the most significantly underexpressed. Attenuated expression of BRINP3 in UC was independent of current inflammation, unrelated to phenotype or treatment, and remained low at rebiopsy an average of 22 months later. BRINP3 is localized to the brush border of the colonic epithelium and expression is influenced by DNA methylation within its promoter. CONCLUSIONS: Genome-wide expression analysis of noninflamed mucosal biopsies from patients with UC identified BRINP3 as significantly underexpressed throughout the colon in a large subset of patients with UC. Low levels of this gene could predispose or contribute to the maintenance of the characteristic mucosal inflammation seen in this condition.
Assuntos
Biomarcadores/metabolismo , Colite Ulcerativa/genética , Doença de Crohn/genética , Proteínas de Ligação a DNA/genética , Perfilação da Expressão Gênica , Mucosa Intestinal/metabolismo , Adolescente , Adulto , Idoso , Western Blotting , Estudos de Casos e Controles , Colite Ulcerativa/patologia , Doença de Crohn/patologia , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto JovemRESUMO
SUMMARY: Complex human diseases can show significant heterogeneity between patients with the same phenotypic disorder. An outlier detection strategy was developed to identify variants at the level of gene transcription that are of potential biological and phenotypic importance. Here we describe a graphical software package (z-score outlier detection (ZODET)) that enables identification and visualisation of gross abnormalities in gene expression (outliers) in individuals, using whole genome microarray data. Mean and standard deviation of expression in a healthy control cohort is used to detect both over and under-expressed probes in individual test subjects. We compared the potential of ZODET to detect outlier genes in gene expression datasets with a previously described statistical method, gene tissue index (GTI), using a simulated expression dataset and a publicly available monocyte-derived macrophage microarray dataset. Taken together, these results support ZODET as a novel approach to identify outlier genes of potential pathogenic relevance in complex human diseases. The algorithm is implemented using R packages and Java. AVAILABILITY: The software is freely available from http://www.ucl.ac.uk/medicine/molecular-medicine/publications/microarray-outlier-analysis.
Assuntos
Regulação da Expressão Gênica , Genes , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Software , Sequência de Bases , Humanos , Macrófagos/metabolismo , Dados de Sequência Molecular , Monócitos/citologia , Curva ROC , Reprodutibilidade dos Testes , Interface Usuário-ComputadorRESUMO
In this study we have developed a rapid method for the shotgun analysis of bile acids in intestinal fluid. The method is semi-quantitative, and requires little sample preparation. Bile salts might contribute to the pathogenesis of Crohn's disease. In a pilot study we demonstrate the method by analysing the bile acid content of ileal fluid from seven Crohn's disease patients and three healthy controls. The dominant bile acids observed were di and/or trihydroxycholanoates, di- and/or trihydroxycholanoylglycines, di- and/or tri-hydroxycholanoyltaurines, monosulphated dihydroxycholanoates and monosulphated dihydroxycholanoylglycine. The method can be similarly applied to samples derived from other parts of the intestine.
Assuntos
Ácidos e Sais Biliares/metabolismo , Líquidos Corporais/metabolismo , Íleo/metabolismo , Espectrometria de Massas/métodos , Estudos de Casos e Controles , Doença de Crohn/metabolismo , HumanosRESUMO
Crohn's disease is a chronic inflammatory condition largely affecting the terminal ileum and large bowel. A contributing cause is the failure of an adequate acute inflammatory response as a result of impaired secretion of pro-inflammatory cytokines by macrophages. This defective secretion arises from aberrant vesicle trafficking, misdirecting the cytokines to lysosomal degradation. Aberrant intestinal permeability is also well-established in Crohn's disease. Both the disordered vesicle trafficking and increased bowel permeability could result from abnormal lipid composition. We thus measured the sphingo- and phospholipid composition of macrophages, using mass spectrometry and stable isotope labelling approaches. Stimulation of macrophages with heat-killed Escherichia coli resulted in three main changes; a significant reduction in the amount of individual ceramide species, an altered composition of phosphatidylcholine, and an increased rate of phosphatidylcholine synthesis in macrophages. These changes were observed in macrophages from both healthy control individuals and patients with Crohn's disease. The only difference detected between control and Crohn's disease macrophages was a reduced proportion of newly-synthesised phosphatidylinositol 16:0/18:1 over a defined time period. Shotgun lipidomics analysis of macroscopically non-inflamed ileal biopsies showed a significant decrease in this same lipid species with overall preservation of sphingolipid, phospholipid and cholesterol composition.
Assuntos
Ceramidas/metabolismo , Doença de Crohn/metabolismo , Metabolômica , Fosfatidilcolinas/metabolismo , Fosfatidilinositóis/metabolismo , Fosfatidilserinas/metabolismo , Adulto , Biópsia , Estudos de Casos e Controles , Doença de Crohn/microbiologia , Doença de Crohn/patologia , Demografia , Escherichia coli , Feminino , Humanos , Íleo/metabolismo , Íleo/patologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Esfingolipídeos/metabolismoRESUMO
BACKGROUND: Recent work provides evidence of a failure of acute inflammation in Crohn's disease (CD), and suggests that the primary defect operates at the level of the macrophage and cytokine release. Here we extend the characterization of the innate immune defect in CD by investigating the macrophage response to Toll-like receptor (TLR) agonists and assess potential links between genome-wide association study (GWAS) susceptibility loci, disease phenotype, and therapeutic regimens on tumor necrosis factor α (TNF) release. METHODS: Peripheral blood-derived macrophages were cultured from control subjects and patients with CD, stimulated with TLR ligands, and the release of TNF measured. Genomic DNA was purified from blood and genotyped for 34 single nucleotide polymorphisms (SNPs) identified as being associated with CD by GWAS. RESULTS: All stimuli resulted in a reduction (32%-48%) in TNF release from macrophages derived from CD patients (n = 28-101) compared to those from healthy control (HC) subjects. All phenotypes demonstrated impaired TNF release, with the greatest defect in patients with colonic disease. There was no detectable relationship between the level of TNF released and the presence of GWAS susceptibility loci in CD patients. Reduced TNF levels were not influenced by age, gender, or use of aminosalicylate (5-ASA) medication. CONCLUSIONS: This study supports the hypothesis of defective proinflammatory cytokine secretion and an innate immunodeficiency in CD. Abnormal TNF secretion is evident downstream of multiple TLRs, affects all disease phenotypes, and is unrelated to 34 polymorphisms associated with CD by GWAS.
Assuntos
Doença de Crohn/imunologia , Estudo de Associação Genômica Ampla , Mediadores da Inflamação/metabolismo , Inflamação/imunologia , Macrófagos/metabolismo , Receptores Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Doença de Crohn/genética , Citocinas/genética , Citocinas/metabolismo , Feminino , Genoma Humano , Humanos , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Transdução de Sinais , Adulto JovemRESUMO
Crohn's disease and ulcerative colitis are idiopathic chronic inflammatory diseases that primarily affect the gastrointestinal tract. The underlying causes remain poorly understood, but there is a growing body of evidence advocating a likely primary pathogenic role for immunodeficiency in the development of Crohn's lesions. Concordantly, a number of congenital immunodeficiencies disrupting the cellular innate immune system strongly predispose to noninfectious, Crohn's-like inflammatory bowel disease. There are case reports and series suggesting that the same may be true for some of the congenital adaptive and complement immunodeficiencies. This review considers and critiques these potential associations.
Assuntos
Imunidade Adaptativa , Colite Ulcerativa/imunologia , Proteínas do Sistema Complemento/imunologia , Doença de Crohn/imunologia , Síndromes de Imunodeficiência/congênito , Síndromes de Imunodeficiência/complicações , Animais , Linfócitos B/imunologia , Colite Ulcerativa/genética , Proteínas do Sistema Complemento/genética , Doença de Crohn/genética , Suscetibilidade a Doenças , Humanos , Camundongos , Linfócitos T/imunologiaRESUMO
Crohn's disease is a chronic inflammatory disorder primarily affecting the gastrointestinal tract. Its clinical manifestations arise from a substantial infiltration of the intestinal mucosa by activated leukocytes and the downstream consequences of chronic inflammation. The underlying cause driving this immunological reaction remains poorly understood. A number of hypotheses have been proposed, most of which postulate a primary over-activation of the immune response, based on the pathological appearances of active Crohn's lesions. Interestingly, none of these theories have been mechanistically proven. It is possible that the immunological events responsible for disease initiation are quite different from those contributing to its persistence and propagation. A substantial body of data has emerged in recent years to suggest that the primary defect in Crohn's disease is actually one of relative immunodeficiency. This review considers the evidence for such a phenomenon in contrast to alternative prevailing hypotheses and attempts to address some of the potential paradoxes that it generates.
Assuntos
Doença de Crohn , Imunidade Inata , Síndromes de Imunodeficiência , Mucosa Intestinal , Animais , Doença de Crohn/etiologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Citocinas/metabolismo , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/fisiopatologia , Macrófagos/imunologia , Camundongos , Neutrófilos/imunologia , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Crohn's Disease (CD) is a chronic relapsing disorder characterized by granulomatous inflammation of the gastrointestinal tract. Although its pathogenesis is complex, we have recently shown that CD patients have a systemic defect in macrophage function, which results in the defective clearance of bacteria from inflammatory sites. METHODOLOGY/PRINCIPAL FINDINGS: Here we have identified a number of additional macrophage defects in CD following diacylglycerol (DAG) homolog phorbol-12-myristate-13-acetate (PMA) activation. We provide evidence for decreased DNA fragmentation, reduced mitochondrial membrane depolarization, impaired reactive oxygen species production, diminished cytochrome c release and increased IL-6 production compared to healthy subjects after PMA exposure. The observed macrophage defects in CD were stimulus-specific, as normal responses were observed following p53 activation and endoplasmic reticulum stress. CONCLUSION: These findings add to a growing body of evidence highlighting disordered macrophage function in CD and, given their pivotal role in orchestrating inflammatory responses, defective apoptosis could potentially contribute to the pathogenesis of CD.
Assuntos
Apoptose , Doença de Crohn/metabolismo , Trato Gastrointestinal/microbiologia , Macrófagos/metabolismo , Ésteres de Forbol/metabolismo , Espécies Reativas de Oxigênio , Sobrevivência Celular , Diglicerídeos/química , Retículo Endoplasmático/metabolismo , Trato Gastrointestinal/metabolismo , Humanos , Inflamação , Interleucina-6/metabolismo , Potenciais da Membrana , Acetato de Tetradecanoilforbol/farmacologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
The cause of Crohn's disease (CD) remains poorly understood. Counterintuitively, these patients possess an impaired acute inflammatory response, which could result in delayed clearance of bacteria penetrating the lining of the bowel and predispose to granuloma formation and chronicity. We tested this hypothesis in human subjects by monitoring responses to killed Escherichia coli injected subcutaneously into the forearm. Accumulation of (111)In-labeled neutrophils at these sites and clearance of (32)P-labeled bacteria from them were markedly impaired in CD. Locally increased blood flow and bacterial clearance were dependent on the numbers of bacteria injected. Secretion of proinflammatory cytokines by CD macrophages was grossly impaired in response to E. coli or specific Toll-like receptor agonists. Despite normal levels and stability of cytokine messenger RNA, intracellular levels of tumor necrosis factor (TNF) were abnormally low in CD macrophages. Coupled with reduced secretion, these findings indicate accelerated intracellular breakdown. Differential transcription profiles identified disease-specific genes, notably including those encoding proteins involved in vesicle trafficking. Intracellular destruction of TNF was decreased by inhibitors of lysosomal function. Together, our findings suggest that in CD macrophages, an abnormal proportion of cytokines are routed to lysosomes and degraded rather than being released through the normal secretory pathway.
Assuntos
Doença de Crohn/imunologia , Citocinas/metabolismo , Escherichia coli/imunologia , Macrófagos/metabolismo , Adulto , Idoso , Doença de Crohn/microbiologia , Feminino , Perfilação da Expressão Gênica , Humanos , Radioisótopos de Índio , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Neutrófilos/microbiologia , Análise de Sequência com Séries de Oligonucleotídeos , Radioisótopos de Fósforo , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The pathogenesis of Crohn's disease (CD) has remained an enigma for at least a century. There was considerable optimism that genetic linkage and genome-wide association (GWA) studies had identified genes causally responsible. However, the realisation that these genes make a relatively minor contribution to the development of CD has led to the acceptance of a 'missing heritability'. In contrast to the weak genetic effects, patients with CD almost without exception exhibit a gross phenotype, namely a profound systemic failure of the acute inflammatory response. This results in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes, as well as constitutional symptoms.