RESUMO
Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. We whole-genome sequenced 446 colonic crypts from 46 IBD patients and compared these to 412 crypts from 41 non-IBD controls from our previous publication on the mutation landscape of the normal colon. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon, and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR, ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis.
Assuntos
Evolução Clonal/genética , Colite/genética , Doenças Inflamatórias Intestinais/genética , Taxa de Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Evolução Clonal/imunologia , Colite/metabolismo , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , Doença de Crohn/genética , Doença de Crohn/metabolismo , Proteínas de Ligação a DNA/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Humanos , Mutação INDEL , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Interleucina-17/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Filogenia , Mutação Puntual , Receptores de Superfície Celular/genética , Ribonucleases/genética , Receptores Toll-Like/genética , Fatores de Transcrição/genética , Sequenciamento Completo do GenomaRESUMO
Inflammatory bowel disease is a chronic, relapsing condition with two subtypes, Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies (GWASs) in UC implicate a FCGR2A variant that alters the binding affinity of the antibody receptor it encodes, FcγRIIA, for immunoglobulin G (IgG). Here, we aimed to understand the mechanisms whereby changes in FcγRIIA affinity would affect inflammation in an IgA-dominated organ. We found a profound induction of anti-commensal IgG and a concomitant increase in activating FcγR signaling in the colonic mucosa of UC patients. Commensal-IgG immune complexes engaged gut-resident FcγR-expressing macrophages, inducing NLRP3- and reactive-oxygen-species-dependent production of interleukin-1ß (IL-1ß) and neutrophil-recruiting chemokines. These responses were modulated by the FCGR2A genotype. In vivo manipulation of macrophage FcγR signal strength in a mouse model of UC determined the magnitude of intestinal inflammation and IL-1ß-dependent type 17 immunity. The identification of an important contribution of IgG-FcγR-dependent inflammation to UC has therapeutic implications.
Assuntos
Anticorpos Antibacterianos/imunologia , Colite Ulcerativa/imunologia , Microbioma Gastrointestinal/imunologia , Imunoglobulina G/imunologia , Interleucina-1beta/imunologia , Células Th17/imunologia , Animais , Colite/induzido quimicamente , Colite/imunologia , Colite/microbiologia , Colite/patologia , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia , Sulfato de Dextrana/toxicidade , Regulação da Expressão Gênica , Genótipo , Humanos , Inflamação , Interleucina-8/biossíntese , Interleucina-8/genética , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Macrófagos/imunologia , Camundongos , Fagócitos/imunologia , RNA Mensageiro/biossíntese , Espécies Reativas de Oxigênio , Receptores de IgG/biossíntese , Receptores de IgG/genética , Receptores de IgG/imunologiaRESUMO
INTRODUCTION: Methotrexate (MTX) has been utilized for the treatment of Crohn's disease (CD) for decades. Nevertheless, current data provide equivocal evidence on the efficacy of MTX in CD.The aims of this study were to describe the efficacy of MTX for maintenance of remission in CD and to identify the factors associated with the probability of steroid-free clinical remission in a multicenter European referral center cohort. PATIENTS AND METHODS: This was a retrospective cohort analysis. Consecutive patients treated with MTX for CD were included from 11 referral centers. Patients receiving concomitant treatment with tumor necrosis factor inhibitors or thiopurines were excluded. The main outcome was steroid-free clinical remission; the secondary outcomes included the rate of complications leading to MTX discontinuation and duration of relapse-free survival in patients achieving the main outcome. RESULTS: Between July 1992 and January 2012, 118 patients were identified for inclusion. MTX administration route was oral for induction in 31.4% and for maintenance in 49.1% of the patients. Steroid-free remission was achieved in 44/118 (37.2%) patients and was maintained relapse free by 28/44 (63.6%) for a median of 12 (3.5-18.5) months. At least one adverse effect was reported by 28.9% of the patients. No clinical or demographic factors were associated with either likelihood of achieving a clinical response or duration of relapse-free survival. CONCLUSION: MTX treatment induced steroid-free clinical remission in over a third of CD patients and maintained it for a year in almost two-thirds of the responders. MTX should be considered a viable therapeutic option in CD patients refractory to other therapies.