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Targeting interactions between α4ß7 integrin and endothelial adhesion molecule MAdCAM-1 to inhibit lymphocyte migration to the gastrointestinal tract is an effective therapy in inflammatory bowel disease (IBD). Following lymphocyte entry into the mucosa, a subset of these cells expresses αEß7 integrin, which is expressed on proinflammatory lymphocytes, to increase cell retention. The factors governing lymphocyte migration into the intestinal mucosa and αE integrin expression in healthy subjects and IBD patients remain incompletely understood. We evaluated changes in factors involved in lymphocyte migration and differentiation within tissues. Both ileal and colonic tissue from active IBD patients showed upregulation of ICAM-1, VCAM-1, and MAdCAM-1 at the gene and protein levels compared with healthy subjects and/or inactive IBD patients. ß1 and ß7 integrin expression on circulating lymphocytes was similar across groups. TGF-ß1 treatment induced expression of αE on both ß7+ and ß7- T cells, suggesting that cells entering the mucosa independently of MAdCAM-1/α4ß7 can become αEß7+ ITGAE gene polymorphisms did not alter protein induction following TGF-ß1 stimulation. Increased phospho-SMAD3, which is directly downstream of TGF-ß, and increased TGF-ß-responsive gene expression were observed in the colonic mucosa of IBD patients. Finally, in vitro stimulation experiments showed that baseline ß7 expression had little effect on cytokine, chemokine, transcription factor, and effector molecule gene expression in αE+ and αE- T cells. These findings suggest cell migration to the gut mucosa may be altered in IBD and α4ß7-, and α4ß7+ T cells may upregulate αEß7 in response to TGF-ß once within the gut mucosa.
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Antígenos CD/metabolismo , Enfermedades Inflamatorias del Intestino/inmunología , Cadenas alfa de Integrinas/metabolismo , Cadenas beta de Integrinas/metabolismo , Mucosa Intestinal/inmunología , Receptores Mensajeros de Linfocitos/metabolismo , Linfocitos T/inmunología , Adulto , Anciano , Movimiento Celular , Femenino , Humanos , Cadenas beta de Integrinas/genética , Masculino , Persona de Mediana Edad , Transducción de Señal , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
OBJECTIVE: Both endoscopy and histology may be included in the definition of mucosal healing in UC. This study aimed to establish the association between patient-reported outcomes, specifically symptom measures, and the presence of inflammation as measured by endoscopy and histology in UC. DESIGN: Using patient data from an observational multicentre study of UC (n=103), rectal bleeding (RB) and stool frequency (SF) symptom subscores of the Mayo Clinic Score (MCS) were compared with the endoscopic subscore (MCSe) and histology. Faecal calprotectin and biopsy cytokine expression were also evaluated. RESULTS: When identifying UC patients with inactive disease, RB scores were superior to SF scores and the combination (sensitivity/specificity: MCSe=0/1, RB 77%/81%, SF 62%/95%, RB+SF 54%/95%; MCSe=0, RB 87%/66%, SF 76%/83%, RB+SF 68%/86%). Across different definitions of mucosal healing (MCSe≤1; 0; or 0 plus inactive histology), a larger subset of patients reported increased SF (39%, 25% and 27%, respectively) compared with RB (24%, 13% and 10%). Faecal calprotectin and inflammatory cytokine expression were higher in patients with active disease compared with patients with mucosal healing, but there were no differences between patients using increasingly stringent definitions of mucosal healing. CONCLUSIONS: Endoscopically inactive disease is associated with absence of RB but not with complete normalisation of SF. Achieving histological remission did not improve symptomatic relief. In addition, in these patients, higher inflammatory biomarker levels were not observed. These data suggest that non-inflammatory changes, such as bowel damage, may contribute to SF in UC.
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Colitis Ulcerosa/patología , Colonoscopía , Medición de Resultados Informados por el Paciente , Adulto , Biomarcadores/metabolismo , Biopsia , Citocinas/metabolismo , Heces/química , Femenino , Humanos , Mucosa Intestinal/metabolismo , Complejo de Antígeno L1 de Leucocito/metabolismo , Masculino , Estudios Retrospectivos , Sensibilidad y Especificidad , Cicatrización de Heridas/fisiologíaRESUMEN
BACKGROUND & AIMS: Etrolizumab is a humanized monoclonal antibody against the ß7 integrin subunit that has shown efficacy vs placebo in patients with moderate to severely active ulcerative colitis (UC). Patients with colon tissues that expressed high levels of the integrin αE gene (ITGAE) appeared to have the best response. We compared differences in colonic expression of ITGAE and other genes between patients who achieved clinical remission with etrolizumab vs those who did. METHODS: We performed a retrospective analysis of data collected from 110 patients with UC who participated in a phase 2 placebo-controlled trial of etrolizumab, as well as from 21 patients with UC or without inflammatory bowel disease (controls) enrolled in an observational study at a separate site. Colon biopsies were collected from patients in both studies and analyzed by immunohistochemistry and gene expression profiling. Mononuclear cells were isolated and analyzed by flow cytometry. We identified biomarkers associated with response to etrolizumab. In the placebo-controlled trial, clinical remission was defined as total Mayo Clinic Score ≤2, with no individual subscore >1, and mucosal healing was defined as endoscopic score ≤1. RESULTS: Colon tissues collected at baseline from patients who had a clinical response to etrolizumab expressed higher levels of T-cell-associated genes than patients who did not respond (P < .05). Colonic CD4(+) integrin αE(+) cells from patients with UC expressed higher levels of granzyme A messenger RNA (GZMA mRNA) than CD4(+) αE(-) cells (P < .0001); granzyme A and integrin αE protein were detected in the same cells. Of patients receiving 100 mg etrolizumab, a higher proportion of those with high levels of GZMA mRNA (41%) or ITGAE mRNA (38%) than those with low levels of GZMA (6%) or ITGAE mRNA (13%) achieved clinical remission (P < .05) and mucosal healing (41% GZMA(high) vs 19% GZMA(low) and 44% ITGAE(high) vs 19% ITGAE(low)). Compared with ITGAE(low) and GZMA(low) patients, patients with ITGAE(high) and GZMA(high) had higher baseline numbers of epithelial crypt-associated integrin αE(+) cells (P < .01 for both), but a smaller number of crypt-associated integrin αE(+) cells after etrolizumab treatment (P < .05 for both). After 10 weeks of etrolizumab treatment, expression of genes associated with T-cell activation and genes encoding inflammatory cytokines decreased by 40%-80% from baseline (P < .05) in patients with colon tissues expressing high levels of GZMA at baseline. CONCLUSIONS: Levels of GZMA and ITGAE mRNAs in colon tissues can identify patients with UC who are most likely to benefit from etrolizumab; expression levels decrease with etrolizumab administration in biomarker(high) patients. Larger, prospective studies of markers are needed to assess their clinical value.
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Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos CD/metabolismo , Colitis Ulcerosa/tratamiento farmacológico , Colon/efectos de los fármacos , Fármacos Gastrointestinales/uso terapéutico , Granzimas/metabolismo , Cadenas alfa de Integrinas/metabolismo , Antígenos CD/genética , Biopsia , Ensayos Clínicos Fase II como Asunto , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/enzimología , Colitis Ulcerosa/genética , Colon/enzimología , Colon/patología , Perfilación de la Expresión Génica/métodos , Granzimas/genética , Humanos , Inmunohistoquímica , Cadenas alfa de Integrinas/genética , Valor Predictivo de las Pruebas , ARN Mensajero/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Cicatrización de Heridas/efectos de los fármacosRESUMEN
In this issue of Immunity, Chaturvedi et al. (2008) describe a mechanism for the bridging of innate and adaptive immune receptor functions. In their model, B cell-receptor signaling induces the fusion of Toll-like receptor 9 (TLR9)-containing endosomes with internalized signaling-competent BCR into autophagosomes.
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Fagosomas/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de Señal , Receptor Toll-Like 9/metabolismo , Animales , Autoinmunidad , Humanos , Activación de Linfocitos , Fagosomas/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Receptor Toll-Like 9/inmunologíaRESUMEN
Chronic inflammatory disorders are complex and characterized by significant heterogeneity in molecular, pathological, and clinical features. This heterogeneity poses challenges for the development of targeted molecular interventions for these disorders, as not all patients with a given clinical diagnosis have disease driven by a single dominant molecular pathway, hence not all patients will benefit equally from a given intervention. Biomarkers related to molecular manifestations of disease are increasingly being applied to enable stratified approaches to drug development. Biomarkers may be used to identify which patients are most likely to benefit from an intervention (predictive), identify patients at increased risk of disease progression (prognostic), and monitor biological responsiveness to an intervention (pharmacodynamic). Here we consider how biomarker-guided stratification of patients may increase benefit from targeted therapies for asthma, rheumatoid arthritis and inflammatory bowel diseases.
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Artritis Reumatoide/metabolismo , Asma/metabolismo , Biomarcadores/metabolismo , Colitis Ulcerosa/metabolismo , Adalimumab/uso terapéutico , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Asma/diagnóstico , Asma/tratamiento farmacológico , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/tratamiento farmacológico , Humanos , Terapia Molecular Dirigida/métodos , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: The gut microbiota contributes to aberrant inflammation in inflammatory bowel disease, but the bacterial factors causing or exacerbating inflammation are not fully understood. Further, the predictive or prognostic value of gut microbial biomarkers for remission in response to biologic therapy is unclear. METHODS: We perform whole metagenomic sequencing of 550 stool samples from 287 ulcerative colitis patients from a large phase 3 head-to-head study of infliximab and etrolizumab. RESULTS: We identify several bacterial species in baseline and/or post-treatment samples that associate with clinical remission. These include previously described associations (Faecalibacterium prausnitzii_F) as well as new associations with remission to biologic therapy (Flavonifractor plautii). We build multivariate models and find that gut microbial species are better predictors for remission than clinical variables alone. Finally, we describe patient groups that differ in microbiome composition and remission rate after induction therapy, suggesting the potential utility of microbiome-based endotyping. CONCLUSIONS: In this large study of ulcerative colitis patients, we show that few individual species associate strongly with clinical remission, but multivariate models including microbiome can predict clinical remission and have better predictive power compared to clinical data alone.
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BACKGROUND AND AIMS: This study aimed to identify microbial drivers of inflammatory bowel disease [IBD], by investigating mucosal-associated bacteria and their detrimental products in IBD patients. METHODS: We directly cultured bacterial communities from mucosal biopsies from paediatric gastrointestinal patients and examined for pathogenicity-associated traits. Upon identifying Clostridium perfringens as toxigenic bacteria present in mucosal biopsies, we isolated strains and further characterized toxicity and prevalence. RESULTS: Mucosal biopsy microbial composition differed from corresponding stool samples. C. perfringens was present in eight of nine patients' mucosal biopsies, correlating with haemolytic activity, but was not present in all corresponding stool samples. Large IBD datasets showed higher C. perfringens prevalence in stool samples of IBD adults [18.7-27.1%] versus healthy controls [5.1%]. In vitro, C. perfringens supernatants were toxic to cell types beneath the intestinal epithelial barrier, including endothelial cells, neuroblasts, and neutrophils, while the impact on epithelial cells was less pronounced, suggesting C. perfringens may be particularly damaging when barrier integrity is compromised. Further characterization using purified toxins and genetic insertion mutants confirmed perfringolysin O [PFO] toxin was sufficient for toxicity. Toxin RNA signatures were found in the original patient biopsies by PCR, suggesting intestinal production. C. perfringens supernatants also induced activation of neuroblast and dorsal root ganglion neurons in vitro, suggesting C. perfringens in inflamed mucosal tissue may directly contribute to abdominal pain, a frequent IBD symptom. CONCLUSIONS: Gastrointestinal carriage of certain toxigenic C. perfringens may have an important pathogenic impact on IBD patients. These findings support routine monitoring of C. perfringens and PFO toxins and potential treatment in patients.
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Toxinas Bacterianas , Clostridium perfringens , Heces , Enfermedades Inflamatorias del Intestino , Mucosa Intestinal , Humanos , Clostridium perfringens/aislamiento & purificación , Clostridium perfringens/genética , Clostridium perfringens/patogenicidad , Niño , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Enfermedades Inflamatorias del Intestino/microbiología , Toxinas Bacterianas/genética , Heces/microbiología , Femenino , Masculino , Adolescente , Biopsia , Infecciones por Clostridium/microbiología , Proteínas HemolisinasRESUMEN
OBJECTIVES: In Crohn's disease (CD), clinical symptoms correspond poorly to inflammatory disease activity. Biomarkers reflective of mucosal and bowel wall inflammation would be useful to monitor disease activity. The EMBARK study evaluated disease activity in patients with ulcerative colitis (UC) and CD, and used endoscopy with or without cross-sectional imaging for biomarker discovery. METHODS: UC (n=107) and CD (n=157) patients were characterized and underwent ileocolonoscopy (ICO). A subset of CD patients (n=66) also underwent computed tomography enterography (CTE). ICO and CTE were scored by a gastroenterologist and radiologist who incorporated findings of inflammation into a single score (ICO-CTE) for patients that underwent both procedures. Serum and fecal biomarkers were evaluated for association with the Mayo Clinic endoscopy score in UC patients and with ICO alone or ICO-CTE in CD patients. Individual biomarkers with a moderate degree of correlation (P≤0.3) were evaluated using multivariate analysis with model selection using a stepwise procedure. RESULTS: In UC, ordinal logistic regression using Mayo Clinic endoscopy subscore selected the combination of fecal calprotectin and serum matrix metalloproteinase 9 (MMP9; pseudo R(2)=0.353). In CD, we found that use of the ICO-CTE increased specificity of known biomarkers. Using ICO-CTE as the dependent variable for biomarker discovery, the selected biomarkers were the combination of fecal calprotectin, serum MMP9, and serum IL-22 (r=0.699). CONCLUSIONS: Incorporation of both ICO and CTE into a single measure increased biomarker performance in CD. Combinations of fecal calprotectin and serum MMP9 for UC, and combinations of fecal calprotectin, serum MMP9, and serum interleukin-22 in CD, demonstrated the strongest association with imaging/endoscopy-defined inflammation.
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Biomarcadores/metabolismo , Enfermedad de Crohn/metabolismo , Heces/química , Interleucinas/sangre , Complejo de Antígeno L1 de Leucocito/metabolismo , Metaloproteinasa 9 de la Matriz/sangre , Adolescente , Adulto , Anciano , Colonoscopía , Enfermedad de Crohn/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos X , Interleucina-22RESUMEN
Programmed death-1 ligand 1 (PD-L1) is a coinhibitory molecule that negatively regulates multiple tolerance checkpoints. In the NOD mouse model, PD-L1 regulates the development of diabetes. PD-L1 has two binding partners, programmed death-1 and B7-1, but the significance of the PD-L1:B7-1 interaction in regulating self-reactive T cell responses is not yet clear. To investigate this issue in NOD mice, we have compared the effects of two anti-PD-L1 Abs that have different blocking activities. Anti-PD-L1 mAb 10F.2H11 sterically and functionally blocks only PD-L1:B7-1 interactions, whereas anti-PD-L1 mAb 10F.9G2 blocks both PD-L1:B7-1 and PD-L1:programmed death-1 interactions. Both Abs had potent, yet distinct effects in accelerating diabetes in NOD mice: the single-blocker 10F.2H11 mAb was more effective at precipitating diabetes in older (13-wk-old) than in younger (6- to 7-wk-old) mice, whereas the dual-blocker 10F.9G2 mAb rapidly induced diabetes in NOD mice of both ages. Similarly, 10F.2H11 accelerated diabetes in recipients of T cells from diabetic, but not prediabetic mice, whereas 10F.9G2 was effective in both settings. Both anti-PD-L1 mAbs precipitated diabetes in adoptive transfer models of CD4(+) and CD8(+) T cell-driven diabetes. Taken together, these data demonstrate that the PD-L1:B7-1 pathway inhibits potentially pathogenic self-reactive effector CD4(+) and CD8(+) T cell responses in vivo, and suggest that the immunoinhibitory functions of this pathway may be particularly important during the later phases of diabetogenesis.
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Antígeno B7-1/fisiología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/prevención & control , Inhibidores de Crecimiento/fisiología , Glicoproteínas de Membrana/fisiología , Péptidos/fisiología , Transducción de Señal/inmunología , Traslado Adoptivo , Animales , Anticuerpos Bloqueadores/administración & dosificación , Antígenos CD/fisiología , Proteínas Reguladoras de la Apoptosis/fisiología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Antígeno B7-1/genética , Antígeno B7-1/inmunología , Antígeno B7-H1 , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/trasplante , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/trasplante , Diabetes Mellitus Tipo 1/genética , Femenino , Ligandos , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Péptidos/deficiencia , Péptidos/inmunología , Receptor de Muerte Celular Programada 1 , Unión Proteica/inmunología , Transducción de Señal/genéticaRESUMEN
BACKGROUND: IL-22 is induced by aryl hydrocarbon receptor (AhR) signaling and plays a critical role in gastrointestinal barrier function through effects on antimicrobial protein production, mucus secretion, and epithelial cell differentiation and proliferation, giving it the potential to modulate the microbiome through these direct and indirect effects. Furthermore, the microbiome can in turn influence IL-22 production through the synthesis of L-tryptophan (L-Trp)-derived AhR ligands, creating the prospect of a host-microbiome feedback loop. We evaluated the impact IL-22 may have on the gut microbiome and its ability to activate host AhR signaling by observing changes in gut microbiome composition, function, and AhR ligand production following exogenous IL-22 treatment in both mice and humans. RESULTS: Microbiome alterations were observed across the gastrointestinal tract of IL-22-treated mice, accompanied by an increased microbial functional capacity for L-Trp metabolism. Bacterially derived indole derivatives were increased in stool from IL-22-treated mice and correlated with increased fecal AhR activity. In humans, reduced fecal concentrations of indole derivatives in ulcerative colitis (UC) patients compared to healthy volunteers were accompanied by a trend towards reduced fecal AhR activity. Following exogenous IL-22 treatment in UC patients, both fecal AhR activity and concentrations of indole derivatives increased over time compared to placebo-treated UC patients. CONCLUSIONS: Overall, our findings indicate IL-22 shapes gut microbiome composition and function, which leads to increased AhR signaling and suggests exogenous IL-22 modulation of the microbiome may have functional significance in a disease setting. Video Abstract.
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Microbioma Gastrointestinal , Humanos , Animales , Ratones , Receptores de Hidrocarburo de Aril/metabolismo , Interleucinas , Indoles , Interleucina-22RESUMEN
Signal regulatory protein (SIRPα) is an immune inhibitory receptor expressed by myeloid cells to inhibit immune cell phagocytosis, migration, and activation. Despite the progress of SIRPα and CD47 antagonist antibodies to promote anti-cancer immunity, it is not yet known whether SIRPα receptor agonism could restrain excessive autoimmune tissue inflammation. Here, we report that neutrophil- and monocyte-associated genes including SIRPA are increased in inflamed tissue biopsies from patients with rheumatoid arthritis and inflammatory bowel diseases, and elevated SIRPA is associated with treatment-refractory ulcerative colitis. We next identify an agonistic anti-SIRPα antibody that exhibits potent anti-inflammatory effects in reducing neutrophil and monocyte chemotaxis and tissue infiltration. In preclinical models of arthritis and colitis, anti-SIRPα agonistic antibody ameliorates autoimmune joint inflammation and inflammatory colitis by reducing neutrophils and monocytes in tissues. Our work provides a proof of concept for SIRPα receptor agonism for suppressing excessive innate immune activation and chronic inflammatory disease treatment.
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Colitis , Neoplasias , Humanos , Fagocitosis , Neoplasias/tratamiento farmacológico , Neutrófilos/metabolismo , Inflamación/patología , Colitis/metabolismoRESUMEN
Programmed death 1 (PD-1), an inhibitory receptor expressed on activated lymphocytes, regulates tolerance and autoimmunity. PD-1 has two ligands: PD-1 ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells; and PD-L2, which is restricted to macrophages and dendritic cells. To investigate whether PD-L1 and PD-L2 have synergistic or unique roles in regulating T cell activation and tolerance, we generated mice lacking PD-L1 and PD-L2 (PD-L1/PD-L2(-/-) mice) and compared them to mice lacking either PD-L. PD-L1 and PD-L2 have overlapping functions in inhibiting interleukin-2 and interferon-gamma production during T cell activation. However, PD-L1 has a unique and critical role in controlling self-reactive T cells in the pancreas. Our studies with bone marrow chimeras demonstrate that PD-L1/PD-L2 expression only on antigen-presenting cells is insufficient to prevent the early onset diabetes that develops in PD-L1/PD-L2(-/-) non-obese diabetic mice. PD-L1 expression in islets protects against immunopathology after transplantation of syngeneic islets into diabetic recipients. PD-L1 inhibits pathogenic self-reactive CD4+ T cell-mediated tissue destruction and effector cytokine production. These data provide evidence that PD-L1 expression on parenchymal cells rather than hematopoietic cells protects against autoimmune diabetes and point to a novel role for PD-1-PD-L1 interactions in mediating tissue tolerance.
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Antígeno B7-1/biosíntesis , Tolerancia Inmunológica , Glicoproteínas de Membrana/biosíntesis , Linfocitos T/inmunología , Animales , Antígeno B7-1/genética , Antígeno B7-1/fisiología , Antígeno B7-H1 , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Citocinas/antagonistas & inhibidores , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/genética , Células Madre Hematopoyéticas/metabolismo , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Interferón gamma , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Especificidad de Órganos/inmunología , Péptidos/deficiencia , Péptidos/genética , Péptidos/fisiología , Proteína 2 Ligando de Muerte Celular Programada 1 , Linfocitos T/metabolismoRESUMEN
Chronic immune activation and inflammation (e.g., as manifest by production of type I interferons) are major determinants of disease progression in primate lentivirus infections. To investigate the impact of such activation on intrathymic T-cell production, we studied infection of the human thymus implants of SCID-hu Thy/Liv mice with X4 and R5 HIV. X4 HIV was observed to infect CD3(-)CD4(+)CD8(-)CXCR4(+)CCR5(-) intrathymic T-cell progenitors (ITTP) and to abrogate thymopoiesis. R5 HIV, by contrast, first established a nonpathogenic infection of thymic macrophages and then, after many weeks, began to replicate in ITTP. We demonstrate here that the tropism of R5 HIV is expanded and pathogenicity enhanced by upregulation of CCR5 on these key T-cell progenitors. Such CCR5 induction was mediated by interferon-alpha (IFN-alpha) in both thymic organ cultures and in SCID-hu mice, and antibody neutralization of IFN-alpha in R5 HIV-infected SCID-hu mice inhibited both CCR5 upregulation and infection of the T-cell progenitors. These observations suggest a mechanism by which IFN-alpha production may paradoxically expand the tropism of R5 HIV and, in so doing, accelerate disease progression.
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Infecciones por VIH/inmunología , VIH/fisiología , Células Madre Hematopoyéticas/virología , Interferón-alfa/inmunología , Receptores CCR5/biosíntesis , Tropismo Viral/fisiología , Animales , Separación Celular , Progresión de la Enfermedad , Citometría de Flujo , Infecciones por VIH/metabolismo , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/metabolismo , Humanos , Ratones , Ratones SCID , Receptores CCR5/inmunología , Linfocitos T/inmunología , Linfocitos T/virología , Timo/citología , Timo/inmunología , Timo/virología , Regulación hacia ArribaRESUMEN
INTRODUCTION: Magnetic resonance enterography (MRE) is useful for detecting bowel strictures, whereas a number of imaging biomarkers may reflect severity of fibrosis burden in Crohn's disease (CD). This study aimed to verify the association of MRE metrics with histologic fibrosis independent of inflammation. METHODS: This prospective European multicenter study performed MRE imaging on 60 patients with CD with bowel strictures before surgical resection. Locations of 61 histological samples were annotated on MRE examinations, followed by central readings using the Chiorean score and measurement of delayed gain of enhancement (DGE), magnetization transfer ratio, T2-weighted MRI sequences (T2R), apparent diffusion coefficient (ADC), and the magnetic resonance index of activity (MaRIA). Correlations of histology and MRE metrics were assessed. Least Absolute Shrinkage and Selection Operator and receiver operator characteristic (ROC) curve analyses were used to select composite MRE scores predictive of histology and to estimate their predictive value. RESULTS: ADC and MaRIA correlated with fibrosis (R = -0.71, P < 0.0001, and 0.59, P < 0.001) and more moderately with inflammation (R = -0.35, P < 0.01, and R = 0.53, P < 0.001). Lower or no correlations of fibrosis or inflammation were found with DGE, magnetization transfer ratio, or T2R. Least Absolute Shrinkage and Selection Operator and ROC identified a composite score of MaRIA, ADC, and DGE as a very good predictor of histologic fibrosis (ROC area under the curve = 0.910). MaRIA alone was the best predictor of histologic inflammation with excellent performance in identifying active histologic inflammation (ROC area under the curve = 0.966). DISCUSSION: MRE-based scores for histologic fibrosis and inflammation may assist in the characterization of CD stenosis and enable development of fibrosis-targeted therapies and clinical treatment of stenotic patients.
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Enfermedad de Crohn , Constricción Patológica/diagnóstico por imagen , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/diagnóstico por imagen , Fibrosis , Humanos , Inflamación/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética , Estudios ProspectivosRESUMEN
B cells, which are critical for intestinal homeostasis, remain understudied in ulcerative colitis (UC). In this study, we recruited three cohorts of patients with UC (primary cohort, n = 145; validation cohort 1, n = 664; and validation cohort 2, n = 143) to comprehensively define the landscape of B cells during UC-associated intestinal inflammation. Using single-cell RNA sequencing, single-cell IgH gene sequencing and protein-level validation, we mapped the compositional, transcriptional and clonotypic landscape of mucosal and circulating B cells. We found major perturbations within the mucosal B cell compartment, including an expansion of naive B cells and IgG+ plasma cells with curtailed diversity and maturation. Furthermore, we isolated an auto-reactive plasma cell clone targeting integrin αvß6 from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing TFH-like T peripheral helper cells that were associated with the pathogenic B cell response. Finally, across all three cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that correlates with disease activity and predicts disease complications. Our data demonstrate a highly dysregulated B cell response in UC and highlight a potential role of B cells in disease pathogenesis.
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Colitis Ulcerosa , Células Plasmáticas , Linfocitos B , Colitis Ulcerosa/genética , Humanos , Mucosa Intestinal/patología , Recuento de Linfocitos , Linfocitos T Colaboradores-InductoresRESUMEN
Anti-integrins are therapeutically effective for inflammatory bowel disease, yet the relative contribution of α4ß7 and αEß7 to gut lymphocyte trafficking is not fully elucidated. Here, we evaluate the effect of α4ß7 and αEß7 blockade using a combination of murine models of gut trafficking and longitudinal gene expression analysis in etrolizumab-treated patients with Crohn's disease (CD). Dual blockade of α4ß7 and αEß7 reduces CD8+ T cell accumulation in the gut to a greater extent than blockade of either integrin alone. Anti-αEß7 reduces epithelial:T cell interactions and promotes egress of activated T cells from the mucosa into lymphatics. Inflammatory gene expression is greater in human intestinal αEß7+ T cells. Etrolizumab-treated patients with CD display a treatment-specific reduction in inflammatory and cytotoxic intraepithelial lymphocytes (IEL) genes. Concurrent blockade of α4ß7 and αEß7 promotes reduction of cytotoxic IELs and inflammatory T cells in the gut mucosa through a stepwise inhibition of intestinal tissue entry and retention.
Asunto(s)
Enfermedades Inflamatorias del Intestino/inmunología , Integrinas/metabolismo , Linfocitos/inmunología , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Biopsia , Linfocitos T CD8-positivos , Cadherinas/metabolismo , Comunicación Celular , Movimiento Celular , Colon/patología , Epítopos/inmunología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/complicaciones , Inflamación/patología , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Ganglios Linfáticos/patología , Ratones Endogámicos C57BL , Ratones Transgénicos , Linfocitos T Citotóxicos/efectos de los fármacosRESUMEN
The past year has seen significant advances in our understanding of the critical roles of negative immunoregulatory signals delivered by the programmed death 1 (PD-1)-PD-1 ligand (PD-L) pathway in regulating T-cell activation and tolerance. Emerging evidence indicates that PD-Ls play an essential role on dendritic cells (DCs), both directly during DC-T cell interactions and indirectly through signaling into the DC. Recent studies point to a novel role for PD-L1 in maintaining tissue tolerance. Finally, PD-1 has recently been shown to be highly expressed on exhausted T cells during chronic viral infection, and blockade of PD-1 or PD-L1 can revive exhausted T cells, enabling them to proliferate and produce effector cytokines.
Asunto(s)
Antígenos CD/inmunología , Proteínas Reguladoras de la Apoptosis/inmunología , Linfocitos T/inmunología , Animales , Antígenos CD/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Antígeno B7-H1 , Comunicación Celular/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Humanos , Tolerancia Inmunológica , Activación de Linfocitos/inmunología , Receptor de Muerte Celular Programada 1 , Linfocitos T/metabolismoRESUMEN
BACKGROUND: PD-L1 and PD-L2 are ligands for the inhibitory receptor programmed death-1 (PD-1), which is an important regulator of immune responses. PD-L1 is induced on cardiac endothelial cells under inflammatory conditions, but little is known about its role in regulating immune injury in the heart. METHODS AND RESULTS: Cytotoxic T-lymphocyte-mediated myocarditis was induced in mice, and the influence of PD-L1 signaling was studied with PD-L1/L2-deficient mice and blocking antibodies. During cytotoxic T-lymphocyte-induced myocarditis, the upregulation of PD-L1 on cardiac endothelia was dependent on T-cell-derived interferon-gamma, and blocking of interferon-gamma signaling worsened disease. Genetic deletion of both PD-1 ligands [PD-L1/2(-/-)], as well as treatment with PD-L1 blocking antibody, transformed transient myocarditis to lethal disease, in association with widespread polymorphonuclear leukocyte-rich microabscesses but without change in cytotoxic T-lymphocyte recruitment. PD-L1/2(-/-) mice reconstituted with bone marrow from wild-type mice remained susceptible to severe disease, which demonstrates that PD-L1 on non-bone marrow-derived cells confers the protective effect. Finally, depletion of polymorphonuclear leukocytes reversed the enhanced susceptibility to lethal myocarditis attributable to PD-L1 deficiency. CONCLUSIONS: Myocardial PD-L1, mainly localized on endothelium, is critical for control of immune-mediated cardiac injury and polymorphonuclear leukocyte inflammation.
Asunto(s)
Antígeno B7-1/fisiología , Linfocitos T CD8-positivos/metabolismo , Células Endoteliales/metabolismo , Glicoproteínas de Membrana/fisiología , Miocarditis/metabolismo , Péptidos/fisiología , Animales , Antígeno B7-1/biosíntesis , Antígeno B7-1/genética , Antígeno B7-H1 , Linfocitos T CD8-positivos/patología , Células Endoteliales/patología , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/fisiología , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Miocarditis/inmunología , Miocarditis/patología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/patología , Péptidos/genética , Transducción de Señal/inmunologíaRESUMEN
Integrins are cell surface receptors with bidirectional signalling capabilities that can bind to adhesion molecules in order to mediate homing of leukocytes to peripheral tissues. Gut-selective leukocyte homing is facilitated by interactions between α4ß7 and its ligand, mucosal addressin cellular adhesion molecule-1 [MAdCAM-1], while retention of lymphocytes in mucosal tissues is mediated by αEß7 binding to its ligand E-cadherin. Therapies targeting gut-selective trafficking have shown efficacy in inflammatory bowel disease [IBD], confirming the importance of leukocyte trafficking in disease pathobiology. This review will provide an overview of integrin structure, function and signalling, and highlight the role that these molecules play in leukocyte homing and retention. Anti-integrin therapeutics, including gut-selective antibodies against the ß7 integrin subunit [etrolizumab] and the α4ß7 integrin heterodimer [vedolizumab and abrilumab], and the non-gut selective anti-α4 integrin [natalizumab], will be discussed, as well as novel targeting approaches using small molecules.