RESUMEN
A 26-year-old male with no significant medical history presented with hematochezia and was diagnosed with ulcerative colitis (UC) accompanied by immune thrombocytopenia (ITP) as an extraintestinal manifestation (EIM) of UC. This case report delves into the uncommon overlap between UC, a subtype of inflammatory bowel disease primarily affecting the colon and rectum, and ITP, an autoimmune condition leading to platelet destruction. The patient's atypical presentation and subsequent positive response to a treatment regimen targeting both UC and ITP underscores the necessity for a thorough and multifaceted diagnostic approach in individuals with UC, especially when faced with non-gastrointestinal symptoms like unexplained thrombocytopenia. The findings from this study enhance the understanding of UC's diverse manifestations and highlight its potential intersection with other autoimmune diseases, advocating for integrated care strategies in managing such intricate clinical cases.
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Inflammatory bowel disease (IBD) is a chronic and progressive inflammatory intestinal disease that affects people around the world. The primary cause of IBD is an imbalance in the host immune response to intestinal flora. Several human genes, including IL10, STAT3, IRGM, ATG16L1, NOD2 and RUNX3, are associated with inappropriate immune responses in IBD. It has been reported that homozygous Runx3-knockout (ko) mice spontaneously develop colitis. However, the high mortality rate in these mice within the first two weeks makes it challenging to study the role of Runx3 in colitis. To address this issue, a spontaneous colitis (SC) mouse model carrying a C-terminal truncated form of Runx3 with Tyr319stop point mutation has been generated. After weaning, SC mice developed spontaneous diarrhea and exhibited prominent enlargement of the colon, accompanied by severe inflammatory cell infiltration. Results of immunofluorescence staining showed massive CD4+ T cell infiltration in the inflammatory colon of SC mice. Colonic IL-17A mRNA expression and serum IL-17A level were increased in SC mice. CD4+ T cells from SC mice produced stronger IL-17A than those from wildtype mice in Th17-skewing conditions in vitro. In addition, the percentages of Foxp3+ Treg cells as well as the RORγt+Foxp3+ Treg subset, known for its role in suppressing Th17 response in the gut, were notably lower in colon lamina propria of SC mice than those in WT mice. Furthermore, transfer of total CD4+ T cells from SC mice, but not from wildtype mice, into Rag1-ko host mice resulted in severe autoimmune colitis. In conclusion, the C-terminal truncated Runx3 caused autoimmune colitis associated with Th17/Treg imbalance. The SC mouse model is a feasible approach to investigate the effect of immune response on spontaneous colitis.
Asunto(s)
Colitis , Subunidad alfa 3 del Factor de Unión al Sitio Principal , Modelos Animales de Enfermedad , Linfocitos T Reguladores , Células Th17 , Animales , Células Th17/inmunología , Linfocitos T Reguladores/inmunología , Ratones , Colitis/inmunología , Colitis/inducido químicamente , Colitis/genética , Colitis/etiología , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 3 del Factor de Unión al Sitio Principal/metabolismo , Ratones Noqueados , Humanos , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/etiología , Ratones Endogámicos C57BL , Interleucina-17/metabolismo , Interleucina-17/genética , Colon/patología , Colon/inmunologíaRESUMEN
An idiopathic condition known as inflammatory bowel disease (IBD) is characterized by a dysregulated immune response to the intestinal flora of the host. It falls into one of two primary categories: ulcerative colitis or Crohn's disease. A wide range of disorders, both clinically and genetically, can cause IBD. The purpose of this thorough analysis is to determine the significance and reliability of the correlation between perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) and IBD, as well as the implications of this correlation for the diagnosis and treatment of IBD. Ten pertinent studies were identified from a starting pool of 20 articles in this systematic review, which was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. These studies addressed treatment, complications, limitations, and outcome in addition to the presence or lack of p-ANCA in patients with IBD. In conclusion, p-ANCA is more strongly linked to inflammatory bowel illness than Crohn's disease, primarily ulcerative colitis. Some evidence suggests that there is a decrease in p-ANCA to some extent with medical or surgical interventions, but the exact intervention is not yet clear. There is less evidence suggesting that the medical or surgical treatments used in patients with IBD cause an increase or decrease in p-ANCA.
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Toripalimab, a specific immune checkpoint inhibitor targeting the programmed death 1 (PD-1) receptor, represents a novel immunotherapeutic approach for advanced nasopharyngeal carcinoma, showing promising curative potential. However, it is not without drawbacks, as some patients experience immune-related adverse events (irAEs) associated with this treatment, and there remains a limited body of related research. Here, we present a case of advanced nasopharyngeal carcinoma in a patient who developed colitis as an irAE attributed to Toripalimab. Subsequent to Toripalimab treatment, the patient achieved complete remission. Notably, the development of colitis was accompanied by inflammatory manifestations evident in colonoscopy and pathology results. Further investigation revealed cytomegalovirus (CMV) infection, detected through immunohistochemistry in 11 colon biopsies. Subsequent treatment with ganciclovir and steroids resulted in symptom relief, and colonoscopy indicated mucosal healing. Our case highlights the association between irColitis induced by Toripalimab and CMV infection. Toripalimab demonstrates remarkable efficacy in treating advanced nasopharyngeal carcinoma, albeit with a notable risk of irAEs, particularly in the form of colitis. The link between symptoms and endoscopic pathology findings in irColitis is noteworthy. Standardized biopsy procedures can effectively confirm the diagnosis of CMV infection. Our findings may provide valuable guidance for managing acute CMV infection and irAEs associated with Toripalimab in the treatment of nasopharyngeal carcinoma in the future.
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Colitis , Infecciones por Citomegalovirus , Neoplasias Nasofaríngeas , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Carcinoma Nasofaríngeo/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológicoRESUMEN
Given the promising response of immune checkpoint inhibitors (ICPIs) in treating advanced malignancies, their use in clinical practice is on the rise. ICPIs are associated with a wide spectrum of immune-related adverse events (irAEs). The reported side effects of therapy can be severe enough to require interruption or withdrawal. We are presenting a case of a checkpoint inhibitor-induced acute pancreatitis and colitis, treated with high-dose steroids. This case highlights the need for all physicians to be aware of the different presentations of irAEs from checkpoint inhibitors to provide the correct diagnosis and management.
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BACKGROUND: Nivolumab is an immune checkpoint inhibitor specific to the programmed death 1 (PD-1) receptor. Nivolumab has shown clinical responses in many malignancies. Although immune-related adverse events (irAEs) associated with nivolumab are largely tolerable, severe irAEs have occurred in some patients. However, the mechanisms underlying the development of irAEs are not fully clarified. CASE PRESENTATION: We report 2 patients with metastatic melanoma who developed colitis, an irAEs caused by nivolumab. Both patients experienced colitis after nivolumab administration. Pathological examination of the colon showed robust infiltration of CD8+ cells and T-bet expressing CD4+ cells in both cases, indicating helper T cells (Th) 1 to be responsible for the dominant response. Additionally, we observed the serum C-reactive protein level (CRP) as well as interleukin-6 (IL-6) reflected the clinical course of irAEs clearly in the two cases. CONCLUSION: Our two cases suggested that the development of irAEs due to nivolumab is associated with Th1 dominant response. CRP as well as IL-6 was found to be a potential biomarker for irAEs. Our findings may help to understand the mechanisms underlying irAEs caused by nivolumab and manage irAEs in clinical practice.
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Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Colitis/inducido químicamente , Melanoma/tratamiento farmacológico , Nivolumab/efectos adversos , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Células TH1/inmunología , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/farmacología , Biomarcadores de Tumor/análisis , Proteína C-Reactiva/análisis , Linfocitos T CD8-positivos/inmunología , Resultado Fatal , Estudios de Seguimiento , Humanos , Interleucina-6/análisis , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Melanoma/patología , Persona de Mediana Edad , Nivolumab/farmacología , Neoplasias Cutáneas/patologíaRESUMEN
Aim: Autoimmune colitis is a typical and possible severe side effect among patients treated with ipilimumab. Patients & methods: We prospectively included 100 patients with metastasized melanoma under ipilimumab treatment in a radiological study of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT). PET evidence of pancolitis ('PET-colitis') was correlated with clinical variables. Results: We observed a significant correlation between PET-colitis and clinically significant diarrhoea, although PET-colitis was more frequent (49 vs 29% of patients, respectively). Neither PET-colitis nor diarrhoea was significantly correlated with response to therapy. Other immune-related adverse events, however, such as hypophysitis and hepatitis were associated with response to therapy and overall survival. Conclusion: Increased 18F-FDG uptake in the colon correlated with clinical symptoms but did not predict clinical outcome to ipilimumab.
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Enfermedades Autoinmunes , Colitis , Fluorodesoxiglucosa F18/administración & dosificación , Ipilimumab/administración & dosificación , Melanoma , Tomografía Computarizada por Tomografía de Emisión de Positrones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/diagnóstico por imagen , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/patología , Colitis/diagnóstico por imagen , Colitis/tratamiento farmacológico , Colitis/patología , Femenino , Humanos , Masculino , Melanoma/diagnóstico por imagen , Melanoma/tratamiento farmacológico , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de NeoplasiasRESUMEN
Vitamin D deficiency is an established risk factor for many autoimmune diseases and the anti-inflammatory properties of vitamin D underscore its potential therapeutic value for these diseases. However, results of vitamin D3 supplementation clinical trials have been varied. To understand the clinical heterogeneity, we reviewed the pre-clinical data on vitamin D activity in four common autoimmune diseases: multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD), in which patients are commonly maintained on oral vitamin D3 supplementation. In contrast, many pre-clinical studies utilize other methods of manipulation (i.e. genetic, injection). Given the many actions of vitamin D3 and data supporting a vitamin D-independent role of the Vitamin D receptor (VDR), a more detailed mechanistic understanding of vitamin D3 activity is needed to properly translate pre-clinical findings into the clinic. Therefore, we assessed studies based on route of vitamin D3 administration, and identified where discrepancies in results exist and where more research is needed to establish the benefit of vitamin D supplementation.
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Enfermedades Autoinmunes , Colecalciferol/uso terapéutico , Receptores de Calcitriol/inmunología , Deficiencia de Vitamina D , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Humanos , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/inmunología , Deficiencia de Vitamina D/patologíaRESUMEN
CCR6 is a G protein-coupled receptor (GPCR) that binds to a specific chemokine, CCL20. The role of CCR6-CCL20 is very well studied in the migration of immune cells, but the non-chemotaxis functions of CCR6 signaling were not known. Here, we show that during gut inflammation, the frequency of Foxp3+CD4+ T cells (Tregs) reduced in the secondary lymphoid tissues and CCR6+ Tregs enhanced the expression of RORγt. The peripheral blood mononuclear cells (PBMCs) of ulcerative colitis (UC) patients showed lower percentages of Foxp3+CD4+ T cells, as compared to healthy individuals, with CCR6+ Tregs showing higher RORγt expression as compared to CCR6-Tregs. CCL20 inhibited the TGF-ß1-induced Treg (iTreg) differentiation and directed them towards the pathogenic Th17-lineage in a CCR6-dependent manner. The iTreg that differentiated in the presence of CCL20 showed lower surface expression of suppressor molecules such as CD39, CD73 and FasL, and had impaired suppressive function. Furthermore, CCR6 signaling induced phosphorylation of Akt, mTOR, and STAT3 molecules in T cells. In conclusion, we have identified a new role of CCR6 signaling in the differentiation of iTregs during inflammation and gut autoimmunity.
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Colitis Ulcerosa/inmunología , Inflamación/inmunología , Intestinos/inmunología , Receptores CCR6/metabolismo , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Autoinmunidad/genética , Diferenciación Celular , Células Cultivadas , Quimiocina CCL20/metabolismo , Quimiotaxis , Factores de Transcripción Forkhead/metabolismo , Humanos , Tolerancia Inmunológica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Transducción de SeñalRESUMEN
Induction of tolerance is a key mechanism to maintain or to restore immunological homeostasis. Here we show that Foxp3+ regulatory T (Treg) cells use Dickkopf-1 (DKK-1) to regulate T-cell-mediated tolerance in the T-cell-mediated autoimmune colitis model. Treg cells from DKK-1 hypomorphic doubleridge mice failed to control CD4+ T-cell proliferation, resulting in CD4 T-cell-mediated autoimmune colitis. Thymus-derived Treg cells showed a robust expression of DKK-1 but not in naive or effector CD4 T cells. DKK-1 expression in Foxp3+ Treg cells was further increased upon T-cell receptor stimulation in vitro and in vivo. Interestingly, Foxp3+ Treg cells expressed DKK-1 in the cell membrane and the functional inhibition of DKK-1 using DKK-1 monoclonal antibody abrogated the suppressor function of Foxp3+ Treg cells. DKK-1 expression was dependent on de novo protein synthesis and regulated by the mitogen-activated protein kinase pathway but not by the canonical Wnt pathway. Taken together, our results highlight membrane-bound DKK-1 as a novel Treg-derived mediator to maintain immunological tolerance in T-cell-mediated autoimmune colitis.
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Enfermedades Autoinmunes/metabolismo , Membrana Celular/metabolismo , Colitis/metabolismo , Colon/metabolismo , Factores de Transcripción Forkhead/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Autotolerancia , Linfocitos T Reguladores/metabolismo , Traslado Adoptivo , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Autoinmunidad , Células CHO , Membrana Celular/inmunología , Proliferación Celular , Colitis/genética , Colitis/inmunología , Colitis/patología , Colon/inmunología , Colon/patología , Cricetulus , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Predisposición Genética a la Enfermedad , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/inmunología , Activación de Linfocitos , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fenotipo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/trasplante , Factores de Tiempo , TransfecciónRESUMEN
Immune-related adverse events (irAEs) induced by checkpoint inhibitors are well known. Since fatal outcomes have been reported early detection and adequate management are crucial. In particular, colitis is frequently observed and can result in intestinal perforation. This is the first report of an autoimmune colitis that was treated according to algorithms but became resistant due to a CMV reactivation. The 32-y-old male patient with metastatic melanoma treated within an anti-PD-1/ipilimumab combination study developed severe immune-mediated colitis (CTCAE grade 3) with up to 18 watery stools per day starting 2 weeks after treatment initiation. After improving upon therapy with immunosuppressive treatment (high dose steroids and infliximab) combined with parenteral nutrition diarrhea again exacerbated. Additionally, the patient had asymptomatic grade 3 CTCAE amylase and lipase elevation. Colitis was monitored by weekly endoscopies and colon biopsies were analyzed histologically with CMV staining, multi-epitope ligand cartography (MELC) and qRT-PCR for inflammatory genes. In the course, CMV reactivation was detected in the colon and treated with antiviral medication in parallel to a reduction of corticosteroids. Subsequently, symptoms improved. The patient showed a complete response for 2 y now including regression of bone metastases. CMV reactivation under checkpoint inhibitor therapy in combination with immunosuppressive treatment for autoimmune side effects has to be considered in these patients and if present treated. Potentially, CMV reactivation is underdiagnosed. Treatment algorithms should include CMV diagnostics.
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IL-27 is a heterodimeric cytokine that is composed of two subunits, i.e., EBV-induced gene 3 and IL-27p28 (also known as IL-30). Although the role of endogenous IL-27 in the pathogenesis of autoimmune colitis, an experimental model of human inflammatory bowel disease, remains controversial, IL-27 local delivery has been shown to inhibit autoimmune colitis. IL-30 has been shown to inhibit Th1 and Th17 responses and is considered a potential therapeutic for certain autoimmune diseases. In this study, we have compared the therapeutic efficacy of adeno-associated viral vector-delivered IL-27 and IL-30 in a murine model of autoimmune colitis. We found that 1 single administration of adeno-associated viral vector-delivered IL-27, but not adeno-associated viral vector-delivered IL-30, nearly completely inhibited autoimmune colitis. Adeno-associated viral vector-delivered IL-27 administration inhibited Th17 responses and induced T cell expression of IL-10, programmed death ligand 1, and stem cell antigen 1. Intriguingly, adeno-associated viral vector-delivered IL-27 treatment enhanced Th1 responses and inhibited regulatory T cell responses. Experiments involving the adoptive transfer of IL-10-deficient T cells revealed that adeno-associated viral vector-delivered IL-27-induced IL-10 production was insufficient to mediate inhibition of autoimmune colitis, whereas anti-programmed death 1 antibody treatment resulted in the breaking of adeno-associated viral vector-delivered IL-27-induced T cell tolerance. Thus, systemic delivery of IL-27 inhibits Th17 responses and induces multiple inhibitory pathways, including programmed death ligand 1 in T cells, and adeno-associated viral vector-delivered IL-27, but not IL-30, may have a therapeutic potential for the treatment of human inflammatory bowel disease.
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Enfermedades Autoinmunes/terapia , Colitis/terapia , Dependovirus/genética , Vectores Genéticos/administración & dosificación , Interleucina-27/genética , Linfocitos T Reguladores/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Colitis/inmunología , Colitis/metabolismo , Citocinas/inmunología , Interleucina-10/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Inflammatory bowel Disease (IBD) is a group of chronic inflammatory diseases that can be associated with different autoimmune diseases, including autoimmune hepatitis (AIH). Some specific and differential characteristics in children with IBD associated to AIH have been described. Our aim is to describe the clinical pattern of this association observed in our patients, confirming its differential characteristics as compared to classical IBD in children.