PURPOSE: Crohn's disease is a chronic gastrointestinal inflammatory disease with possible extraintestinal symptoms. There are predisposing genetic factors and even monogenic variants of the disorder. One of the possible genetic factors are variants of the DUOX2 gene. The protein product of the DUOX2 gene is a dual oxidase enzyme producing H2O2 in the bowel. Reduced H2O2 levels impact mucosal homeostasis and contribute to the development of inflammatory bowel disease. Thus far, only 19 patients with IBD with the DUOX2 variants have been described. METHODS: Here we present a case report of an adolescent female diagnosed at eleven years of age with IBD that was subsequently reclassified as Crohn's disease. She was treated with immunosuppressants and biological therapy but experienced additional complications. Her peripheral blood lymphocyte DNA was studied using massive parallel sequencing. Detected variants were functionally studied. RESULTS: Whole exome sequencing found two novel DUOX2 gene variants: a de novo variant c.3646C>T; p.R1216W and a maternally inherited variant c.3391G>A; p.A1131T which were initially classified as variants of unknown significance. However, follow-up functional studies demonstrated that both DUOX2 variants led to impaired H2O2 generation, which led to their reclassification to the likely pathogenic class according to the ACMG.net. Therefore, we conclude that these variants are causative for the disease. CONCLUSIONS: Identifying novel variants in patients with Crohn's disease and their families is important for precision medicine approaches and understanding of the pathogenesis of likely "monogenic" rare forms of inflammatory bowel disease.

• MeSH
• Crohnova nemoc * genetika   MeSH
• duální oxidázy genetika   MeSH
• idiopatické střevní záněty * genetika   MeSH
• lidé MeSH
• mladiství MeSH
• peroxid vodíku MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

OBJECTIVE: One of the current hypotheses to explain the proinflammatory immune response in IBD is a dysregulated T cell reaction to yet unknown intestinal antigens. As such, it may be possible to identify disease-associated T cell clonotypes by analysing the peripheral and intestinal T-cell receptor (TCR) repertoire of patients with IBD and controls. DESIGN: We performed bulk TCR repertoire profiling of both the TCR alpha and beta chains using high-throughput sequencing in peripheral blood samples of a total of 244 patients with IBD and healthy controls as well as from matched blood and intestinal tissue of 59 patients with IBD and disease controls. We further characterised specific T cell clonotypes via single-cell RNAseq. RESULTS: We identified a group of clonotypes, characterised by semi-invariant TCR alpha chains, to be significantly enriched in the blood of patients with Crohn's disease (CD) and particularly expanded in the CD8+ T cell population. Single-cell RNAseq data showed an innate-like phenotype of these cells, with a comparable gene expression to unconventional T cells such as mucosal associated invariant T and natural killer T (NKT) cells, but with distinct TCRs. CONCLUSIONS: We identified and characterised a subpopulation of unconventional Crohn-associated invariant T (CAIT) cells. Multiple evidence suggests these cells to be part of the NKT type II population. The potential implications of this population for CD or a subset thereof remain to be elucidated, and the immunophenotype and antigen reactivity of CAIT cells need further investigations in future studies.

• MeSH
• CD8-pozitivní T-lymfocyty MeSH
• Crohnova nemoc * genetika   MeSH
• lidé MeSH
• NKT buňky * MeSH
• receptory antigenů T-buněk alfa-beta genetika   MeSH
• receptory antigenů T-buněk metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: The inflammatory process in Crohn's disease (CD) is closely associated with the formation of reactive oxygen species. Antioxidant enzymes can play an important role in the outcome of CD and may influence postoperative recurrence in these patients. The aim of our study was to evaluate gene expression of intracellular antioxidant enzymes in surgically resected intestinal specimens of patients with CD, both in macroscopically normal and in inflamed tissue. METHODS: A total of 28 patients referred for elective bowel resection were enrolled in the study. Full-thickness small intestinal specimens were investigated. Gene expression of antioxidant enzymes - superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione reductase (GSR) - was evaluated both in macroscopically normal and inflamed samples. RESULTS: There were significantly lower levels of SOD1 mRNA (p = 0.007) and GSR mRNA (p = 0.027) in inflamed tissue compared to macroscopically normal areas. No significant differences were found between affected and non-affected intestinal segments in mRNA for SOD2, SOD3 and GPX. CONCLUSIONS: Our pilot data clearly showed that the gene expression of major antioxidant enzymes is not a uniform mechanism in the pathogenesis of Crohn's disease. Topically decreased gene expression of SOD1 and GSR might facilitate the segmental tissue injury caused by reactive oxygen species.

• MeSH
• antioxidancia * MeSH
• Crohnova nemoc * genetika   metabolismus   MeSH
• exprese genu * MeSH
• glutathionperoxidasa genetika   MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• reaktivní formy kyslíku MeSH
• střeva MeSH
• superoxid dismutáza 1 * genetika   metabolismus   MeSH
• superoxiddismutasa genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.

• MeSH
• adalimumab terapeutické užití   MeSH
• autoimunitní nemoci farmakoterapie   genetika   MeSH
• biologická terapie metody   MeSH
• biologické přípravky imunologie   terapeutické užití   MeSH
• celogenomová asociační studie metody   MeSH
• Crohnova nemoc farmakoterapie   genetika   MeSH
• dospělí MeSH
• HLA-DQ alfa řetězec genetika   MeSH
• humanizované monoklonální protilátky terapeutické užití   MeSH
• imunosupresiva terapeutické užití   MeSH
• infliximab terapeutické užití   MeSH
• interferon beta 1a terapeutické užití   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• revmatoidní artritida farmakoterapie   genetika   MeSH
• rituximab terapeutické užití   MeSH
• roztroušená skleróza farmakoterapie   genetika   MeSH
• ulcerózní kolitida farmakoterapie   genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Prevalence of inflammatory bowel disease (IBD), a chronic inflammatory disorder of the gut, has been on the rise in recent years-not only in the adult population but also especially in pediatric patients. Despite the absence of curative treatments, current therapeutic options are able to achieve long-term remission in a significant proportion of cases. To this end, however, there is a need for biomarkers enabling accurate diagnosis, prognosis, and prediction of response to therapies to facilitate a more individualized approach to pediatric IBD patients. In recent years, evidence has continued to evolve concerning noncoding RNAs (ncRNAs) and their roles as integral factors in key immune-related cellular pathways. Specific deregulation patterns of ncRNAs have been linked to pathogenesis of various diseases, including pediatric IBD. In this article, we provide an overview of current knowledge on ncRNAs, their altered expression profiles in pediatric IBD patients, and how these are emerging as potentially valuable clinical biomarkers as we enter an era of personalized medicine.

• MeSH
• biologické markery analýza   MeSH
• Crohnova nemoc genetika   MeSH
• dítě MeSH
• genetické markery genetika   MeSH
• idiopatické střevní záněty genetika   MeSH
• individualizovaná medicína trendy   MeSH
• lidé MeSH
• nekódující RNA analýza   MeSH
• signální transdukce genetika   MeSH
• transkriptom MeSH
• ulcerózní kolitida genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• úvodní články MeSH

X-linked inhibitor of apoptosis (XIAP) is the most potent human inhibitor of apoptosis, and is also involved in NOD2-dependent NFκB and MAPK signalling cascade activation. The absence or defective function of XIAP leads to the development of a rare and severe primary immunodeficiency known as X-linked lymphoproliferative syndrome type 2 (XLP-2), which is characterized by a triad of clinical manifestations, including a high incidence of haemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and inflammatory bowel disease (IBD), usually with very early onset. Here, we present a novel XIAP mutation identified in a patient with atypical adult-onset IBD complicated by relapsing HLH, splenomegaly and sarcoid-like disease. The c.266delA mutation in the XIAP gene creates a premature stop codon, and causes a severe reduction in XIAP protein expression. The mutation is also associated with impaired spontaneous and staurosporine- and PMA-induced apoptosis accompanied by significantly increased expression of pro-apoptotic genes. We also confirmed the negative impact of this particular XIAP mutation on NOD2-dependent NFκB and MAPK activation, while NOD2-independent activation was found to be unaffected. Moreover, we assume that the mutation has an impact on the overproduction of IL-12 and IFNγ, the shift towards the Th1 immune response and increased numbers of central memory and effector memory CD4+ and CD8+ T cells. All these changes contribute to immune dysregulation and the clinical manifestation of XLP-2.

• MeSH
• apoptóza MeSH
• Crohnova nemoc genetika   patologie   MeSH
• dospělí MeSH
• lidé MeSH
• mutace MeSH
• signální adaptorový protein Nod2 metabolismus   MeSH
• signální transdukce MeSH
• X-vázaný inhibitor apoptózy metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

PURPOSE: Crohn's disease (CD) belongs to chronic disorders with unpredictable disease course. The aim of this study was to identify how genetic testing (NOD2/CARD15) can be used in patients with CD to predict the need for surgical treatment (to define an aggressive type of disease where the patient can profit from early surgery). METHODS: The patients who were tested genetically had undergone a surgery due to CD at the Department of Surgery University Hospital Brno Bohunice between 2010 and 2016. The control group consisted of patients with CD who had been diagnosed with CD at least 5 years prior to the testing and had not required any surgical intervention. The second control group was healthy subjects. RESULTS: In total, there were 117 operated patients for CD, 77 patients with CD that had not undergone surgery for CD and 30 healthy subjects. For patients with at least one genetic mutation, the risk of the necessity of surgical treatment of CD is 1.96 times higher than for patients with no mutation. Patients with two or more mutations were generally operated on at a younger age, in a shorter time after being diagnosed and each patient had a partial resection of the ileum. CONCLUSION: The group of operated patients with CD had a significantly higher distribution of at least one genetic mutation as opposed to the non-operated group. In patients with two or more mutations, the disease course was more aggressive. This group of patients might profit from the conservative top-down or early surgical therapy.

• MeSH
• alely MeSH
• Crohnova nemoc genetika   chirurgie   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• genetické asociační studie MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace genetika   MeSH
• prognóza MeSH
• rizikové faktory MeSH
• signální adaptorový protein Nod2 genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• Crohnova nemoc * farmakoterapie   genetika   terapie   MeSH
• lidé MeSH
• serpiny MeSH
• Check Tag
• lidé MeSH

Osteoporosis in chronic diseases is very frequent and pathogenetically varied. It complicates the course of the underlying disease by the occurrence of fractures, which aggravate the quality of life and increase the mortality of patients from the underlying disease. The secondary deterioration of bone quality in chronic diseases, such as diabetes of type 1 and type 2 and/or other endocrine and metabolic disorders, as well as inflammatory diseases, including rheumatoid arthritis - are mostly associated with structural changes to collagen, altered bone turnover, increased cortical porosity and damage to the trabecular and cortical microarchitecture. Mechanisms of development of osteoporosis in some inborn or acquired disorders are discussed.

• MeSH
• celiakie komplikace   genetika   metabolismus   MeSH
• Crohnova nemoc komplikace   genetika   metabolismus   MeSH
• diabetes mellitus genetika   metabolismus   MeSH
• lidé MeSH
• metabolické nemoci komplikace   genetika   metabolismus   MeSH
• osteoporóza komplikace   genetika   metabolismus   MeSH
• remodelace kosti fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND AND OBJECTIVES: Crohn's disease is a multifactorial inflammatory disease affecting mainly the gastrointestinal tract. The genetic factors that are involved in the disease include mainly three mutations of the gene NOD2/CARD15 (R702W, G908R, 3020insC). The aim of this study was to determine the relationship between the presence of these variants and disease phenotype. MATERIAL AND METHODS: 70 patients with Crohn's disease were examined for the presence of the above-mentioned mutations. The researchers used the medical records to retrospectively obtain clinical data and together with the information obtained prospectively according to the protocol they analysed the connection between gene mutations and disease phenotype. RESULTS: At least one mutation was found in 22 patients with Crohn's disease (32%), four patients were found to have two different mutations (composed heterozygotes - 6%) and six patients (9%) were homozygotes for the 3020insC gene. No significant differences were found between the groups with wild-type form and the mutated form of the NOD2 / CARD15 gene with respect to age at the time of diagnosis, form of the disease or localization according to the Montreal classification. CONCLUSION: Mutations of the NOD2 / CARD15 gene did not significantly affect the frequency of reoperations, homozygotes with 3020insC gene mutations, however, represented a high risk group. The phenotype was not related significantly to the presence of the examined mutations.

• MeSH
• Crohnova nemoc genetika   chirurgie   MeSH
• dospělí MeSH
• fenotyp MeSH
• genetická predispozice k nemoci genetika   MeSH
• heterozygot MeSH
• homozygot MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mutace genetika   MeSH
• prospektivní studie MeSH
• reoperace MeSH
• senioři MeSH
• signální adaptorový protein Nod2 genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH