Celiac disease (CeD) manifests with autoimmune intestinal inflammation from gluten and genetic predisposition linked to human leukocyte antigen class-II (HLA-II) gene variants. Antigen-presenting cells facilitate gluten exposition through the interaction of their surface major histocompatibility complex (MHC) with the T cell receptor (TCR) on T lymphocytes. This fundamental mechanism of adaptive immunity has broadened upon recognition of extracellular exosomal MHC, raising awareness of an alternative means for antigen presentation. This study demonstrates that conditioned growth media (CGM) previously exposed to monocyte-derived dendritic cells from CeD significantly downregulates the CD3+ lineage marker of control T cells. Such increased activation was reflected in their elevated IL-2 secretion. Exosome localization motif identification and quantification within HLA-DQA1 and HLA-DQB1 transcripts highlighted their significant prevalence within HLA-DQB1 alleles associated with CeD susceptibility. Flow cytometry revealed the strong correlation between HLA-DQ and the CD63 exosomal marker in T cells exposed to CGM from MoDCs sourced from CeD patients. This resulted in lower concentrations of CD25+ CD127- T cells, suggestive of their compromised induction to T-regulatory cells associated with CeD homeostasis. This foremost comparative study deciphered the genomic basis and extracellular exosomal effects of HLA transfer on T lymphocytes in the context of CeD, offering greater insight into this auto-immune disease.
- MeSH
- alely MeSH
- celiakie * MeSH
- gluteny genetika MeSH
- HLA-DQ antigeny genetika MeSH
- lidé MeSH
- regulační T-lymfocyty MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The autoimmune condition, Celiac Disease (CeD), displays broad clinical symptoms due to gluten exposure. Its genetic association with DQ variants in the human leukocyte antigen (HLA) system has been recognised. Monocyte-derived mature dendritic cells (MoDCs) present gluten peptides through HLA-DQ and co-stimulatory molecules to T lymphocytes, eliciting a cytokine-rich microenvironment. Having access to CeD associated families prevalent in the Czech Republic, this study utilised an in vitro model to investigate their differential monocyte profile. The higher monocyte yields isolated from PBMCs of CeD patients versus control individuals also reflected the greater proportion of dendritic cells derived from these sources following lipopolysaccharide (LPS)/ peptic-tryptic-gliadin (PTG) fragment stimulation. Cell surface markers of CeD monocytes and MoDCs were subsequently profiled. This foremost study identified a novel bio-profile characterised by elevated CD64 and reduced CD33 levels, unique to CD14++ monocytes of CeD patients. Normalisation to LPS stimulation revealed the increased sensitivity of CeD-MoDCs to PTG, as shown by CD86 and HLA-DQ flow cytometric readouts. Enhanced CD86 and HLA-DQ expression in CeD-MoDCs were revealed by confocal microscopy. Analysis highlighted their dominance at the CeD-MoDC membrane in comparison to controls, reflective of superior antigen presentation ability. In conclusion, this investigative study deciphered the monocytes and MoDCs of CeD patients with the identification of a novel bio-profile marker of potential diagnostic value for clinical interpretation. Herein, the characterisation of CD86 and HLA-DQ as activators to stimulants, along with robust membrane assembly reflective of efficient antigen presentation, offers CeD targeted therapeutic avenues worth further exploration.
- MeSH
- autoimunitní nemoci imunologie MeSH
- biologické markery metabolismus MeSH
- buněčná membrána metabolismus MeSH
- CD antigeny metabolismus MeSH
- celiakie epidemiologie imunologie MeSH
- cytotoxické T-lymfocyty imunologie MeSH
- dendritické buňky imunologie MeSH
- dospělí MeSH
- gliadin škodlivé účinky MeSH
- HLA-DQ antigeny metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipopolysacharidy MeSH
- mladiství MeSH
- mladý dospělý MeSH
- monocyty metabolismus MeSH
- náchylnost k nemoci MeSH
- prezentace antigenu imunologie MeSH
- rodina MeSH
- rodokmen MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10-3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
- MeSH
- alely MeSH
- bipolární porucha farmakoterapie genetika MeSH
- dospělí MeSH
- farmakogenetika MeSH
- frekvence genu MeSH
- genetická predispozice k nemoci * MeSH
- genetická variace MeSH
- genotyp MeSH
- haplotypy MeSH
- HLA-DQ beta řetězec genetika MeSH
- HLA-DRB1 řetězec genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- lithium terapeutické užití MeSH
- výsledek terapie 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
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
Celiakie je celoživotní autoimunitní onemocnění, které vzniká u geneticky predisponovaných jedinců vlivem konzumace glutenu. Glutenem navozená autoimunitní enteropatie narušuje komplexní fyziologické, bariérové a imunitní funkce tenkého střeva, čímž způsobuje neobyčejně pestré klinické projevy. Kromě příznaků střevních a malabsorpčních má velmi variabilní příznaky mimostřevní, a proto je chápána jako systémová autoimunitní choroba. Článek podává přehled o současném stavu znalostí o etiopatogenezi celiakie, včetně patogeneze jejích intestinálních a extraintestinálních projevů.
Celiac disease is a lifelong autoimmune disease occuring in genetically predisposed individuals upon ingestion of gluten. Gluten-induced autoimmune enteropathy disrupts complex physiological, barrier and immune functions of small intestine leading to extraordinary broad clinical symptomatology. Besides intestinal complaints, celiac patients have a large variety of extraintestinal symptoms. Therefore, celiac disease is considered as a systemic autoimmune disorder. The article provides an overview on etiopathogenesis of celiac disease, including pathogenesis of the intestinal and extraintestinal symptomatology.
- MeSH
- alergie etiologie patofyziologie MeSH
- autoimunita MeSH
- celiakie * etiologie genetika patofyziologie MeSH
- gluteny analýza fyziologie metabolismus MeSH
- HLA-DQ antigeny MeSH
- lidé MeSH
- rizikové faktory MeSH
- střevní sliznice patofyziologie MeSH
- tenké střevo patofyziologie MeSH
- transglutaminasy fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Pro vysokou prevalenci je celiakie jedním z nejdůležitějších onemocnění trávicího ústrojí. Pacientů je přibližně 1 % v populaci, a proto je vyhledávání tohoto onemocnění nezbytné. Prvním krokem v diagnostice celiakie je vyšetření protilátek proti tkáňové transglutamináze ve třídě A imunoglobulinů (anti‑TG‑IgA) a vyloučení deficitu IgA stanovením jeho celkové hodnoty. Tato kombinace dvou vyšetření je nejpřesnějším a nejrentabilnějším úvodním vyšetřením. Během prvního vyšetření není potřeba stanovovat protilátky proti endomysiu ve třídě IgA (EMA‑IgA) a protilátky proti deamidovanému gliadinu ve třídě G imunoglobulinů (anti‑DGP- IgG). Pokud má dítě dvakrát, tj. i ve druhém vzorku krve 10× vyšší hodnoty anti‑TG‑IgA a současně je také pozitivní EMA -IgA, je možno stanovit diagnózu celiakie bez následné biopsie. Děti, u kterých byla nalezena hodnota anti‑TG‑IgA nižší než 10násobek normální hodnoty, mají podstoupit střevní biopsii ke snížení rizika falešně pozitivní diagnózy. HLA vyšetření a přítomnost symptomů nejsou potřeba ke stanovení diagnózy celiakie bez biopsie.
For high prevalence celiac disease (CD) is one of the most important diseases of the digestive tract. Patients are approximately 1% in the population and therefore a search for this disease is necessary. The first step in the diagnosis of CD is to test antibodies to tissue transglutaminase in class A immunoglobulins (anti-TG-IgA) and to eliminate IgA deficiency by determining its total value. This combination of total IgA and anti-TG- IgA is the most accurate and cost-effective initial testing. At this time, there is no need to test antibodies to endomysium in class IgA (EMA-IgA) and antibodies to deamided gliadin in class G immunoglobulins (anti-DGP-IgG). If the child was twice found high values of the anti-TG-IgA >10 times the upper normal limit (ULN), i.e. even in the second blood sample and at the same time was also positive EMA-IgA, it is possible to make the diagnosis of CD without biopsy. Children who have been found to have an anti-TG-IgA value <10 times ULN should undergo an intestinal biopsy to reduce the risk of false positive diagnosis. HLA testing and presence of symptoms are not needed for a sérology based diagnosis without biopsy.
- MeSH
- autoprotilátky krev MeSH
- biopsie normy MeSH
- celiakie * diagnóza genetika imunologie MeSH
- deficience IgA MeSH
- dítě MeSH
- duodenum patologie MeSH
- gliadin imunologie MeSH
- gluteny škodlivé účinky MeSH
- HLA-DQ antigeny genetika MeSH
- lidé MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- transglutaminasy imunologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
Next-generation sequencing (NGS) is increasingly used in transplantation settings, but also as a method of choice for in-depth analysis of population-specific HLA genetic architecture and its linkage to various diseases. With respect to complex ethnic admixture characteristic for East Croatian population, we aimed to investigate class-I (HLA-A, -B, -C) and class-II (HLA-DRB1, -DQA1, -DQB1) HLA diversity at the highest, 4-field resolution level in 120 healthy, unrelated, blood donor volunteers. Genomic DNA was extracted and HLA genotypes of class I and DQA1 genes were defined in full-length, -DQB1 from intron 1 to 3' UTR, and -DRB1 from intron 1 to intron 4 (Illumina MiSeq platform, Omixon Twin algorithms, IMGT/HLA release 3.30.0_5). Linkage disequilibrium statistics, Hardy-Weinberg departures, and haplotype frequencies were inferred by exact tests and iterative Expectation-Maximization algorithm using PyPop 0.7.0 and Arlequin v3.5.2.2 software. Our data provide first description of 4-field allele and haplotype frequencies in Croatian population, revealing 192 class-I and class-II alleles and extended haplotypic combinations not apparent from the existing 2-field HLA reports from Croatia. This established reference database complements current knowledge of HLA diversity and should prove useful in future population studies, transplantation settings, and disease-associated HLA screening.
- MeSH
- běloši genetika MeSH
- dárci krve MeSH
- dospělí MeSH
- frekvence genu MeSH
- haplotypy MeSH
- HLA-A antigeny genetika MeSH
- HLA-B antigeny genetika MeSH
- HLA-C antigeny genetika MeSH
- HLA-DQ alfa řetězec genetika MeSH
- HLA-DQ beta řetězec genetika MeSH
- HLA-DRB1 řetězec genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- sekvenční analýza DNA MeSH
- vazebná nerovnováha MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- zdraví dobrovolníci pro lékařské studie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Chorvatsko MeSH
Celiac disease (CD) is an autoimmune disorder that is expressed by chronic food sensitivity to gluten. Among the autoimmune diseases, CD is the one that has more expression, having the numbers of new cases increased steadily during the last years. In addition to the most common symptoms, such as low weight, diarrhea and abdominal pain, atypical cases, such as overweight, arise which imply the development of new approaches and diagnostic methodologies. The most obvious diagnosis involves endoscopy, an invasive and costly method that causes discomfort to the patient and overload of the health systems. The protocol methodology for CD diagnosis from WGO, NASPGHAN, ESPGHAN and BSPGHAN, the worldwide most recognized specialist ‘organizations, was analyzed in order to assess if social implications were considered on their guidelines. After a detailed review of the literature, a global chart was completed in order to summarize the most referenced protocols for the screening and CD diagnosis.
- MeSH
- autoprotilátky krev MeSH
- celiakie * diagnóza krev MeSH
- HLA-DQ antigeny MeSH
- lidé MeSH
- plošný screening MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- směrnice pro lékařskou praxi MeSH
Differential expression of HLA-DQA1 and HLA-DQB1 gene alleles was analysed in three different cell populations isolated from peripheral blood-B lymphocytes, monocytes and whole-blood cells. Interallelic differences in mRNA levels were observed: DQA1*03 alleles were among the most expressed in all cell types, whereas DQA1*05 alleles were least expressed in whole blood and monocytes and among the most expressed in B cells. For DQB1 gene, DQB1*06 group of alleles were the most expressed, and DQB1*02 group the least expressed within all cell populations examined. In comparison with the rest alleles, DQB1*06 and DQB1*05:02 alleles have higher expression in monocytes than in B cells, professional antigen-presenting cells. Cell type-specific regulation of expression was observed as well, with higher and more balanced expression of alleles in B lymphocytes compared to monocytes.
- MeSH
- alely MeSH
- B-lymfocyty imunologie metabolismus MeSH
- dospělí MeSH
- exprese genu * MeSH
- frekvence genu MeSH
- haplotypy MeSH
- HLA-DQ alfa řetězec genetika MeSH
- HLA-DQ beta řetězec genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- messenger RNA genetika MeSH
- mladý dospělý MeSH
- monocyty imunologie metabolismus MeSH
- orgánová specificita MeSH
- senioři MeSH
- zdraví dobrovolníci pro lékařské studie 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
Celiac disease (CD), an autoimmune disorder triggered by gluten ingestion, negatively affects individuals' health if left untreated. In individuals with the requisite genes, CD destroys the intestinal lining because specific peptide fragments of gluten (protein found in wheat and related grains) bind to the receptor proteins coded for by HLA-DQ2 and DQ8 genes, thereby causing an autoimmune response that damages intestinal cells and results in malnutrition. Because the disease has a genetic basis and can lead to impaired reproductive functioning and death, natural selection should lead to a decrease in CD prevalence over time. However, evidence suggesting CD increases in some populations contradicts this hypothesis, resulting in the ‘Celiac Disease Evolutionary Paradox.' The worldwide average prevalence rate is around 1%, although rates of up to 5% have been observed in certain populations. Maintenance or increase in the frequency of CD-predisposing genes in certain populations suggests potential evolutionary benefits for those genes, which may exhibit antagonistic pleiotropy, such as being beneficial for infectious disease but detrimental for chronic disease such as CD. Recent dietary and environmental changes (including dietary gluten exposure, breastfeeding duration and the intestinal microbiome, and immune function) may have led to discordance with the Environment of Evolutionary Adaptedness, thus contributing to increases in CD. Consideration of potential benefits of CD-risk gene alleles, in conjunction with a deeper understanding of environmental factors exerting positive and negative selection on those alleles, may help to explain population variation in CD prevalence rates, and shed light on the complex gene-environment interactions influencing this devastating disease.
