Search

Celiac Disease (CeD) is a complex immune disorder involving villous atrophy in the small intestine that is triggered by gluten intake. Current CeD diagnosis is based on late-stage pathophysiological parameters such as detection of specific antibodies in blood and histochemical detection of villus atrophy and lymphocyte infiltration in intestinal biopsies. To date, no early onset biomarkers are available that would help prevent widespread villous atrophy and severe symptoms and co-morbidities. To search for novel CeD biomarkers, we used single-cell RNA sequencing (scRNAseq) to investigate PBMC samples from 11 children before and after seroconversion for CeD and 10 control individuals matched for age, sex and HLA-genotype. We generated scRNAseq profiles of 9559 cells and identified the expected major cellular lineages. Cell proportions remained stable across the different timepoints and health conditions, but we observed differences in gene expression profiles in specific cell types when comparing patient samples before and after disease development and comparing patients with controls. Based on the time when transcripts were differentially expressed, we could classify the deregulated genes as biomarkers for active CeD or as potential pre-diagnostic markers. Pathway analysis showed that active CeD biomarkers display a transcriptional profile associated with antigen activation in CD4+ T cells, whereas NK cells express a subset of biomarker genes even before CeD diagnosis. Intersection of biomarker genes with CeD-associated genetic risk loci pinpointed genetic factors that might play a role in CeD onset. Investigation of potential cellular interaction pathways of PBMC cell subpopulations highlighted the importance of TNF pathways in CeD. Altogether, our results pinpoint genes and pathways that are altered prior to and during CeD onset, thereby identifying novel potential biomarkers for CeD diagnosis in blood.

Celiac disease is an auto-immune disease in which an immune response to dietary gluten leads to inflammation and subsequent atrophy of small intestinal villi, causing severe bowel discomfort and malabsorption of nutrients. The major instigating factor for the immune response in celiac disease is the activation of gluten-specific CD4+ T cells expressing T cell receptors that recognize gluten peptides presented in the context of HLA-DQ2 and DQ8. Here we provide an in-depth characterization of 28 gluten-specific T cell clones. We assess their transcriptional and epigenetic response to T cell receptor stimulation and link this to genetic factors associated with celiac disease. Gluten-specific T cells have a distinct transcriptional profile that mostly resembles that of Th1 cells but also express cytokines characteristic of other types of T-helper cells. This transcriptional response appears not to be regulated by changes in chromatin state, but rather by early upregulation of transcription factors and non-coding RNAs that likely orchestrate the subsequent activation of genes that play a role in immune pathways. Finally, integration of chromatin and transcription factor binding profiles suggest that genes activated by T cell receptor stimulation of gluten‑specific T cells may be impacted by genetic variation at several genetic loci associated with celiac disease.

Circulatory inflammatory proteins play a significant role in anti-Candidahost immune defence. However, little is known about the genetic variation that contributes to the variability of inflammatory responses in response toC. albicans. To systematically characterize inflammatory responses inCandidainfection, we profiled 91 circulatory inflammatory proteins in peripheral blood mononuclear cells (PBMCs) stimulated withC. albicansyeast isolated from 378 individuals of European origin from the 500 Functional Genomics (500FG) cohort of the Human Functional Genomics Project (HFGP) and Lifelines Deep cohort. To identify the genetic factors that determine variation in inflammatory protein responses, we correlated genome-wide single nucleotide polymorphism (SNP) genotypes with protein abundance (protein quantitative trait loci, pQTLs) produced by theCandida-stimulated PBMCs. Furthermore, we investigated whether differences in survival of candidaemia patients can be explained by modulating levels of inflammatory proteins. We identified five genome-wide significant pQTLs that modulate IL-8, MCP-2, MMP-1, and CCL3 in response toC. albicans. In addition, our genetic analysis suggested thatGADD45Gfrom rs10114707 locus that reached genome-wide significance could be a potential core gene that regulates a cytokine network uponCandidainfection. Last but not least, we observed that a trans-pQTL marked from SNP rs7651677 at chromosome 3 that influences urokinase plasminogen activator (uPA) is strongly associated with patient survival (Psurvival= 3.52 x 10-5, OR 3). Overall, our genetic analysis showed that genetic variation determines the abundance of circulatory proteins in response toCandidainfection.

Background & AimsCeliac disease (CeD), an immune-mediated disease with enteropathy triggered by gluten, affects ~1% of the general European population. Currently, there are no biomarkers to predict CeD development. MicroRNAs (miRNAs) are short RNAs involved in post-transcriptional gene regulation, and certain disease- and stage-specific miRNA profiles have been found previously. We aimed to investigate whether circulating miRNAs can predict the development of CeD.MethodsUsing next-generation miRNA-sequencing, we determined miRNAs in >200 serum samples from 53 participants of the PreventCD study, of whom 33 developed CeD during follow-up. Following study inclusion at 3 months of age, samples were drawn at predefined ages, diagnosis (first anti-transglutaminase antibody (TGA) positivity or diagnostic biopsy) and after the start of a gluten-free diet (GFD). This allowed identification of circulating miRNAs that are deregulated before TGA positivity. For validation of the biomarkers for CeD and GFD response, two additional cohorts were included in subsequent meta-analyses. Additionally, miRNAs were measured in duodenal biopsies in a case-control cohort.Results53 circulating miRNAs were increased (27) or decreased (26) in CeD versus controls. We assessed specific trends in these individual miRNAs in the PreventCD cohort by grouping the pre-diagnostic samples of the CeD patients (all had negative TGA) by how close to seroconversion (first sample positive TGA) the samples were taken. 8/53 miRNAs differed significantly between controls and samples taken ConclusionsWe identified 53 circulating miRNAs that are potential early biomarkers for CeD, of which several can be detected more than a year before TGA positivity and some start to normalize upon GFD.

The respective effects of tissue alarmins interleukin (IL)-15 and interferon beta (IFNβ), and IL-21 produced by T cells on the reprogramming of cytotoxic T lymphocytes (CTLs) that cause tissue destruction in celiac disease is poorly understood. Transcriptomic and epigenetic profiling of primary intestinal CTLs showed massive and distinct temporal transcriptional changes in response to tissue alarmins, while the impact of IL-21 was limited. Only anti-viral pathways were induced in response to all the three stimuli, albeit with differences in dynamics and strength. Moreover, changes in gene expression were primarily independent of changes in H3K27ac, suggesting that other regulatory mechanisms drive the robust transcriptional response. Finally, we found that IL-15/IFNβ/IL-21 transcriptional signatures could be linked to transcriptional alterations in risk loci for complex immune diseases. Together these results provide new insights into molecular mechanisms that fuel the activation of CTLs under conditions that emulate the inflammatory environment in patients with autoimmune diseases., Highlights • We report the epigenetic and transcriptomic response of IE-CTLs to tissue-derived alarmins and adaptive cytokine. • IL-15 and IFNβ induce massive and distinct transcriptional changes in IE-CTLs, while the impact of IL-21 was limited. • Genes associated with immune-mediated intestinal diseases are enriched in genes responding to IL-15, IFNβ and IL-21 in IE-CTLs.

Hepatocyte apoptosis in nonalcoholic steatohepatitis (NASH) can lead to fibrosis and cirrhosis, which permanently damage the liver. Understanding the regulation of hepatocyte apoptosis is therefore important to identify therapeutic targets that may prevent the progression of NASH to fibrosis. Recently, increasing evidence has shown that long noncoding (lnc) RNAs are involved in various biological processes and that their dysregulation underlies a number of complex human diseases. By performing gene expression profiling of 4,383 lncRNAs in 82 liver samples from individuals with NASH (n = 48), simple steatosis but no NASH (n = 11), and healthy controls (n = 23), we discovered a liver-specific lncRNA (RP11-484N16.1) on chromosome 18 that showed significantly elevated expression in the liver tissue of NASH patients. This lncRNA, which we named lnc18q22.2 based on its chromosomal location, correlated with NASH grade (r = 0.51, P = 8.11 × 10-7 ), lobular inflammation (r = 0.49, P = 2.35 × 10-6 ), and nonalcoholic fatty liver disease activity score (r = 0.48, P = 4.69 × 10-6 ). The association of lnc18q22.2 to liver steatosis and steatohepatitis was replicated in 44 independent liver biopsies (r = 0.47, P = 0.0013). We provided a genetic structure of lnc18q22.2 showing an extended exon 2 in liver. Knockdown of lnc18q22.2 in four different hepatocyte cell lines resulted in severe phenotypes ranging from reduced cell growth to lethality. This observation was consistent with pathway analyses of genes coexpressed with lnc18q22.2 in human liver or affected by lnc18q22.2 knockdown. Conclusion We identified an lncRNA that can play an important regulatory role in liver function and provide new insights into the regulation of hepatocyte viability in NASH. (Hepatology 2017;66:794-808).

BackgroundCandidemia, one of the most common causes of fungal bloodstream infection, leads to mortality rates up to 40% in affected patients. Understanding genetic mechanisms for differential susceptibility to candidemia may aid in designing host-directed therapies.MethodsWe performed the first genome-wide association study on candidemia, and we integrated these data with variants that affect cytokines in different cellular systems stimulated with Candida albicans.ResultsWe observed strong association between candidemia and a variant, rs8028958, that significantly affects the expression levels of PLA2G4B in blood. We found that up to 35% of the susceptibility loci affect in vitro cytokine production in response to Candida. Furthermore, potential causal genes located within these loci are enriched for lipid and arachidonic acid metabolism. Using an independent cohort, we also showed that the numbers of risk alleles at these loci are negatively correlated with reactive oxygen species and interleukin-6 levels in response to Candida. Finally, there was a significant correlation between susceptibility and allelic scores based on 16 independent candidemia-associated single-nucleotide polymorphisms that affect monocyte-derived cytokines, but not with T cell-derived cytokines.ConclusionsOur results prioritize the disturbed lipid homeostasis and oxidative stress as potential mechanisms that affect monocyte-derived cytokines to influence susceptibility to candidemia.

In sepsis, dysregulated immune responses to infections cause damage to the host. Previous studies have attempted to capture pathogen-induced leukocyte responses. However, the impact of mediators released after pathogen-leukocyte interaction on endothelial cells, and how endothelial cell responses vary depending on the pathogen-type is lacking. Here, we comprehensively characterized the transcriptomic responses of human leukocytes and endothelial cells to Gram negative-bacteria, Gram positive-bacteria, and fungi. We showed that whole pathogen lysates induced strong activation of leukocytes but not endothelial cells. Interestingly, the common response of leukocytes to various pathogens converges on endothelial activation. By exposing endothelial cells to leukocyte-released mediators, we observed a strong activation of endothelial cells at both transcription and protein levels. By adding IL-1RA and TNF-alpha antibody in leukocyte-released mediators before exposing to endothelial cells, we identified specific roles for IL-1 and TNF-alpha in driving the most, but not all, endothelial activation. We also showed for the first time, activation of interferon response by endothelial cells in response to leukocyte-released mediators, independently from IL-1 and TNF-alpha pathways. Our study therefore, not only provides pathogen-dependent transcriptional changes in leukocytes and endothelial cells during infections, but also reveals a role for IFN, together with IL1 and TNF alpha signaling, in mediating leukocyte-endothelial interaction in infections.

Contains fulltext : 165674.pdf (Publisher’s version ) (Closed access) As part of the Human Functional Genomics Project, which aims to understand the factors that determine the variability of immune responses, we investigated genetic variants affecting cytokine production in response to ex vivo stimulation in two independent cohorts of 500 and 200 healthy individuals. We demonstrate a strong impact of genetic heritability on cytokine production capacity after challenge with bacterial, fungal, viral, and non-microbial stimuli. In addition to 17 novel genome-wide significant cytokine QTLs (cQTLs), our study provides a comprehensive picture of the genetic variants that influence six different cytokines in whole blood, blood mononuclear cells, and macrophages. Important biological pathways that contain cytokine QTLs map to pattern recognition receptors (TLR1-6-10 cluster), cytokine and complement inhibitors, and the kallikrein system. The cytokine QTLs show enrichment for monocyte-specific enhancers, are more often located in regions under positive selection, and are significantly enriched among SNPs associated with infections and immune-mediated diseases. PAPERCLIP.

Contains fulltext : 171367.pdf (Publisher’s version ) (Open Access) Genome-wide association and fine-mapping studies in 14 autoimmune diseases (AID) have implicated more than 250 loci in one or more of these diseases. As more than 90% of AID-associated SNPs are intergenic or intronic, pinpointing the causal genes is challenging. We performed a systematic analysis to link 460 SNPs that are associated with 14 AID to causal genes using transcriptomic data from 629 blood samples. We were able to link 71 (39%) of the AID-SNPs to two or more nearby genes, providing evidence that for part of the AID loci multiple causal genes exist. While 54 of the AID loci are shared by one or more AID, 17% of them do not share candidate causal genes. In addition to finding novel genes such as ULK3, we also implicate novel disease mechanisms and pathways like autophagy in celiac disease pathogenesis. Furthermore, 42 of the AID SNPs specifically affected the expression of 53 non-coding RNA genes. To further understand how the non-coding genome contributes to AID, the SNPs were linked to functional regulatory elements, which suggest a model where AID genes are regulated by network of chromatin looping/non-coding RNAs interactions. The looping model also explains how a causal candidate gene is not necessarily the gene closest to the AID SNP, which was the case in nearly 50% of cases.

Contains fulltext : 193382.pdf (Publisher’s version ) (Closed access) The immune response to pathogens varies substantially among people. Whereas both genetic and nongenetic factors contribute to interperson variation, their relative contributions and potential predictive power have remained largely unknown. By systematically correlating host factors in 534 healthy volunteers, including baseline immunological parameters and molecular profiles (genome, metabolome and gut microbiome), with cytokine production after stimulation with 20 pathogens, we identified distinct patterns of co-regulation. Among the 91 different cytokine-stimulus pairs, 11 categories of host factors together explained up to 67% of interindividual variation in cytokine production induced by stimulation. A computational model based on genetic data predicted the genetic component of stimulus-induced cytokine production (correlation 0.28-0.89), and nongenetic factors influenced cytokine production as well.

Contains fulltext : 177448.pdf (Publisher’s version ) (Open Access) Candidaemia is a bloodstream infection caused by Candida species that primarily affects specific groups of at-risk patients. Because only small candidaemia patient cohorts are available, classical genome wide association cannot be used to identify Candida susceptibility genes. Therefore, we have applied an integrative genomics approach to identify novel susceptibility genes and pathways for candidaemia. Candida-induced transcriptome changes in human primary leukocytes were assessed by RNA sequencing. Genetic susceptibility to candidaemia was assessed using the Illumina immunochip platform for genotyping of a cohort of 217 patients. We then integrated genetics data with gene-expression profiles, Candida-induced cytokine production capacity, and circulating concentrations of cytokines. Based on the intersection of transcriptome pathways and genomic data, we prioritized 31 candidate genes for candidaemia susceptibility. This group of genes was enriched with genes involved in inflammation, innate immunity, complement, and hemostasis. We then validated the role of MAP3K8 in cytokine regulation in response to Candida stimulation. Here, we present a new framework for the identification of susceptibility genes for infectious diseases that uses an unbiased, hypothesis-free, systems genetics approach. By applying this approach to candidaemia, we identified novel susceptibility genes and pathways for candidaemia, and future studies should assess their potential as therapeutic targets.

Many endocrine diseases, including type 1 diabetes mellitus, Graves disease, Addison disease and Hashimoto disease, originate as an autoimmune reaction that affects disease-specific target organs. These autoimmune diseases are characterized by the development of specific autoantibodies and by the presence of autoreactive T cells. They are caused by a complex genetic predisposition that is attributable to multiple genetic variants, each with a moderate-to-low effect size. Most of the genetic variants associated with a particular autoimmune endocrine disease are shared between other systemic and organ-specific autoimmune and inflammatory diseases, such as rheumatoid arthritis, coeliac disease, systemic lupus erythematosus and psoriasis. Here, we review the shared and specific genetic background of autoimmune diseases, summarize their treatment options and discuss how identifying the genetic and environmental factors that predispose patients to an autoimmune disease can help in the diagnosis and monitoring of patients, as well as the design of new treatments.

Cellular differentiation is regulated on the level of gene expression and it is known that dysregulation of gene expression can lead to deficiencies in differentiation that contribute to a variety of diseases, particularly of the immune system. Until recently, it was thought that the dysregulation was governed by changes in the binding or activity of a class of proteins called transcription factors. However, the discovery of micro-RNAs and recent descriptions of long noncoding RNAs have given enormous momentum to a whole new field of biology: the regulatory RNAs. In this review, we describe these two classes of regulatory RNAs and summarize what is known about how they regulate aspects of the adaptive and innate immune systems. Finally, we describe what is known about the involvement of micro-RNAs and long noncoding RNAs in three different autoimmune diseases (celiac disease, inflammatory bowel disease, and multiple sclerosis).

Celiac disease (CD) is an immune mediated, polygenic disorder, where HLA-DQ2/DQ8 alleles contribute around 35% to genetic risk, but several other genes are also involved. Genome-wide association studies (GWASs) and the more recent immunochip genotyping projects have fine-mapped 39 regions of genetic susceptibility to the disease, most of which harbor candidate genes that could participate in this disease process. We focused our attention to the GWAS peak on chr6: 127.99–128.38 Mb, a region including two genes, thymocyte-expressed molecule involved in selection (THEMIS) and protein tyrosine phosphatase, receptor type, kappa (PTPRK), both of which have immune-related functions. The aim of this work was to evaluate the expression levels of these two genes in duodenal mucosa of active and treated CD patients and in controls, and to determine whether SNPs (rs802734, rs55743914, rs72975916, rs10484718 and rs9491896) associated with CD have any influence on gene expression. THEMIS showed higher expression in active CD compared with treated patients and controls, whereas PTPRK showed lower expression. Our study confirmed the association of this region with CD in our population, but only the genotype of rs802734 showed some influence in the expression of THEMIS. On the other hand, we found a significant positive correlation between THEMIS and PTPRK mRNA levels in CD patients but not in controls. Our results suggest a possible role for both candidate genes in CD pathogenesis and the existence of complex, regulatory relationships that reside in the vast non-coding, functional intergenic regions of the genome. Further investigation is needed to clarify the impact of the disease-associated SNPs on gene function., Facultad de Ciencias Exactas, Laboratorio de Investigaciones del Sistema Inmune

Several studies suggest that tumor necrosis factor-alpha (TNF) is able to overcome drug resistance in tumors. Whether TNF is able to do so in tumor cell lines that are drug resistant due to a mutation in the tumor suppressor gene p53 is unclear. Therefore, we studied the in vitro cytotoxic effects of TNF combined with various cytotoxic agents in a model consisting of a human ovarian cancer cell line containing endogenous wild-type p53 (wtp53) and sublines that were made drug resistant against various cytotoxic agents by transfection of several forms of mutated p53 (mtp53). Using the microculture tetrazolium assay, the cytotoxic effects of TNF alone, the cytotoxic agents VM-26, melphalan, cisplatin, vinblastine, paclitaxel, and mitoxantrone, plus the combined effects of 10 ng/ml TNF added 30 min before various concentrations of the cytotoxic agents were established. Compared with the control cell line (A2780/cmv), two cell lines transfected with mtp53 (A2780/m248 and A2780/m273) showed increased resistance against several cytotoxic agents but also an enhanced sensitivity to TNF. Interaction of TNF with the cytotoxic drugs was additive in the drug-sensitive control cell line as well as in the drug-resistant sublines. However, because of the increased sensitivity of A2780/m248 to TNF at the dose used for the combinations, the combination of TNF with several cytotoxic drugs reduced the level of resistance in A2780/m248 compared with the control cell line A2780/cmv. In conclusion, this study shows that addition of TNF can ameliorate resistance to cytotoxic agents in a subline that is drug-resistant because of mutated p53. This reduction in resistance by TNF is not due to synergistic interaction, but to collateral sensitivity to TNF.

Micro-RNAs (miRNAs) have been recognized as critical regulators of gene expression, and deregulation of miRNA expression has been implicated in a wide spectrum of diseases. To provide a framework for the role of miRNAs in B-cell development and malignancy, we deep-sequenced miRNAs from B1 cells and 10 developmental stages that can be identified within the mouse B2 B-cell lineage. The expression profiles of the 232 known miRNAs that are expressed during B-cell development display stage-specific induction patterns, yet hierarchical clustering analysis showed relationships that are in full agreement with the model of the B2 B-cell developmental pathway. Analysis of exemplary miRNA expression profiles (miR-150, miR-146a, miR-155, miR-181) confirmed that our data are in agreement with previous results. The high resolution of the expression data allowed for the identification of the sequential expression of oncomir-1/miR-17-92 and its paralogs miR-106a-363 and miR-106b-25 in subsequent developmental stages in the BM. Further, we have identified and validated 45 novel miRNAs and 6 novel miRNA candidates expressed in developing B cells.

Ab binding to CD20 has been shown to induce apoptosis in B cells. In this study, we demonstrate that rituximab sensitizes lymphoma B cells to Fas-induced apoptosis in a caspase-8-dependent manner. To elucidate the mechanism by which Rituximab affects Fas-mediated cell death, we investigated rituximab-induced signaling and apoptosis pathways. Rituximab-induced apoptosis involved the death receptor pathway and proceeded in a caspase-8-dependent manner. Ectopic overexpression of FLIP (the physiological inhibitor of the death receptor pathway) or application of zIETD-fmk (specific inhibitor of caspase-8, the initiator-caspase of the death receptor pathway) both specifically reduced rituximab-induced apoptosis in Ramos B cells. Blocking the death receptor ligands Fas ligand or TRAIL, using neutralizing Abs, did not inhibit apoptosis, implying that a direct death receptor/ligand interaction is not involved in CD20-mediated cell death. Instead, we hypothesized that rituximab-induced apoptosis involves membrane clustering of Fas molecules that leads to formation of the death-inducing signaling complex (DISC) and downstream activation of the death receptor pathway. Indeed, Fas coimmune precipitation experiments showed that, upon CD20-cross-linking, Fas-associated death domain protein (FADD) and caspase-8 were recruited into the DISC. Additionally, rituximab induced CD20 and Fas translocation to raft-like domains on the cell surface. Further analysis revealed that, upon stimulation with rituximab, Fas, caspase-8, and FADD were found in sucrose-gradient raft fractions together with CD20. In conclusion, in this study, we present evidence for the involvement of the death receptor pathway in rituximab-induced apoptosis of Ramos B cells with concomitant sensitization of these cells to Fas-mediated apoptosis via Fas multimerization and recruitment of caspase-8 and FADD to the DISC.

This review will focus on the role of nuclear factor kappaB (NF-kappaB) signaling in hematopoietic differentiation. We will also discuss several hematopoietic pathologies associated with deregulation of NF-kappaB and their potential therapies.

It has long been suspected that NF-kappaB signaling has a pivotal role in chronic inflammation-associated malignancies, although genetic evidence for this hypothesis has been lacking. However, recent papers have lent credence to this concept and show that NF-kappaB activation in pre-malignant cells contributes to cell survival and metastatic potential. Furthermore, NF-kappaB activation in tumor-associated leukocytes, especially macrophages, contributes towards tumorigenesis by upregulating tumor-promoting proinflammatory proteins. This emphasizes the importance of NF-kappaB inhibitors as immunotherapeutic agents for chronic inflammation and suggests that these reagents might prevent, or at least inhibit, chronic inflammation-associated tumorigenesis.

Previous studies have shown that the in vitro-selected adriamycin-resistant human small-cell lung-carcinoma cell line GLC4-ADR150 displays multidrug resistance as the result of 3-fold decreased DNA-topoisomerase II (topo II) activity and a 6-fold reduction in adriamycin accumulation. Not the MDR1 gene, but the MRP gene, was over-expressed in this cell line. The aim of our study was to establish which of these drug-resistance-associated factors are already involved in drug resistance occurring at early steps of selection with adriamycin. To address this question, changes in expression of topo II alpha/topo II beta, MRP and drug accumulation were measured along with adriamycin resistance (from 2- to 10- to 150-fold) and in a partial revertant cell line (10-fold resistant). Topo II alpha and II beta mRNA and protein levels were decreased in the resistant sub-lines, except in the 10-fold-resistant cell line. Cellular daunorubicin accumulation was decreased 1.2- to 5-fold with increasing resistance. MRP mRNA was over-expressed in all resistant sub-lines, with a marked increase in the 10-fold-resistant cells (level of expression as high as in the GLC4-ADR150 cells). Expression of an ATP-binding 190-kDa membrane protein and Western-blot analysis with anti-MRP anti-serum ASPKE, was in accordance with the expression of MRP mRNA in all cell lines. Expression of MRP mRNA and protein, however, was not proportional with the decrease in drug accumulation in all resistant sub-lines. This study also shows that drug accumulation, topo II and MRP expression were all changed at the earliest stage of resistance development of GLC4 cells upon adriamycin selection.

Celiac disease is characterized by a chronic inflammatory reaction in the intestine and is triggered by gluten, a constituent derived from grains which is present in the common daily diet in the Western world. Despite decades of research, the mechanisms behind celiac disease etiology are still not fully understood, although it is clear that both genetic and environmental factors are involved. To improve the understanding of the disease, the genetic component has been extensively studied by genome-wide association studies. These have uncovered a wealth of information that still needs further investigation to clarify its importance. In this review, we summarize and discuss the results of the genetic studies in celiac disease, focusing on the "non-HLA" genes. We also present novel approaches to identifying the causal variants in complex susceptibility loci and disease mechanisms.

Background Although genome-wide association studies (GWAS) have identified hundreds of variants associated with a risk for autoimmune and immune-related disorders (AID), our understanding of the disease mechanisms is still limited. In particular, more than 90% of the risk variants lie in non-coding regions, and almost 10% of these map to long non-coding RNA transcripts (lncRNAs). lncRNAs are known to show more cell-type specificity than protein-coding genes. Methods We aimed to characterize lncRNAs and protein-coding genes located in loci associated with nine AIDs which have been well-defined by Immunochip analysis and by transcriptome analysis across seven populations of peripheral blood leukocytes (granulocytes, monocytes, natural killer (NK) cells, B cells, memory T cells, naive CD4+ and naive CD8+ T cells) and four populations of cord blood-derived T-helper cells (precursor, primary, and polarized (Th1, Th2) T-helper cells). Results We show that lncRNAs mapping to loci shared between AID are significantly enriched in immune cell types compared to lncRNAs from the whole genome (α