Review article: Faecal biomarkers for assessing small intestinal damage in coeliac disease and environmental enteropathy.

BACKGROUND: In coeliac disease and environmental enteropathy, dietary gluten and enteric infections cause reversible inflammation and morphological changes to the small intestinal mucosa that can be detected in biopsy samples obtained by endoscopy. However, there is a clear need for non-invasive biomarkers. Constant shedding of mucosal material into the bowel lumen and faeces, together with easy availability of stool, makes it an interesting sample matrix. AIMS: To conduct a systematic literature search and summarize the existing evidence for host mucosa-derived faecal biomarkers in evaluating small intestinal damage. METHODS: We searched for studies on PubMed (MEDLINE) until 1 March 2024. RESULTS: We identified 494 studies and included 35 original case-control and cohort studies. These assessed host mucosal transcripts and 14 other markers aiming specifically to reflect inflammation and cell-mediated, innate and gluten-induced immune responses. In coeliac disease, faecal calprotectin and anti-gliadin, tissue transglutaminase, endomysium and deamidated gliadin peptide antibodies were the most studied but with inconsistent results. Single studies reported positive findings about microRNA transcripts, ß-defensin-2, lipocalin-2, zonulin-related proteins and angiotensin-converting enzyme. In environmental enteropathy, a non-significant association was reported between calprotectin and urine lactulose/mannitol ratio; there were conflicting results for neopterin, myeloperoxidase and host transcripts. Single studies reported a positive association for lactoferrin, and a negative association for regenerating islet-derived protein 1. Studies comparing faecal markers against small intestinal biopsy findings were not identified in environmental enteropathy. CONCLUSIONS: Further studies are needed to determine reliable faecal markers as a proxy for small intestinal mucosal damage.

Indirect Markers of Intestinal Damage in IgA Nephropathy.

INTRODUCTION: Presence of subclinical intestinal inflammation has repeatedly been shown in IgA nephropathy (IgAN) and the degree of histological inflammation has correlated with abnormal urinary findings. There is lack of noninvasive biomarkers evaluating the presence of subclinical intestinal damage in IgAN. We conducted this study hypothesizing that selected biomarkers regarded as indirect markers of intestinal damage could be elevated in IgAN. METHODS: Eighty-five primary IgAN patients (median age 55 years, 54% men) participated in this single-center study in Tampere, Finland. None had end-stage kidney disease or previously diagnosed enteropathies. Celiac disease was excluded with serum transglutaminase 2 antibody (TG2Ab) and endomysial antibody tests and inflammatory bowel disease with fecal calprotectin. Intestinal damage was evaluated from sera with analyses of intestinal fatty-acid binding protein (I-FABP), soluble cluster of differentiation molecule 14 (sCD14), and lipopolysaccharide binding protein. Fourteen people suffering from dyspepsia and 15 healthy people served as controls. RESULTS: I-FABP levels among IgAN patients were higher than in the healthy controls (median 830 pg/mL vs. 289 pg/mL, p < 0.001). Also, sCD14 was increased in IgAN patients compared to dyspepsia controls. Although TG2Ab levels were within the normal range among IgAN patients, they were higher than in the healthy controls (median 1.3 U/mL vs. 0.6 U/mL, p < 0.001). CONCLUSIONS: Elevated serum levels of I-FABP were present in primary IgAN patients without known enteropathies. Serum I-FABP may indicate the presence of subclinical intestinal damage. These findings encourage further investigation into the role of the intestine in the pathophysiology of IgAN.

Coeliac disease: what can we learn from prospective studies about disease risk?

Paediatric prospective studies of coeliac disease with longitudinal collection of biological samples and clinical data offer a unique perspective on disease risk. This Review highlights the information now available from international paediatric prospective studies on genetic and environmental risk factors for coeliac disease. In addition, recent omics studies have made it possible to study complex interactions between genetic and environmental factors and thereby further our insight into the causes of the disease. In the future, paediatric prospective studies will be able to provide more detailed risk prediction models combining genes, the environment, and biological corroboration from multiomics. Such studies could also contribute to biomarker development and an improved understanding of disease pathogenesis.

Prevalence of vomiting and nausea and associated factors after chronic and acute gluten exposure in celiac disease.

BACKGROUND: Vomiting and nausea seem to be relatively specific symptoms related to gluten ingestion in treated celiac disease. However, the overall prevalence and associated factors of these symptoms after chronic gluten exposure at celiac disease diagnosis and acute re-exposure during gluten challenge remain obscure. METHODS: Medical data on 815 adult celiac disease patients were collected at diagnosis from the medical records and through supplementary interviews. An additional 74 patients underwent a three-day (10 g/day) gluten challenge (wheat, barley, rye or a combination of the three grains) while in remission. Prevalence of vomiting/nausea and associated factors were evaluated in both cohorts. A literature review was conducted to summarize earlier studies. RESULTS: Twenty-eight (3%) patients presented with vomiting at diagnosis. They were less often screen-detected and suffered from extra-intestinal symptoms, and had more often abdominal pain (71% vs. 49%, p = 0.021), diarrhea (61% vs. 40%, p = 0.031), weight loss (36% vs. 17%, p = 0.019) and childhood symptoms (61% vs. 33%, p = 0.002) than those without vomiting (n = 787). The groups were comparable in other clinical-demographic data and in genetic, serological, and histological findings. Short-term gluten challenge provoked vomiting/nausea in 14/74 (19%) patients. They consumed gluten-free oats less often than those without these symptoms (64% vs. 92%, p = 0.017), whereas the groups did not differ in clinical-demographic features at diagnosis, presence of comorbidities, duration of gluten-free diet, or in other symptoms or grain used ingested during the challenge. According to the literature, prevalence of vomiting/nausea at celiac disease diagnosis has varied 3-46% and during gluten challenge 13-61%. CONCLUSIONS: In chronic gluten exposure at celiac disease diagnosis, vomiting was associated with other gastrointestinal symptoms and onset of symptoms already in childhood, whereas regular consumption of oats may increase the tolerance against vomiting/nausea after acute re-exposure in treated celiac disease.

Separate Gut Plasma Cell Populations Produce Auto-Antibodies against Transglutaminase 2 and Transglutaminase 3 in Dermatitis Herpetiformis.

Dermatitis herpetiformis (DH) is an inflammatory skin disorder often considered as an extra intestinal manifestation of celiac disease (CeD). Hallmarks of CeD and DH are auto-antibodies to transglutaminase 2 (TG2) and transglutaminase 3 (TG3), respectively. DH patients have auto-antibodies reactive with both transglutaminase enzymes. Here it is reported that in DH both gut plasma cells and serum auto-antibodies are specific for either TG2 or TG3 with no TG2-TG3 cross reactivity. By generating monoclonal antibodies from TG3-specific duodenal plasma cells of DH patients, three conformational epitope groups are defined. Both TG2-specific and TG3-specific gut plasma cells have few immunoglobulin (Ig) mutations, and the two transglutaminase-reactive populations show distinct selection of certain heavy and light chain V-genes. Mass spectrometry analysis of TG3-specific serum IgA corroborates preferential usage of IGHV2-5 in combination with IGKV4-1. Collectively, these results demonstrate parallel induction of anti-TG2 and anti-TG3 auto-antibody responses involving separate B-cell populations in DH patients.

Gluten-free diet adherence in children with screening-detected celiac disease using a prospective birth cohort study.

BACKGROUND: Celiac disease has an increasing incidence worldwide and is treated with lifelong adherence to a gluten-free diet. We aimed to describe gluten-free diet adherence rates in children with screening-identified celiac disease, determine adherence-related factors, and compare adherence to food records in a multinational prospective birth cohort study. METHODS: Children in The Environmental Determinants of Diabetes in the Young study with celiac disease were included. Subjects had at least annual measurement of adherence (parent-report) and completed 3-day food records. Descriptive statistics, t-tests, Kruskal-Wallis tests and multivariable logistic and linear regression were employed. RESULTS: Two hundred ninety (73%) and 199 (67%) of subjects were always adherent to a gluten-free diet at 2 and 5 years post celiac disease diagnosis respectively. The percentage of children with variable adherence increased from 1% at 2 years to 15% at 5 years. Children with a first-degree relative with celiac disease were more likely to be adherent to the gluten-free diet. Gluten intake on food records could not differentiate adherent from nonadherent subjects. Adherent children from the United States had more gluten intake based on food records than European children (P < .001 and P = .007 at 2 and 5 years respectively). CONCLUSION: Approximately three-quarters of children with screening-identified celiac disease remain strictly adherent to a gluten-free diet over time. There are no identifiable features associated with adherence aside from having a first-degree relative with celiac disease. Despite good parent-reported adherence, children from the United States have more gluten intake when assessed by food records. Studies on markers of gluten-free diet adherence, sources of gluten exposure (particularly in the United States), and effects of adherence on mucosal healing are needed.

Incidence of Pediatric Celiac Disease Varies by Region.

INTRODUCTION: The Environmental Determinants of Diabetes in the Young study follows an HLA risk selected birth cohort for celiac disease (CD) development using a uniform protocol. Children under investigation come from 6 different regions within Europe and the United States. Our aim was to identify regional differences in CD autoimmunity and CD cumulative incidence for children born between 2004 and 2010. METHODS: Children (n = 6,628) with DQ2.5 and/or DQ8.1 were enrolled prospectively from birth in Georgia, Washington, Colorado, Finland, Germany, and Sweden. Children underwent periodic study screening for tissue transglutaminase antibodies and then CD evaluation per clinical care. Population-specific estimates were calculated by weighting the study-specific cumulative incidence with the population-specific haplogenotype frequencies obtained from large stem cell registries from each site. RESULTS: Individual haplogenotype risks for CD autoimmunity and CD varied by region and affected the cumulative incidence within that region. The CD incidence by age 10 years was highest in Swedish children at 3%. Within the United States, the incidence by age 10 years in Colorado was 2.4%. In the model adjusted for HLA, sex, and family history, Colorado children had a 2.5-fold higher risk of CD compared to Washington. Likewise, Swedish children had a 1.4-fold and 1.8-fold higher risk of CD compared with those in Finland and Germany, respectively. DISCUSSION: There is high regional variability in cumulative incidence of CD, which suggests differential environmental, genetic, and epigenetic influences even within the United States. The overall high incidence warrants a low threshold for screening and further research on region-specific CD triggers.

Validation of the X-ray microtomography in the assessment of duodenal morphometry and surface area in celiac disease.

Background: Duodenal histology remains the diagnostic reference standard in celiac disease. However, traditional methods have suboptimal sensitivity and reproducibility for early mucosal changes and research purposes. We validated a recently introduced micro-CT imaging method for an accurate digital evaluation of duodenal histomorphometry and mucosal surface areas. Methods: Endoscopic biopsies from 58 individuals were utilized for the micro-CT imaging, selecting histological changes ranging from normal to severely damaged mucosa. The imaging protocol was optimized for practicability and resolution. The Bland-Altman method was applied to test intra- and interobserver variations in the blinded measurements. Results: The 3D micro-CT reconstructions enabled easy and precise digital cutting with optimal orientation and computer-assisted measurement of the surface area. Intraobserver analysis of morphological measurements showed a mean difference of 0.011 with limits of agreement (LA) from -0.397 to 0.375 and a standard deviation (SD) of 0.197. The corresponding figures for interobserver analysis were 0.080, from -0.719 to 0.537 and 0.320, respectively. The intraclass correlation coefficients (ICC) for the intraobserver and interobserver variations were 0.981 and 0.954, respectively. Intraobserver surface area analysis yielded a mean difference of 0.010, LA from -0.764 to 0.785 and an SD of 0.395, and an interobserver analysis mean difference of 0.028, LA from -0.642 to 0.698 and SD of 0.342. The respective ICCs for the intra- and interobserver variations were 0.963 and 0.972. Conclusions: Micro-CT showed excellent accuracy and reproducibility in the evaluation of mucosal morphometry and surface areas. The improved sensitivity for histological changes is a powerful tool for the diagnosis of celiac disease and for clinical and pharmacological studies.

Coeliac disease re-screening among once seronegative at-risk relatives: A long-term follow-up study.

BACKGROUND: Serological screening of the relatives of coeliac disease patients is widely endorsed. However, the need for and the optimal timing of possible re-testing of once seronegative at-risk individuals for coeliac disease remain unclear. OBJECTIVE: We investigated this issue by inviting a large cohort of previously screening-negative relatives of patients with coeliac disease to participate in a follow-up study. METHODS: Altogether 599 relatives of coeliac disease index patients not diagnosed with coeliac disease in a screening study carried out in 2006-2010 were asked about possible later diagnosis or re-tested with coeliac disease autoantibodies in 2017-2021. Besides incidence, the possible impact of various patient-related clinical factors and HLA haplotype on the later diagnosis or screening positivity was examined. RESULTS: Fifteen (2.5%) relatives were either diagnosed with a coeliac disease (n = 8) during the follow-up period or were found to be screening-positive in the re-testing (n = 7), giving a combined annual incidence of 221/100,000 person-years in all relatives and 336/100,000 among those carrying coeliac disease-associated HLA DQ2/DQ8. The new cases more often carried the high-risk (DQ2.5/2.5 or DQ2.5/2.2; 35.7% vs. 7.4%, respectively, p < 0.001) HLA and were younger at initial screening (23.3 vs. 40.5 years, p = 0.028) and - in spite of a negative screening outcome - had higher median transglutaminase antibody level in the first study than those not affected. There were no significant differences between the affected and non-affected relatives in other demographic data, degree of kinship with the index, current symptoms or frequency of chronic co-morbidities. CONCLUSION: The incidence rate for later coeliac disease diagnosis or new seropositivity in relatives who had been tested once was 221/100,000 person-years in all and 336/100,000 among those carrying at-risk HLA genetics after ∼10 years of follow-up. HLA-typing could help to target a subgroup of relatives who would benefit most from re-testing.

Antibody Responses to Transglutaminase 3 in Dermatitis Herpetiformis: Lessons from Celiac Disease.

Dermatitis herpetiformis (DH) is the skin manifestation of celiac disease, presenting with a blistering rash typically on the knees, elbows, buttocks and scalp. In both DH and celiac disease, exposure to dietary gluten triggers a cascade of events resulting in the production of autoantibodies against the transglutaminase (TG) enzyme, mainly TG2 but often also TG3. The latter is considered to be the primary autoantigen in DH. The dynamics of the development of the TG2-targeted autoimmune response have been studied in depth in celiac disease, but the immunological process underlying DH pathophysiology is incompletely understood. Part of this process is the occurrence of granular deposits of IgA and TG3 in the perilesional skin. While this serves as the primary diagnostic finding in DH, the role of these immunocomplexes in the pathogenesis is unknown. Intriguingly, even though gluten-intolerance likely develops initially in a similar manner in both DH and celiac disease, after the onset of the disease, its manifestations differ widely.

Toward Xeno-Free Differentiation of Human Induced Pluripotent Stem Cell-Derived Small Intestinal Epithelial Cells.

The small intestinal epithelium has an important role in nutrition, but also in drug absorption and metabolism. There are a few two-dimensional (2D) patient-derived induced pluripotent stem cell (iPSC)-based intestinal models enabling easy evaluation of transcellular transport. It is known that animal-derived components induce variation in the experimental outcomes. Therefore, we aimed to refine the differentiation protocol by using animal-free components. More specifically, we compared maturation of 2D-cultured iPCSs toward small intestinal epithelial cells when cultured either with or without serum, and either on Geltrex or on animal-free, recombinant laminin-based substrata. Differentiation status was characterized by qPCR, immunofluorescence imaging, and functionality assays. Our data suggest that differentiation toward definitive endoderm is more efficient without serum. Both collagen- and recombinant laminin-based coating supported differentiation of definitive endoderm, posterior definitive endoderm, and small intestinal epithelial cells from iPS-cells equally well. Small intestinal epithelial cells differentiated on recombinant laminin exhibited slightly more enterocyte specific cellular functionality than cells differentiated on Geltrex. Our data suggest that functional small intestinal epithelial cells can be generated from iPSCs in serum-free method on xeno-free substrata. This method is easily converted to an entirely xeno-free method.

Dissecting the contribution of single nucleotide polymorphisms in CCR9 and CCL25 genomic regions to the celiac disease phenotype.

PURPOSE AND OBJECTIVES: Given their role in homing immune cells to the intestine, CC motif chemokine receptor 9 (CCR9) and its specific ligand CC motif chemokine ligand 25 (CCL25) are interesting candidate genes for celiac disease. These genes are located in regions previously shown to be associated with or linked to celiac disease, but no investigations on their association with various celiac disease phenotypes have so far been conducted. Here we studied such associations of both genotyped and imputed single nucleotide polymorphisms (SNPs) with either regulatory function or exonic location of the CCR9 and CCL25 loci. RESULTS: Exploiting a carefully phenotyped cohort of 625 celiac disease patients and 1817 non-celiac controls, we identified that multiple SNPs with predicted regulatory function (RegulomeDB score ≤3a and/or eQTL effect) located between 100 kB upstream and downstream of CCR9 and CCL25 are associated with celiac disease and/or selected phenotypes. Of the genotyped SNPs in the CCR9 loci, rs213360 with an eQTL effect on CCR9 expression in blood was associated with celiac disease and all investigated phenotypes except high HLA risk. Rs1545985 with an eQTL on CCR9 expression and rs7652331 and rs12493471, both with RegulomeDB score ≤3a, were all associated with gastrointestinal symptoms and malabsorption and the latter additionally with anemia. The genotyped CCL25 SNPs rs952444 and rs882951, with RegulomeDB scores 1d and 1f respectively and eQTL effect on CCL25 expression in small intestine, were associated with gastrointestinal symptoms and malabsorption. The CCL25 SNP rs2303165 identified in sequencing followed by imputation was associated with partial villous atrophy. However, the association did not pass the permutation based multiple testing correction (PEMP2 > 0.05). CONCLUSIONS: We conclude that SNPs in the region of CCR9 and CCL25 with predicted functional effect or exonic localization likely contribute only modestly to various celiac disease phenotypes.

Presence of high-risk HLA genotype is the most important individual risk factor for coeliac disease among at-risk relatives.

BACKGROUND: Family screening has been advocated as a means to reduce the major underdiagnosis of coeliac disease. However, the precise risk of the disease in relatives and the impact of patient- and relative-related individual factors remain obscure. AIMS: To investigate the individual risk of coeliac disease among patients' relatives. METHODS: Altogether 2943 relatives of 624 index patients were assessed for the presence of previous coeliac disease diagnosis, or were screened for the disease. Coeliac disease-associated human leucocyte antigen (HLA) genotype was determined from all participants. The association between individual factors and new screening positivity was assessed by logistic regression. RESULTS: There were 229 previously diagnosed non-index relatives with coeliac disease and 2714 non-affected (2067 first-degree, 647 more distant) relatives. Of these 2714 relatives, 129 (4.8%) were screening-positive (first-degree 5.1%, second-degree 3.6%, more distant 3.5%). The combined prevalence of the previously diagnosed and now detected cases in relatives was 12.2% (6.3% clinically detected, 5.9% screen-detected). In univariate analysis, age <18 years at diagnosis (odds ratio 1.60, 95% CI 1.04-2.45) in index, and age 41-60 years (1.73, 1.10-2.73), being a sibling (1.65, 1.06-2.59) and having the high-risk genotype (3.22, 2.01-5.15 DQ2.5/2.5 or DQ2.5/2.2 vs other risk alleles) in relatives were associated with screening positivity. Only high-risk HLA remained significant (2.94, 1.80-4.78) in multivariable analysis. CONCLUSIONS: Unrecognised coeliac disease was common among at-risk relatives even in a country with an active case-finding policy, and also in relatives more distant than first-degree. The presence of a high-risk genotype was the most important predictor for screening positivity. ClinicalTrials.gov identifier NCT03136731.

Celiac Disease-Type Tissue Transglutaminase Autoantibody Deposits in Kidney Biopsies of Patients with IgA Nephropathy.

An association between celiac disease and IgA nephropathy (IgAN) has been suggested. In celiac disease, in addition to circulating in serum, IgA-class tissue transglutaminase (tTG) autoantibodies are deposited in the small bowel mucosa and extraintestinal organs. In this case series of IgAN patients with or without celiac disease, we studied whether celiac disease-type IgA-tTG deposits occur in kidney biopsies. The study included nine IgAN patients, four of them with celiac disease. At the time of the diagnostic kidney biopsy serum tTG autoantibodies were measured and colocalization of IgA and tTG was investigated in the frozen kidney biopsies. Three IgAN patients with celiac disease had IgA-tTG deposits in the kidney even though in two of these the celiac disease diagnosis had been set years later. These deposits were not found in a patient with already diagnosed celiac disease following a gluten-free diet. Of the five non-celiac IgAN patients, three had IgA-tTG deposits in the kidney. We conclude that tTG-targeted IgA deposits can be found in the kidney biopsies of gluten-consuming IgAN patients but their specificity to celiac disease seems limited.

Missing Insight Into T and B Cell Responses in Dermatitis Herpetiformis.

Dermatitis herpetiformis is a cutaneous form of celiac disease manifesting as an itching rash typically on the elbows, knees and buttocks. It is driven by the ingestion of gluten-containing cereals and characterized by granular deposits of immunoglobulin A in the papillary dermis. These antibodies target transglutaminase (TG) 3 and in the majority of patients they are also found in circulation. The circulating antibodies disappear and skin symptoms resolve as a result of gluten-free diet but the cutaneous anti-TG3 IgA deposits may persist for several years. In dermatitis herpetiformis, plasma cells secreting antibodies against TG3 are located in the intestinal mucosa similarly to those producing TG2 antibodies characteristic for celiac disease. In fact, both TG2- and TG3-specific plasma cells and gluten responsive T cells are found in dermatitis herpetiformis patients but the interplay between these cell populations is unknown. The small bowel mucosal damage in celiac disease is believed to be mediated by co-operation of cytotoxic intraepithelial T cells and the inflammatory milieu contributed by gluten-reactive CD4+ T cells, whereas the skin lesions in dermatitis herpetiformis appear to be devoid of gluten reactive T cells. Thus, how celiac disease-type intestinal T and B cell responses develop into an autoimmune condition affecting the skin is still incompletely understood. Finally, the skin and small bowel lesions may reappear upon reintroduction of gluten in patients treated with gluten-free diet but virtually nothing is known about the long-lived B cell and memory T cell populations activating in response to dietary gluten in dermatitis herpetiformis.

Iron Transporter Protein Expressions in Children with Celiac Disease.

Anemia is a frequent finding in children with celiac disease but the detailed pathophysiological mechanisms in the intestine remain obscure. One possible explanation could be an abnormal expression of duodenal iron transport proteins. However, the results have so far been inconsistent. We investigated this issue by comparing immunohistochemical stainings of duodenal cytochrome B (DCYTB), divalent metal transporter 1 (DMT1), ferroportin, hephaestin and transferrin receptor 1 (TfR1) in duodenal biopsies between 27 children with celiac disease and duodenal atrophy, 10 celiac autoantibody-positive children with potential celiac disease and six autoantibody-negative control children. Twenty out of these 43 subjects had anemia. The expressions of the iron proteins were investigated with regard to saturation and the percentage of the stained area or stained membrane length of the enterocytes. The results showed the stained area of ferroportin to be increased and the saturation of hephaestin to be decreased in celiac disease patients compared with controls. There were no differences in the transporter protein expressions between anemic and non-anemic patients. The present results suggest an iron status-independent alteration of ferroportin and hephaestin proteins in children with histologically confirmed celiac disease.

Independent and cumulative coeliac disease-susceptibility loci are associated with distinct disease phenotypes.

The phenotype of coeliac disease varies considerably for incompletely understood reasons. We investigated whether established coeliac disease susceptibility variants (SNPs) are individually or cumulatively associated with distinct phenotypes. We also tested whether a polygenic risk score (PRS) based on genome-wide associated (GWA) data could explain the phenotypic variation. The phenotypic association of 39 non-HLA coeliac disease SNPs was tested in 625 thoroughly phenotyped coeliac disease patients and 1817 controls. To assess their cumulative effects a weighted genetic risk score (wGRS39) was built, and stratified by tertiles. In our PRS model in cases, we took the summary statistics from the largest GWA study in coeliac disease and tested their association at eight P value thresholds (PT) with phenotypes. Altogether ten SNPs were associated with distinct phenotypes after correction for multiple testing (PEMP2 ≤ 0.05). The TLR7/TLR8 locus was associated with disease onset before and the SH2B3/ATXN2, ITGA4/UBE2E3 and IL2/IL21 loci after 7 years of age. The latter three loci were associated with a more severe small bowel mucosal damage and SH2B3/ATXN2 with type 1 diabetes. Patients at the highest wGRS39 tertiles had OR > 1.62 for having coeliac disease-related symptoms during childhood, a more severe small bowel mucosal damage, malabsorption and anaemia. PRS was associated only with dermatitis herpetiformis (PT = 0.2, PEMP2 = 0.02). Independent coeliac disease-susceptibility loci are associated with distinct phenotypes, suggesting that genetic factors play a role in determining the disease presentation. Moreover, the increased number of coeliac disease susceptibility SNPs might predispose to a more severe disease course.

Differences Between Familial and Sporadic Celiac Disease.

BACKGROUND: It is not known if genetic background, characteristics at diagnosis, physical and psychological well-being, and adherence to a gluten-free diet are comparable between patients with familial or sporadic celiac disease. These issues were investigated in a follow-up study. METHODS: Altogether 1064 patients were analyzed for celiac disease-associated serology, predisposing HLA-DQ, and non-HLA genotypes. Medical data were collected from patient records and supplementary interviews. Current symptoms and quality of life were further evaluated with the Gastrointestinal Symptom Rating Scale (GSRS), the Psychological General Well-Being questionnaire (PGWB), and Short Form 36 (SF-36) questionnaires. RESULTS: Familial and sporadic groups differed (P < 0.001) in the reason for diagnosis and clinical presentation at diagnosis, familial patients being more often screen-detected (26% vs. 2%, P < 0.001) and having less often gastrointestinal (49% vs. 69%) and severe symptoms (47% vs. 65%). The groups were comparable in terms of histological damage, frequency of malabsorption, comorbidities, childhood diagnoses, and short-term treatment response. At the time of the study, familial cases reported fewer symptoms (21% vs. 30%, P = 0.004) and lower prevalence of all (78% vs. 86%, P = 0.007), neurological (10% vs. 15%, P = 0.013), and dermatological (9% vs. 17%, P = 0.001) comorbidities. Dietary adherence and GSRS scores were comparable, but familial cases had better quality of life according to PGWB and SF-36. High-risk genotype HLA-DQ2.5/DQ2.5 was more frequent among familial cases, and four non-HLA SNPs were associated with familial celiac disease. CONCLUSIONS: Despite the greater proportion of high-risk genotypes, familial cases had milder symptoms at presentation than did sporadic cases. Worse experience of symptoms and poorer quality of life in sporadic disease indicate a need for intensified support.

The use of peripheral blood mononuclear cells in celiac disease diagnosis and treatment.

Introduction: Celiac disease is characterized by an abnormal immune activation driven by the ingestion of gluten from wheat, barley, and rye. Gluten-specific CD4+ T cells play an important role in disease pathogenesis and are detectable among peripheral blood mononuclear cells (PBMCs). Areas covered: This review summarizes the use of celiac disease patient PBMCs in clinical applications focusing on their exploitation in the development of diagnostic approaches and novel drugs to replace or complement gluten-free diet. Expert opinion: The most used PBMC-based methods applied in celiac disease research include ELISpot and HLA-DQ:gluten tetramer technology. ELISpot has been utilized particularly in research aiming to develop a celiac disease vaccine and in studies addressing the toxicity of different grains in celiac disease. HLA-DQ:gluten tetramer technology on the other hand initially focused on improving current diagnostics but in combination with additional markers it is also a useful outcome measure in clinical trials to monitor the efficacy of drug candidates. In addition, the technology serves well in the more detailed characterization of celiac disease-specific T cells, thereby possibly revealing novel therapeutic targets. Future studies may also reveal clinical applications for PBMC microRNAs and/or dendritic cells or monocytes present among PBMCs.