[The disease under chronic urticaria: beyond itching]. / La enfermedad crónica bajo la urticaria: más allá del prurito.

BACKGROUND: Brief erythematous-papular skin rashes suggest the diagnosis of urticaria; However, it may be another type of dermatitis, and complementary examinations must be carried out to establish its diagnosis. CASE REPORT: 53-year-old female patient, diagnosed in 2016 with diffuse large B cell lymphoma, in complete remission. Since 2010, he has had episodes of erythematous-papular lesions lasting 24-36 hours. He received antihistamines, corticosteroids and omalizumab without clinical improvement. The ANA determination was positive (1/320), nuclear mitotic pattern. The skin biopsy was compatible with dermatitis herpetiformis. The study of celiac and locus antibodies showed positivity for HLA-DQ2 and DQ2.5 in heterozygosity. The diagnosis of dermatitis herpetiformis was established. Treatment consisted of a gluten-free diet and prescription of dapsone, with satisfactory results. CONCLUSION: It is important to establish the differential diagnosis of patients with chronic urticaria who do not respond to the reference treatment, in addition to carrying out a thorough clinical examination and physical examination before starting treatment and relying on a multidisciplinary team to establish an accurate diagnosis and treatment. appropriate. Due to the side effects of dapsone, subsequent follow-up of patients is essential.

ANTECEDENTES: Los exantemas cutáneos eritemato-papulares de breve duración sugieren el diagnóstico clínico de urticaria; no obstante, puede tratarse de otro tipo de dermatitis, y para establecer el diagnóstico deben llevarse a cabo exploraciones complementarias. REPORTE DE CASO: Paciente femenina de 53 años, diagnosticada en 2016 con linfoma difuso de células B grandes, en remisión completa. Desde el 2010 manifestó episodios de lesiones eritemato-papulosas, de 24-36 horas de duración. Recibió antihistamínicos, corticoides y omalizumab sin mejoría clínica. La determinación de ANA resultó positiva (1/320), con patrón mitótico nuclear. La biopsia cutánea fue compatible con dermatitis herpetiforme. El estudio de anticuerpos de celiaquía y locus mostró positividad para HLA-DQ2 y DQ2.5 con heterocigosis. Se estableció el diagnosticó de dermatitis herpetiforme. El tratamiento consistió en dieta exenta de gluten y prescripción de dapsona, con resultados satisfactorios. CONCLUSIÓN: Es importante establecer el diagnóstico diferencial de pacientes con urticaria crónica que no responden al tratamiento de referencia, además de efectuar el examen clínico y la exploración física exhaustivos antes de iniciar el protocolo, y apoyarse de un equipo multidisciplinario para establecer el diagnóstico certero y tratamiento adecuado. Debido a los efectos secundarios de la dapsona, es imprescindible el seguimiento posterior de los pacientes.

Evaluation of HLA-DQ2 and HLA-DQ8 haplotypes in patients with endometriosis, A case-control study.

OBJECTIVE: To evaluate the relationship between genetic haplotypes associated with celiac disease (Human Leucocyte Antigen [HLA] DQ2 and DQ8) with the diagnosis, clinical presentation, and location of endometriosis in Brazilian women. METHOD: A retrospective cross-sectional study, was conducted in a Tertiary hospital. PATIENTS: Women aged 18-50 years who underwent HLA-DQ2 and HLA-DQ8 haplotype analysis. INTERVENTION: The patients were divided into endometriosis and control groups and evaluated for symptoms; endometriosis location, American Society for Reproductive Medicine (ASRM) stage, and the presence of anti-tissue transglutaminase IgA (anti-TgA), HLA-DQ2, and HLA-DQ8 markers. RESULTS: A total of 434 consecutive patients with (n = 315) and without (n = 119) endometriosis were included. Pain and infertility were more frequent in the endometriosis group than in the control group. The presence of HLA-DQ2, HLA-DQ8, and anti-TgA was similar between both groups. The presence of HLA-DQ2 and HLA-DQ8 markers did not differ based on age, pain symptoms, ASRM stage, or endometriosis location. CONCLUSION: Although there are similarities in inflammatory markers and pathophysiology between celiac disease and endometriosis, this study found no significant associations in the presence of HLA-DQ2 or HLA-DQ8 haplotypes and endometriosis.

Islet transplantation outcomes in type 1 diabetes and transplantation of HLA-DQ8/DR4: results of a single-centre retrospective cohort in Canada.

Background: In solid organ transplantation, HLA matching between donor and recipient is associated with superior outcomes. In islet transplantation, an intervention for Type 1 diabetes, HLA matching between donor and recipient is not performed as part of allocation. Susceptibility to Type 1 diabetes is associated with the presence of certain HLA types. This study was conducted to determine the impact of these susceptibility antigens on islet allograft survival. Methods: This is a single-centre retrospective cohort study. This cohort of transplant recipients (n = 268) received islets from 661 donor pancreases between March 11th, 1999 and August 29th, 2018 at the University of Alberta Hospital (Edmonton, AB, Canada). The frequency of the Type 1 diabetes susceptibility HLA antigens (HLA-A24, -B39, -DQ8, -DQ2 and-DQ2-DQA1∗05) in recipients and donors were determined. Recipient and donor HLA antigens were examined in relation to time to first C-peptide negative status/graft failure or last observation point. Taking into account multiple transplants per patient, we fitted a Gaussian frailty survival analysis model with baseline hazard function stratified by transplant number, adjusted for cumulative islet dose and other confounders. Findings: Across all transplants recipients of donors positive for HLA-DQ8 had significantly better graft survival (adjusted HRs 0.33 95% CI 0.17-0.66; p = 0.002). At first transplant only, donors positive for HLA-DQ2-DQA1∗05 had inferior graft survival (adjusted HR 1.96 95% CI 1.10-3.46); p = 0.02), although this was not significant in the frailty analysis taking multiple transplants into account (adjusted HR 1.46 95% CI 0.77-2.78; p = 0.25). Other HLA antigens were not associated with graft survival after adjustment for confounders. Interpretation: Our findings suggest islet transplantation from HLA-DQ8 donors is associated with superior graft outcomes. A donor positive for HLA-DQ2-DQA1∗05 at first transplant was associated with inferior graft survival but not when taking into account multiple transplants per recipient. The relevance of HLA-antigens on organ allocation needs further evaluation and inclusion in islet transplant registries and additional observational and interventional studies to evaluate the role of HLA-DQ8 in islet graft survival are required. Funding: None.

Modeling Peptide-Protein Interactions by a Logo-Based Method: Application in Peptide-HLA Binding Predictions.

Peptide-protein interactions form a cornerstone in molecular biology, governing cellular signaling, structure, and enzymatic activities in living organisms. Improving computational models and experimental techniques to describe and predict these interactions remains an ongoing area of research. Here, we present a computational method for peptide-protein interactions' description and prediction based on leveraged amino acid frequencies within specific binding cores. Utilizing normalized frequencies, we construct quantitative matrices (QMs), termed 'logo models' derived from sequence logos. The method was developed to predict peptide binding to HLA-DQ2.5 and HLA-DQ8.1 proteins associated with susceptibility to celiac disease. The models were validated by more than 17,000 peptides demonstrating their efficacy in discriminating between binding and non-binding peptides. The logo method could be applied to diverse peptide-protein interactions, offering a versatile tool for predictive analysis in molecular binding studies.

Evaluation of HLA-DQ2 and HLA-DQ8 haplotypes in patients with endometriosis, A case-control study

Abstract Objective To evaluate the relationship between genetic haplotypes associated with celiac disease (Human Leucocyte Antigen [HLA] DQ2 and DQ8) with the diagnosis, clinical presentation, and location of endometriosis in Brazilian women. Method A retrospective cross-sectional study, was conducted in a Tertiary hospital. Patients Women aged 18-50 years who underwent HLA-DQ2 and HLA-DQ8 haplotype analysis. Intervention The patients were divided into endometriosis and control groups and evaluated for symptoms; endometriosis location, American Society for Reproductive Medicine (ASRM) stage, and the presence of anti-tissue transglutaminase IgA (anti-TgA), HLA-DQ2, and HLA-DQ8 markers. Results A total of 434 consecutive patients with (n = 315) and without (n = 119) endometriosis were included. Pain and infertility were more frequent in the endometriosis group than in the control group. The presence of HLA-DQ2, HLA-DQ8, and anti-TgA was similar between both groups. The presence of HLA-DQ2 and HLA-DQ8 markers did not differ based on age, pain symptoms, ASRM stage, or endometriosis location. Conclusion Although there are similarities in inflammatory markers and pathophysiology between celiac disease and endometriosis, this study found no significant associations in the presence of HLA-DQ2 or HLA-DQ8 haplotypes and endometriosis.

Associations of dietary patterns between age 9 and 24 months with risk of celiac disease autoimmunity and celiac disease among children at increased risk.

BACKGROUND: Higher gluten intake in childhood is associated with increased incidence of celiac disease autoimmunity (CDA) and celiac disease. It remains to be studied whether different dietary patterns independent of gluten intake contribute to the incidence. OBJECTIVES: This study aimed to explore associations of dietary patterns by age 2 y with risk of CDA and celiac disease in genetically susceptible children. METHODS: Data was used from 6726 participants at genetic risk of type 1 diabetes and celiac disease enrolled in the observational cohort, The Environmental Determinants of Diabetes in the Young (TEDDY) study. Children were annually screened for tissue transglutaminase autoantibodies (tTGAs) from age 2 y. Principal component analysis extracted dietary patterns, based on intake of 27 food groups assessed by 3-d food records at age 9 to 24 mo. The primary outcome was CDA (i.e., persistently tTGA-positive in at least 2 consecutive samples), and the secondary outcome was celiac disease. During follow-up to mean age 11.0 (standard deviation 3.6) y, 1296 (19.3%) children developed CDA, and 529 (7.9%) were diagnosed with celiac disease. Associations of adherence to dietary patterns (per 5-unit increase) with the study outcomes were estimated by Cox regression models adjusted for risk factors including gluten intake. RESULTS: At age 9 mo, a dietary pattern higher in the food groups vegetable fats and milk was associated with reduced risk of CDA (hazard ratio [HR]: 0.88; 95% confidence interval [CI]: 0.79, 0.98; P = 0.02). At 24 mo, a dietary pattern higher in the food groups wheat, vegetable fats, and juices, and lower in milk, meat, and oats at age 24 mo was associated with increased risk of CDA (HR: 1.18; 95% CI: 1.05, 1.33; P < 0.001) and celiac disease (HR: 1.24; 95% CI: 1.03, 1.50; P = 0.03). CONCLUSIONS: Dietary patterns in early childhood are associated with risk of CDA and celiac disease in genetically predisposed children, independent of gluten intake.

Assessing the Prevalence of HLA-DQ2 and HLA-DQ8 in Lipedema Patients and the Potential Benefits of a Gluten-Free Diet.

Objective The aim of this study is to assess the prevalence of HLA-DQ2 and HLA-DQ8 in women diagnosed with lipedema. Methods Leukocyte histocompatibility antigen (HLA) tests of 95 women diagnosed with lipedema were analyzed using non-probabilistic sampling for convenience. The prevalence of HLA-DQ2 and HLA-DQ8 was compared to the general population. Results The prevalence of HLA-DQ2+ was 47.4%, that of HLA-DQ8+ was 22.2%, the presence of any celiac disease associated HLA (HLA-DQ2+ or HLA-DQ8+) was 61.1%, both HLA (HLA-DQ2+ and HLA-DQ8+) was 7.4%, and the absence of celiac disease associated HLA was 39%. Compared to the general population, there was a significantly higher prevalence of HLA-DQ2, HLA-DQ8, any HLA, and both HLAs in lipedema patients. The mean weight of patients with HLA-DQ2+ was significantly lower than the overall study population, and their mean BMI significantly differed from the overall mean BMI. Conclusion Lipedema patients seeking medical assistance have a higher prevalence of HLA-DQ2 and HLA-DQ8. Considering the role of gluten in inflammation, further research is needed to establish if this association supports the benefit of gluten withdrawal from the diet in managing lipedema symptoms.

Two-Sample Mendelian Randomization detects bidirectional causality between gut microbiota and celiac disease in individuals with high genetic risk.

Background: Celiac Disease (CeD) is an autoimmune disorder triggered by gluten intake in genetically susceptible individuals. Highest risk individuals are homozygous for the Human Leucocyte Antigen (HLA) DQ2.5 haplotype or DQ2.5/DQ2.2 heterozygous. Both the HLA-DQ2-positive high genetic risk individuals and those that have developed the disease have altered intestinal microbiota, but it remains unclear whether these alterations are a cause or a consequence of CeD. Objective: To investigate a potential bidirectional causality between gut microbiota (GM) and CeD in HLA-DQ2 high genetic risk individuals. Materials and Methods: We performed a bidirectional Two-Sample Mendelian Randomization (2SMR) test using summary statistics from the largest publicly available Genome-Wide Association Study (GWAS) of GM and the summary statistics of the Immunochip CeD study of those individuals with the HLA-DQ2 high-risk haplotype. To test whether changes in GM composition were causally linked to CeD, GM data were used as exposure and CeD data as outcome; to test for reverse causation, the exposure and outcome datasets were inverted. Results: We identified several bacteria from Ruminococcaceae and Lachnospiraceae families of the Firmicutes phylum as potentially causal in both directions. In addition, our results suggest that changes in the abundance of Veillonellaceae family might be causal in the development of CeD, while alterations in Pasteurellaceae family might be a consequence of the disease itself. Conclusion: Our results suggest that the relationship between GM and HLA-DQ2 high risk individuals is highly complex and bidirectional.

HLA-Haplotypes Influence Microbiota Structure in Northwestern Mexican Schoolchildren Predisposed for Celiac Disease or Type 1 Diabetes.

To contribute to and elucidate the participation of microbiota in celiac disease (CD) and type 1 diabetes (T1D) development, we evaluated the influence of HLA haplotypes, familial risk, and diet on the microbiota of schoolchildren. We conducted a cross-sectional study on 821 apparently healthy schoolchildren, genotyping HLA DQ2/DQ8, and registering familial risk. We analyzed the fecal microbiota using 16S rRNA gene sequencing, and autoantibodies for CD or T1D by ELISA. After analyses, we created three groups: at-high-risk children (Group 1), at-high-risk children plus autoantibodies (Group 2), and nonrisk children (Group 3). HLA influenced the microbiota of Groups 1 and 2, decreasing phylogenetic diversity in comparison to Group 3. The relative abundance of Oscillospiraceae UCG_002, Parabacteroides, Akkermansia, and Alistipes was higher in Group 3 compared to Groups 1 and 2. Moreover, Oscillospiraceae UCG_002 and Parabacteroides were protectors of the autoantibodies' positivity (RRR = 0.441 and RRR = 0.034, respectively). Conversely, Agathobacter was higher in Group 2, and Lachnospiraceae was in both Groups 1 and 2. Lachnospiraceae correlated positively with the sucrose degradation pathway, while the principal genera in Group 3 were associated with amino acid biosynthesis pathways. In summary, HLA and familial risk influence microbiota composition and functionality in children predisposed to CD or T1D, increasing their autoimmunity risk.

The Second Highest Prevalence of Celiac Disease Worldwide: Genetic and Metabolic Insights in Southern Brazilian Mennonites.

Celiac disease (CD), despite its high morbidity, is an often-underdiagnosed autoimmune enteropathy. Using a modified version of the Brazilian questionnaire of the 2013 National Health Survey, we interviewed 604 Mennonites of Frisian/Flemish origin that have been isolated for 25 generations. A subgroup of 576 participants were screened for IgA autoantibodies in serum, and 391 participants were screened for HLA-DQ2.5/DQ8 subtypes. CD seroprevalence was 1:29 (3.48%, 95% CI = 2.16-5.27%) and biopsy-confirmed CD was 1:75 (1.32%, 95% CI = 0.57-2.59%), which is superior to the highest reported global prevalence (1:100). Half (10/21) of the patients did not suspect the disease. HLA-DQ2.5/DQ8 increased CD susceptibility (OR = 12.13 [95% CI = 1.56-94.20], p = 0.003). The HLA-DQ2.5 carrier frequency was higher in Mennonites than in Brazilians (p = 7 × 10-6). HLA-DQ8 but not HLA-DQ2.5 carrier frequency differed among settlements (p = 0.007) and was higher than in Belgians, a Mennonite ancestral population (p = 1.8 × 10-6), and higher than in Euro-Brazilians (p = 6.5 × 10-6). The glutathione pathway, which prevents reactive oxygen species-causing bowel damage, was altered within the metabolic profiles of untreated CD patients. Those with lower serological positivity clustered with controls presenting close relatives with CD or rheumatoid arthritis. In conclusion, Mennonites have a high CD prevalence with a strong genetic component and altered glutathione metabolism that calls for urgent action to alleviate the burden of comorbidities due to late diagnosis.

Prediction of celiac disease associated epitopes and motifs in a protein.

Introduction: Celiac disease (CD) is an autoimmune gastrointestinal disorder causes immune-mediated enteropathy against gluten. Gluten immunogenic peptides have the potential to trigger immune responses which leads to damage the small intestine. HLA-DQ2/DQ8 are major alleles that bind to epitope/antigenic region of gluten and induce celiac disease. There is a need to identify CD associated epitopes in protein-based foods and therapeutics. Methods: In this study, computational tools have been developed to predict CD associated epitopes and motifs. Dataset used for training, testing and evaluation contain experimentally validated CD associated and non-CD associate peptides. We perform positional analysis to identify the most significant position of an amino acid residue in the peptide and checked the frequency of HLA alleles. We also compute amino acid composition to develop machine learning based models. We also developed ensemble method that combines motif-based approach and machine learning based models. Results and Discussion: Our analysis support existing hypothesis that proline (P) and glutamine (Q) are highly abundant in CD associated peptides. A model based on density of P&Q in peptides has been developed for predicting CD associated peptides which achieve maximum AUROC 0.98 on independent data. We discovered motifs (e.g., QPF, QPQ, PYP) which occurs specifically in CD associated peptides. We also developed machine learning based models using peptide composition and achieved maximum AUROC 0.99. Finally, we developed ensemble method that combines motif-based approach and machine learning based models. The ensemble model-predict CD associated motifs with 100% accuracy on an independent dataset, not used for training. Finally, the best models and motifs has been integrated in a web server and standalone software package "CDpred". We hope this server anticipate the scientific community for the prediction, designing and scanning of CD associated peptides as well as CD associated motifs in a protein/peptide sequence (https://webs.iiitd.edu.in/raghava/cdpred/).

Meta-Analysis and Systematic Review of HLA DQ2/DQ8 in Adults with Celiac Disease.

Although people with human leukocyte antigens (HLA) DQ2 and/or DQ8 are more likely to develop celiac disease (CD), the condition cannot be fully explained by this genetic predisposition alone. Multiple, as yet unidentified, factors contribute to the genesis of CD, including genetics, the environment, and the immune system. In order to provide insight into a prospective possibility and an expanded screening technique, we aim to undertake a comprehensive and meta-analytical study of the assessment and distribution of HLA class II (HLA-DQ2/DQ8) in adult CD patients. A systematic review was conducted using an electronic search of databases (PubMed, Google Scholar, Embase, and Direct Science) from January 2004 to February 2022. DQ2/DQ2 homozygotes have the highest risk of developing CD. DQ2/DQ8 typing is an effective test to exclude CD from the differential diagnosis of a patient with CD symptoms. Although other non-HLA genes have been associated with CD, they are rarely considered at diagnosis because they account for only a small proportion of the heritability of CD. This finding, together with the information gathered previously, may be useful in considering widely available and economically feasible screening options for celiac disease in young people.

Celiac disease prevalence and predisposing-HLA in a cohort of 93 Williams-Beuren syndrome patients.

Williams-Beuren syndrome is considered to be at increased risk for celiac disease, as for recent literature data and celiac disease guidelines, despite pathogenic mechanisms are still unclear. Our study analyzed the prevalence of autoimmune disorders, HLA DQ2 and/or DQ8 haplotypes, of transglutaminase antibodies and of diagnosis of celiac disease in a cohort of 93 Williams-Beuren syndrome's patients (mean age 21.26 years). Our study showed an increased prevalence of celiac disease equal to 10.8% (10/93 patients). We did not find a significant different frequency of predisposing HLA in subjects with Williams-Beuren syndrome compared to literature data in the general population (49.5% vs. 42.9%, with p > .1), nor a susceptibility to autoimmunity. This suggests that the increased prevalence of celiac disease in Williams-Beuren syndrome cannot be ascribed to HLA haplotype and may be related to other factors that still need to be identified in these patients.

Assessment of Novel Proteins Triggering Celiac Disease via Docking-Based Approach.

Human leukocyte antigens (HLAs) are pivotal in antigen processing, presenting to CD4+ T cells, and are linked to autoimmune disease susceptibility. In celiac disease, HLA-DQ2.5 and HLA-DQ8.1 bind gluten peptides on APCs, some recognized by CD4+ T cells, prompting inflammation and tissue damage. While extensively studied experimentally, these alleles lack comprehensive in silico analysis. To explore peptide-HLA preferences, we used molecular docking on peptide libraries, deriving quantitative matrices (QMs) for evaluating amino acids at nine-residue peptide binding cores. Our findings tie specific residue preferences to peptide backbone conformations. Validating QMs on known binders and non-binders showed strong predictive power (89-94% accuracy). These QMs excel in screening protein libraries, even whole proteomes, notably reducing time and costs for celiac disease risk assessment in novel proteins. This computational approach aligns with European Food Safety Authority guidance, promising efficient screening for potential celiac disease triggers.

Clinical presentation, biochemical profile, and HLA haplotype frequency of celiac disease among adults in Northwest China.

OBJECTIVE: To evaluate the clinical characteristics, biochemical parameters and the distribution of HLA-DQ genotypes among adult patients with celiac disease (CD) in Northwest China. METHODS: This cross-sectional study retrospectively collected clinical, biochemical, and HLA-DQ genotype of patients with CD from a tertiary hospital in Xinjiang Uygur Autonomous Region, China between March 2016 and December 2021. Small intestinal biopsy and serum-specific antibodies were used to diagnose CD. RESULTS: Of the 102 CD patients, 63.7% were women (female: male = 1.76:1), and the mean age was 47.3 ± 14.7 years at diagnosis. Common gastrointestinal symptoms included abdominal pain (50.0%), diarrhea (39.2%), and abdominal distension (24.5%). While common extraintestinal manifestations were anemia (48.0%), osteopenia or osteoporosis (36.3%), and fatigue (35.3%). Approximately 34.3% of patients with CD had comorbidities, with the most common being thyroid diseases (18.6%). Biochemical profiles showed lower hemoglobin, higher platelet count, and 25-hydroxyvitamin D (25[OH]D) deficiency. HLA-DQ2/DQ8 was detected among all 53 patients who underwent genotype testing; the frequency of the HLA-DQ2.5, DQ2.2, and DQ8 haplotypes was 71.7%, 24.5%, and 3.8%, respectively. CONCLUSIONS: CD was more common among women. Clinical manifestations include primarily gastrointestinal symptoms, but extraintestinal manifestations were not uncommon. Lower hemoglobin level, higher platelet count, and 25[OH]D deficiency are the main biochemical manifestations. The HLA-DQ2.5 and DQ2.2 haplotypes are the most common genotypes in CD.

Prevalence of haplotype DQ2/DQ8 and celiac disease in children with type 1 diabetes.

Type 1 diabetes (T1D) and celiac disease (CD) coexist very often. Identification of the human leukocyte antigen (HLA) DQ2/DQ8 can confirm the genetic predisposition to CD. Negative result of this test allows to exclude CD with a high probability. It was suggested that in individuals with higher risk of CD, including T1D patients, the implementation of genetic testing should reduce the number of patients requiring systematic immunological screening. The aim of this study was to analyze the prevalence of different haplotypes predisposing to CD in children and adolescents with previously diagnosed T1D. MATERIAL AND METHODS: A retrospective analysis was performed on 166 T1D children (91 girls) in whom HLA DQ2/DQ8 alleles were tested. In 9.6% CD was also diagnosed. RESULTS: In 12.7% both HLA DQ2/DQ8 were negative. In 87.3% patients HLA DQ2 and/or DQ8 was positive, including 27.7% patients with both haplotypes DQ2.5 and DQ8 positive. In all CD patients the disease predisposing alleles were positive, while none of the HLA DQ2/DQ8 negative children were diagnosed with CD. CONCLUSIONS: The prevalence of HLA DQ2.5 and the HLA DQ2.5 / HLA DQ8 configuration is higher in patients with T1D, and CD compared to children with T1D alone. The combination of HLA DQ2 and HLA DQ8 most significantly increases the risk of developing CD. The group of HLA DQ2/DQ8 negative patients with improbable CD diagnosis, is relatively small. Most of T1D patients HLA DQ2/DQ8 positive need further regular antibody assessment. In patients with T1D, who are at high risk of developing CD, genetic testing may be considered to select those who require further systematic serological evaluation. Due to its retrospective nature, the study was not registered in the database of clinical trials and the Clinical trial registration number is not available.

Combination of HLA-DQ2/-DQ8 Haplotypes and a Single MSH5 Gene Variant in a Polish Population of Patients with Type 1 Diabetes as a First Line Screening for Celiac Disease?

Patients with type 1 diabetes (T1D) are at increased risk for developing celiac disease (CD). The aim of the study was to assess the usefulness of celiac-specific human leukocyte antigen (HLA) haplotype and the rs3130484 variant of MSH5 gene, a previously described non-HLA variant associated with CD in the Polish population as a first-line screening for CD in T1D pediatric patients. Serological CD screening performed in the T1D group (n = 248) and healthy controls (n = 551) allowed for CD recognition in 20 patients (8.1%) with T1D (T1D + CD group). HLA-DQ2, HLA-DQ8 and the rs3130484 variant were genotyped with TaqMan SNP Genotyping Assays. The T1D + CD group presented a higher, but not statistically significant, frequency of HLA-DQ2 in comparison with T1D subjects. Combining the rs3130484 with HLA-DQ2/HLA-DQ8 typing significantly increased the sensitivity of HLA testing from 32.7% to 68.7%, and the accuracy of estimating CD prediction from 51.7% to 86.4% but decreased the specificity from 100% to 78.2%. The receiver operating characteristic curve analysis confirmed the best discrimination for the combination of both genetic tests with an area under curve reaching 0.735 (95% CI: 0.700-0.7690) in comparison with 0.664 (95% CI: 0.632-0.696) for HLA typing alone. Results show the low utility of HLA-DQ2/HLA-DQ8 typing for CD screening in T1D pediatric patients. Combination of the rs3130484 variant of the MSH5 gene and HLA testing increases both the sensitivity and the predictive value of the test accuracy, but still, the obtained values are not satisfactory for recommending such testing as the first-line screening for CD in T1D patients.

Celiac disease may be rare among children in South China.

OBJECTIVE: The prevalence of celiac disease (CD) varies geographically and ethnically; however, the prevalence among children in South China remains unknown. We therefore determined the occurrence of CD among Chinese children in South China. METHODS: Serum samples were collected from children and assessed for anti-tissue transglutaminase IgA antibodies (anti-tTG-IgA) and total IgA. Anti-tTG-IgA+ participants underwent human leukocyte antigen (HLA) DQ2/DQ8 determination. Samples with serum total IgA <0.05 g/L were also analyzed for anti-tTG-IgG, and for HLA-DQ2/DQ8 if the values were above borderline. Participants who were anti-tTG-IgA/IgG+ and HLA-DQ2+ and/or HLA-DQ8+ underwent small bowel biopsy. RESULTS: A total of 8794 children were enrolled, of whom 479 had chronic unexplained abdominal symptoms. Three (0.034%) children were anti-tTG-IgA+ and ten (0.114%) had serum total IgA <0.05 g/L, all of whom were anti-tTG-IgG-. The three positive children were all HLA-DQ2+ and/or HLA-DQ8+. Two underwent gastroscopy, and histopathology of small intestinal biopsy showed duodenal villous blunting in one and increased intraepithelial lymphocytes in the other, neither consistent with a diagnosis of CD. CONCLUSION: Our study showed a prevalence of CD autoimmunity of 0.034% and failed to identify any cases of CD, suggesting a low prevalence of CD among children in South China.

Possible effect of the HLA-DQ2/DQ8 polymorphism on autoimmune parameters and lymphocyte subpopulation in recurrent pregnancy losses.

Recurrent pregnancy loss (RPL) affects 1-2 % of women. Allo- and autoimmune disorders are a recognized factor for RPL and poor pregnancy outcomes. There is a link between antiphospholipid syndrome (APS), Hashimoto's thyroiditis or coeliac disease, and pregnancy losses. The prevalence of the HLA-DQ2/DQ8 polymorphism and genetic susceptibility to the development of celiac disease may be higher in women who experience RPL. A total of 95 women who had experienced two or more miscarriages were qualified into the study: 49 women with the HLA-DQ2/DQ8 polymorphism as the study group, and 46 as the control group. The prenatal test results of the women were evaluated, which revealed that the foetuses from the study group had higher nuchal translucency measurements than those of controls (1.85 mm vs 1.50 mm; p = 0.0024). A higher level of anticardiolipin antibodies (aCL) in the IgG class (18.38 GP L vs 11.37 GP L; p = 0.0039) and antithyroid peroxidase antibodies (aTPO) (87.67 IU/mL vs 11.87 IU/mL; p = 0.0062) was observed when compared to the control group. The presence of the HLA-DQ2.2 polymorphism was observed when higher nuchal translucency measurements and a higher aTPO concentration occurred. A relationship between the aTPO concentration and a higher birth weight of newborns was also shown. No significant differences between the groups were observed for peripheral blood lymphocyte subsets. A statistically significant relationship between the HLA-DQ2/DQ8 polymorphism and the increased concentrations of indicators of autoimmune disorders was indicated.

Interplay Between Gluten, HLA, Innate and Adaptive Immunity Orchestrates the Development of Coeliac Disease.

Several environmental, genetic, and immune factors create a "perfect storm" for the development of coeliac disease: the antigen gluten, the strong association of coeliac disease with HLA, the deamidation of gluten peptides by the enzyme transglutaminase 2 (TG2) generating peptides that bind strongly to the predisposing HLA-DQ2 or HLA-DQ8 molecules, and the ensuing unrestrained T cell response. T cell immunity is at the center of the disease contributing to the inflammatory process through the loss of tolerance to gluten and the differentiation of HLA-DQ2 or HLA-DQ8-restricted anti-gluten inflammatory CD4+ T cells secreting pro-inflammatory cytokines and to the killing of intestinal epithelial cells by cytotoxic intraepithelial CD8+ lymphocytes. However, recent studies emphasize that the individual contribution of each of these cell subsets is not sufficient and that interactions between these different populations of T cells and the simultaneous activation of innate and adaptive immune pathways in distinct gut compartments are required to promote disease immunopathology. In this review, we will discuss how tissue destruction in the context of coeliac disease results from the complex interactions between gluten, HLA molecules, TG2, and multiple innate and adaptive immune components.