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Vazquez-Roque, Maria I., Michael Camilleri, Thomas Smyrk, et al. "Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea." American Journal of Physiology-Gastrointestinal and Liver Physiology 303, no. 11 (2012): G1262—G1269. http://dx.doi.org/10.1152/ajpgi.00294.2012.
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Patients with irritable bowel syndrome (IBS) with diarrhea (IBS-D) carrying human leukocyte antigen (HLA)-DQ2/8 genotypes benefit from gluten withdrawal. Our objective was to compare gastrointestinal barrier function, mucosal inflammation, and transit in nonceliac IBS-D patients and assess association with HLA-DQ2/8 status. In 45 IBS-D patients who were naive to prior exclusion of dietary gluten, we measured small bowel (SB) and colonic mucosal permeability by cumulative urinary lactulose and mannitol excretion (0–2 h for SB and 8–24 h for colon), inflammation on duodenal and rectosigmoid mucosal biopsies (obtained in 28 of 45 patients), tight junction (TJ) protein mRNA and protein expression in SB and rectosigmoid mucosa, and gastrointestinal and colonic transit by validated scintigraphy. SB mucosal biopsies were stained with hematoxylin-eosin to assess villi and intraepithelial lymphocytes, and immunohistochemistry was used to assess CD3, CD8, tryptase, and zonula occludens 1 (ZO-1); colonic biopsy intraepithelial lymphocytes were quantitated. Associations of HLA-DQ were assessed using Wilcoxon's rank-sum test. Relative to healthy control data, we observed a significant increase in SB permeability ( P < 0.001), a borderline increase in colonic permeability ( P = 0.10), and a decrease in TJ mRNA expression in rectosigmoid mucosa in IBS-D. In HLA-DQ2/8-positive patients, ZO-1 protein expression in the rectosigmoid mucosa was reduced compared with that in HLA-DQ2/8-negative patients and colonic transit was slower than in HLA-DQ2/8-negative patients. No other associations with HLA genotype were identified. There is abnormal barrier function (increased SB permeability and reduced mRNA expression of TJ proteins) in IBS-D relative to health that may be, in part, related to immunogenotype, given reduced ZO-1 protein expression in rectosigmoid mucosa in HLA-DQ2/8-positive relative to HLA-DQ2/8-negative patients.
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Odermarsky, Michal, Anita Nilsson, Åke Lernmark, Sture Sjöblad, and Petru Liuba. "Atherogenic vascular and lipid phenotypes in young patients with Type 1 diabetes are associated with diabetes high-risk HLA genotype." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 5 (2007): H3175—H3179. http://dx.doi.org/10.1152/ajpheart.00795.2007.
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Expression of human leukocyte antigen (HLA) class II molecules on islet endothelial cells is a central vascular event in the pathogenesis of Type 1 diabetes. Previous studies demonstrated the ability of other vascular endothelial cells to express HLA and thereby to process islet autoantigens on their surface. We investigated whether the HLA-DQ2/8 genotype, which confers the highest risk for Type 1 diabetes, is associated with early atherosclerosis in youths with this disease. Brachial artery endothelium-dependent, flow-mediated dilation (BA-FMD) and carotid artery intima-media thickness (CA-IMT), as well as markers of systemic inflammation [C-reactive protein (CRP), fibrinogen, and orosomucoid], HbA1C, LDL, HDL, and total cholesterol, were assessed in 86 children and adolescents with Type 1 diabetes (mean age and diabetes duration, 15 and 7 yr, respectively) between 2004 and 2006. HLA genotypes were determined in dried blood spots by an oligoblot hybridization method. As a result, HLA-DQ2/8 was detected in 34 patients (DQ2/8). When this group was compared with the remaining patients (non-DQ2/8, n = 52), there were no differences in age, diabetes duration, HbA1C, body mass index, inflammatory markers, and IMT ( P ≥ 0.4). In the DQ2/8 group, LDL-to-HDL ratio was elevated compared with that in the non-DQ2/8 group (1.8 vs. 1.3, respectively; P = 0.001), whereas FMD did not significantly differ between the groups (5.3% vs. 6.7%, respectively; P = 0.08). When patients were further categorized in relation to CRP (cut-off value, 1 mg/l), BA-FMD was significantly lower (3%, P < 0.01), whereas LDL-to-HDL ratio increased further (2.2, P < 0.001) in the subgroup of DQ2/8 and CRP ≥ 1 patients compared with the remaining three subgroups. These associations remained significant after adjustment for age, diabetes duration, and HbA1C by analysis of covariance. The brachial artery responses to nitroglycerine were similar in all subgroups. In conclusion, the diabetes-predisposing HLA-DQ2/8 genotype in children and adolescents with Type 1 diabetes interferes with endothelial and lipid-related mechanisms of early atherosclerosis, possibly in part through inflammatory pathways.
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Paul, Siba P., Matthew Hoghton, and Bhupinder Sandhu. "Limited role of HLA DQ2/8 genotyping in diagnosing coeliac disease." Scottish Medical Journal 62, no. 1 (2017): 25–27. http://dx.doi.org/10.1177/0036933016689008.
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The European guidelines for diagnosing coeliac disease in children were revised in 2012. These recommend that in symptomatic children, a diagnosis of coeliac disease can be made without small-bowel biopsies provided their anti-tissue transglutaminase (anti-tTG) titre is >10 times of upper-limit-of-normal (>10×ULN) and anti-endomysial antibody is positive. In order to firm up the diagnosis in these children with very high anti-tTG titre, HLA-DQ2/DQ8 should be checked and be positive. Approximately 25–40% of white Caucasian population has HLA-DQ2/DQ8 haplotype. However, only 0.1–1% of the population will develop coeliac disease. Therefore, HLA-DQ2/DQ8 testing must not be done to ‘screen’ or ‘diagnose’ children with coeliac disease. Its use by paediatricians should be limited to children with anti-tTG>10×ULN, where the diagnosis of coeliac disease is being made on serology alone. A review of case referrals made to a tertiary paediatric gastroenterology centre in Southwest England demonstrated that HLA-DQ2/DQ8 testing is being requested inappropriately both in primary and secondary care suggesting a poor understanding of its role in diagnosis of coeliac disease. This article aims to clarify the role of HLA-DQ2/DQ8 testing for clinicians working in non-specialist settings.
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DiGiacomo, Daniel, Antonella Santonicola, Ilaria Russo, et al. "61 HLA DQ2/8 Prevalence in Non-Celiac Patients With Gastrointestinal Diseases." Gastroenterology 142, no. 5 (2012): S—16. http://dx.doi.org/10.1016/s0016-5085(12)60061-4.
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Paredes-Echeverri, Sara, Ayda N. Rodríguez, Wilmer A. Cárdenas, Belén Mendoza de Molano, and John M. González. "Seroprevalence of Antitransglutaminase and Antiendomysium Antibodies in Adult Colombian Blood Bank Donors." Canadian Journal of Gastroenterology and Hepatology 2020 (November 30, 2020): 1–6. http://dx.doi.org/10.1155/2020/7541941.
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Celiac disease (CD) is an autoimmune enteropathy induced by the ingestion of gluten from wheat, barley, and rye in genetically susceptible individuals. The global prevalence of CD is 1.4%. However, most of the prevalence studies have been conducted in Caucasian populations; few studies have been performed in Latin America. The aim of this study is to determine the seroprevalence of auto-antibodies used as markers for CD in a Colombian cohort. In this cross-sectional study, the serum samples from Colombian donors of the National Red Cross Blood Bank were collected between June and September 2017 in Bogotá, Colombia. All sera were tested for IgA antitissue transglutaminase (TTG) by enzyme-linked immunosorbent assay. Seropositive sera were tested for IgA antiendomysium (EMA) using indirect immunofluorescence assay. The ancestral genetic composition was determined in donor samples with antibody assay reactivity. Those with two seroreactive assays were typed for HLA class II DQ2 and DQ8. In total, 228 blood donors participated in the study. Among them, 113 were females (49.56%) with an average age of 31.63 years (SD ± 12.99); males had an average of 34.71 years (SD ± 13.01). Only 3 (1.31%) donors reported chronic diarrhea and nonintentional weight loss; 11 (4.82%) had a family history of CD. For the serological assays, 11 donors (4.82%) were seroreactive to IgA anti-TTG: 3 had high reactivity and 8 had low reactivity. Of those seroreactive to IgA anti-TTG, 3 (1.32%) were also seroreactive to anti-EMA, and they were typed as HLA-DQ8 or HLA-DQ2. The baseline ancestral percentage of the seroreactive donors was higher for European and Native American than for African genes. The seroprevalence for anti-TTG and anti-EMA with the presence of HLA-DQ8 and HLA-DQ2 was 1.32%. Additionally, 4.82% donor participants were reactive only for anti-TTG. Compared with other studies, our findings suggest that Colombia has a high prevalence of CD markers.
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Dehghani, Seyed Mohsen, Naqi Dara, Behrooz Gharesifar, Iraj Shahramian, Fatemeh Dalili, and Morteza Salarzaei. "Prevalence of HLA DQ 2, 8 in children with celiac disease." Human Antibodies 29, no. 2 (2021): 123–28. http://dx.doi.org/10.3233/hab-200437.
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OBJECTIVE: Celiac disease is a chronic disease that affect small bowel by making its villi become atrophic. Various environmental and genetic factors have been identify as inducing factors for celiac disease. Most of the patients has one of the HLA DQ forms. Although the prevalence of these genes are variable in different areas of the world, we do not have a comprehensive information about this issue in our region. Thus the aim of present study is to investigate the prevalence of HLA DQ typing of patients who visited Emam Reza Gastroenterology clinic of Shiraz(IRAN). METHODS: In this case-control study all under 18 years old children who were diagnosed with celiac disease and have visited Emam Reza gastroenterology clinic were investigated. The diagnosis of celiac disease was made by history, physical exam, serologic test, and histopathology of duodenal biopsy. Blood sample was taken and HLA typing performed using PCR method at Motahari clinic cytology laboratory. Also those people who neither them self nor their first degree relatives were not case of celiac disease and underwent HLA typing for other reason were identified as control group. The statistical analysis was done using SPSS 18 software. The p value < 0.05 was identified as statistically significant. RESULTS: A total of 139 patients with celiac disease and 146 normal children were studied. The mean age of the patient with celiac disease were 9.1 years old with standard deviation of 3.4 years old. 64% of the celiac patients were girls and 36% were boys. While this proportion was 54.4% for boy and 48.6% for girls in control group. The most common HLA in celiac patients group were HLA DQ2 and 8 but the most common ones in control group were HLA DQ 8 and 5. Failure to Thrive were the most common signs of the celiac patients with a prevalence of 60 children. Total IgA titer were normal in 98.6% of the patients and TTG IgA titer were positive in 93.5% of the patients. The most common co existing disease with the celiac disease were diabetes with a prevalence of 30 children (66.7%). CONCLUSION: present study reveals that the prevalence of the HLA DQ2 and 8 among patients with celiac disease is 72.6% and 53% in our normal population.
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Baldas, V., A. Taddio, S. Berthrand, et al. "P0453 COELIAC DISEASE AND HLA DQ2/8: A WEEKER ASSOCIATION IN PATIENTS TESTED NEGATIVE FOR ANTIENDOMISIUM ANTIBODIES." Journal of Pediatric Gastroenterology and Nutrition 39, Supplement 1 (2004): S228. http://dx.doi.org/10.1097/00005176-200406001-00577.
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KOTZE, Lorete M. S., Shirley R. R. UTIYAMA, Luiz Roberto KOTZE, and Renato NISIHARA. "SERONEGATIVE CELIAC DISEASE IN BRAZILIAN PATIENTS: A SERIES OF CASES." Arquivos de Gastroenterologia 58, no. 2 (2021): 214–16. http://dx.doi.org/10.1590/s0004-2803.202100000-39.
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ABSTRACT BACKGROUND: Celiac disease (CD) is an autoimmune disease characterized by immune reaction mostly to wheat gluten. The diagnosis is based on clinical, serological and histological findings in patients ingesting gluten. Cases that the clinical profile indicates CD and the autoantibodies are negative bring so a dilemma for the professional, as the risk of missed the diagnosis or a delay at the same. OBJECTIVE: To show the importance of correct diagnosis of cases with seronegative celiac disease (SNCD). METHODS: Ten cases of SNCD Brazilian patients were retrospectively studied (2013 to 2019). Data of clinical complaints, autoantibodies, IgA serum levels, histological findings and HLA-DQ2/DQ-8 were compiled. Dual-X densitometry, delay at diagnosis, previous autoimmune diseases and family history of CD were also checked. RESULTS: All SNCD patients presented clinical symptoms of CD, with confirmed diagnosis by histological findings of the duodenal mucosa and HLA-DQ2 and/or HLA-DQ8 positivity. All patients had normal IgA levels and negative autoantibodies (IgA-anti-transglutaminase and anti-endomysial). Dual-X densitometry detected osteopenia in two women and osteoporosis in two males, all with low levels of vitamin D. Delay diagnostic ranged from 1 to 19 years. Familiar occurrence of CD was reported in 40% of the cases. After one year of gluten-free diet, eight patients refer improve of symptoms, while duodenal biopsies, done in five cases, showed histological improvement. CONCLUSION: Patients who demonstrate the clinical profile of celiac disease with negative serology and normal levels of IgA, especially those who have family members with celiac disease, should be submitted to duodenal biopsies to look for histological findings.
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Aziz, Imran, Nick Trott, Rebecca Briggs, John R. North, Marios Hadjivassiliou, and David S. Sanders. "Efficacy of a Gluten-Free Diet in Subjects With Irritable Bowel Syndrome-Diarrhea Unaware of Their HLA-DQ2/8 Genotype." Clinical Gastroenterology and Hepatology 14, no. 5 (2016): 696–703. http://dx.doi.org/10.1016/j.cgh.2015.12.031.
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So, Michelle, Colleen M. Elso, Eleonora Tresoldi, et al. "Proinsulin C-peptide is an autoantigen in people with type 1 diabetes." Proceedings of the National Academy of Sciences 115, no. 42 (2018): 10732–37. http://dx.doi.org/10.1073/pnas.1809208115.
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Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells, found within the islets of Langerhans in the pancreas, are destroyed by islet-infiltrating T cells. Identifying the antigenic targets of beta-cell reactive T cells is critical to gain insight into the pathogenesis of T1D and develop antigen-specific immunotherapies. Several lines of evidence indicate that insulin is an important target of T cells in T1D. Because many human islet-infiltrating CD4+ T cells recognize C-peptide–derived epitopes, we hypothesized that full-length C-peptide (PI33–63), the peptide excised from proinsulin as it is converted to insulin, is a target of CD4+ T cells in people with T1D. CD4+ T cell responses to full-length C-peptide were detected in the blood of: 14 of 23 (>60%) people with recent-onset T1D, 2 of 15 (>13%) people with long-standing T1D, and 1 of 13 (<8%) HLA-matched people without T1D. C-peptide–specific CD4+ T cell clones, isolated from six people with T1D, recognized epitopes from the entire 31 amino acids of C-peptide. Eighty-six percent (19 of 22) of the C-peptide–specific clones were restricted by HLA-DQ8, HLA-DQ2, HLA-DQ8trans, or HLA-DQ2trans, HLA alleles strongly associated with risk of T1D. We also found that full-length C-peptide was a much more potent agonist of some CD4+ T cell clones than an 18mer peptide encompassing the cognate epitope. Collectively, our findings indicate that proinsulin C-peptide is a key target of autoreactive CD4+ T cells in T1D. Hence, full-length C-peptide is a promising candidate for antigen-specific immunotherapy in T1D.
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Sanz, Yolanda. "Microbiome and Gluten." Annals of Nutrition and Metabolism 67, Suppl. 2 (2015): 27–42. http://dx.doi.org/10.1159/000440991.
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Celiac disease (CD) is a frequent chronic inflammatory enteropathy caused by gluten in genetically predisposed individuals that carry disease susceptibility genes (HLA-DQ2/8). These genes are present in about 30-40% of the general population, but only a small percentage of carriers develops CD. Gluten is the key environmental trigger of CD, but its intake does not fully explain disease onset; indeed, an increased number of cases experience gluten intolerance in late adulthood after many years of gluten exposure. Consequently, additional environmental factors seem to be involved in CD. Epidemiological studies indicate that common perinatal and early postnatal factors influence both CD risk and intestinal microbiota structure. Prospective studies in healthy infants at risk of developing CD also reveal that the HLA-DQ genotype, in conjunction with other environmental factors, influences the microbiota composition. Furthermore, CD patients have imbalances in the intestinal microbiota (dysbiosis), which are not fully normalized despite their adherence to a gluten-free diet. Therefore, it is hypothesized that the disease can promote dysbiosis that aggravates CD pathogenesis, and dysbiosis, in turn, can initiate and sustain inflammation through the expansion of proinflammatory pathobionts and decline of anti-inflammatory mutualistic bacteria. Studies in experimental models are also contributing to understand the role of intestinal bacteria and its interactions with a predisposed genotype in promoting CD. Advances in this area could aid in the development of microbiome-informed intervention strategies that optimize the partnership between the gut microbiota and host immunity for improving CD management.
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Barbaro, Maria Raffaella, Cesare Cremon, Antonio Maria Morselli-Labate, et al. "Serum zonulin and its diagnostic performance in non-coeliac gluten sensitivity." Gut 69, no. 11 (2020): 1966–74. http://dx.doi.org/10.1136/gutjnl-2019-319281.
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ObjectiveNon-coeliac gluten sensitivity (NCGS) is characterised by intestinal and extraintestinal symptoms related to the ingestion of gluten-containing foods, in the absence of coeliac disease (CD) and wheat allergy. No biomarkers are available to diagnose NCGS and the gold standard double-blind placebo-controlled gluten challenge is clinically impractical. The aim of our work was to investigate the role of serum zonulin as a diagnostic biomarker of NCGS and to develop a diagnostic algorithm.DesignIn a multicentre study, we enrolled 86 patients with either self-reported or double-blind confirmed NCGS, 59 patients with diarrhoea-predominant IBS (IBS-D), 15 patients with CD and 25 asymptomatic controls (AC). Zonulin serum levels were assessed and the associated diagnostic power calculated. Clinical and symptomatic data were recorded. The effect of diet on zonulin levels was evaluated in a subgroup of patients with NCGS.ResultsCompared with ACs, the NCGS, irrespective of modality of diagnosis, and patients with CD had significantly increased levels of zonulin, as did both NCGS and patients with CD compared with participants with IBS-D. Self-reported NCGS showed increased zonulin levels compared with double-blind confirmed and not-confirmed NCGS. Six-month wheat avoidance significantly reduced zonulin levels only in HLA-DQ2/8-positive participants with NCGS. The diagnostic accuracy of zonulin levels in distinguishing NCGS from IBS-D was 81%. After exclusion of CD, a diagnostic algorithm combining zonulin levels, symptoms and gender improved the accuracy to 89%.ConclusionZonulin can be considered a diagnostic biomarker in NCGS and combined with demographic and clinical data differentiates NCGS from IBS-D with high accuracy. Wheat withdrawal was associated with a reduction in zonulin levels only in NCGS carrying HLA genotype.
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Lekovic, Zoran, Vladimir Radlovic, Nevena Jovicic, et al. "Rotavirus gastroenteritis as a precipitating factor of celiac crisis in infancy - case reports and review of literature." Srpski arhiv za celokupno lekarstvo, no. 00 (2020): 101. http://dx.doi.org/10.2298/sarh200802101l.
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Introduction. Celiac crisis is a rare and life-threatening complication of celiac disease. Although it occurs in all ages, the most common affects children within the first two years. Outline of cases. We report three infants (two female, one male, age range 9-12) with celiac crises as an initial presentation of celiac disease precipitated with rotavirus gastroenteritis. Celiac crisis was preceded by failure to thrive caused by anorexia, occasional vomiting and frequent abundant stools for 4-8 weeks, and 1-2 days before admission with fever, frequent vomiting and profuse watery diarrhea. They were admitted in a very severe general condition, severely dehydrated, markedly malnourished, with an enormously distended abdomen, edema of the lower legs and feet, and perianal erythema. After correction of dehydration and hypoalbuminemia, they were placed on a gluten- and disaccharide-free diet and within the first 2 weeks on additional parenteral nutrition. The applied therapeutic measures resulted in stabilization and further rapid improvement of the patient's condition. In all three patients the latex agglutination test for rotavirus was positive, IgA anti-TTG antibodies elevated (58.6 to 78 U/ml) and all three were homozygous carriers of the HLA DQ2 gene. Enterobiopsy was performed two weeks after admission and total villous atrophy (Marsh IIIc) was registered in all three patients. In the further course, on a strict gluten-free diet, the complete recovery of the patient followed. Conclusion. Our experience indicates that rotavirus gastroenteritis in timely unrecognized classical celiac disease in infants can lead to celiac crisis.
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Losurdo, Giuseppe, Alessia Todeschini, Floriana Giorgio, et al. "Human Leukocyte Antigen (HLA) Haplotype Does Not Influence the Inflammatory Pattern of Duodenal Lymphocytosis Linked to Irritable Bowel Syndrome." Medicina 56, no. 12 (2020): 660. http://dx.doi.org/10.3390/medicina56120660.
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Background and objectives: Duodenal lymphocytosis (DL) is a condition characterized by enhanced infiltration of intraepithelial lymphocytes (IELs) in the duodenal mucosa, and it can be linked to both gluten- and non-gluten-related diseases, such as irritable bowel syndrome (IBS). Materials and methods: We retrospectively selected patients with DL linked to IBS. Formalin-embedded biopsy samples of the duodenum were collected. CD3 lymphocyte immunohistochemistry was used for IELs. The real-time polymerase chain reaction was used to quantify the amount of mRNA coding for tissue transglutaminase 2 (tTG2), interferon-gamma (IFNγ), toll-like receptor 2 (TLR2), and myeloid differentiation primary response 88 (MyD88). All subjects underwent DQ2-8 haplotype analysis. Controls were represented by subjects with IBS without DL. Results: Thirty-two patients with IBS-DL were retrospectively recruited. Fourteen subjects (43.8%) had a DQ2-8 haplotype. DQ2-8 positive subjects had similar levels compared to negative ones for tTG2, IFNγ, TLR2, and MyD88. Cigarette smoke did not influence molecular expression in our study. Smokers had a statistically higher IELs count than non-smokers (54.2 ± 7.7 vs. 36.0 ± 8.8, p < 0.001). A significant, direct correlation between IELs and duodenal expression of IFNγ was found (r = 0.36, p = 0.04). Conclusions: IBS with DL showed higher expression of inflammatory markers than controls, but DQ2-8 haplotype did not seem to affect their expression. Smoking might increase IELs infiltration.
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Sibon, David, Georgia Malamut, Virginie Verkarre, et al. "Enteropathy-Associated T-Cell Lymphoma Type I, But Not Refractory Celiac Disease, Strongly Expresses CD30 and Might Benefit From Brentuximab Vedotin." Blood 122, no. 21 (2013): 4252. http://dx.doi.org/10.1182/blood.v122.21.4252.4252.
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Abstract Introduction Enteropathy-associated T-cell lymphoma (EATL) is an intestinal tumor of intraepithelial T lymphocytes. The 2008 WHO classification distinguishes two types of EATL: the first type of EATL (type I), the most frequent (80-90%) is strongly associated with celiac disease (CD) and the HLA-DQ2/DQ8 haplotypes. The tumor cells are CD3+CD8-/+CD4-CD56- and contain cytotoxic granules. In almost all cases, a varying proportion of the tumor cells express CD30. The second type of EATL (type II), the monomorphic form, has a distinct immunophenotype (CD3+CD4-CD8+CD56+). In two types, TCRgamma genes are often clonally rearranged. EATL may be preceded by refractory celiac disease (RCD), corresponding to CD refractory to gluten free diet (GFD). RCD is divided in two types based on the absence (type I) or presence (type II) of abnormal intraepithelial lymphocytes (IEL) showing down-regulation of CD8 and often TCRgamma genes rearrangement. RCD II is now considered as a small cell intraepithelial T-cell lymphoma that could be an intermediate stage between CD and EATL. The aim of the present study was to establish the pattern of CD30 expression in EATL. This could have therapeutic implications with the use of anti-CD30 monoclonal antibody like brentuximab vedotin (BV). Methods Consecutive adult patients (pts) diagnosed with EATL between 2007 and 2013 in two university hospitals in Paris (Necker University Hospital and Georges Pompidou European Hospital) were eligible for this study. Diagnosis was confirmed after histopathologic and immunohistochemical review. For the purpose of the present study, two expert hematopathologists (V.V. and N.B.) reviewed all EATL and extended the phenotypic analysis to reclassify them according to the 2008 WHO classification. A panel of antibodies directed against CD20, CD3, CD4, CD5, CD8, CD56, granzyme B and ALK1 was used. CD30 staining was performed with Monoclonal Mouse Anti-Human CD30, Clone Ber-H2 (Dako). Consecutive RCDI and RCDII cases with complete phenotype and clonality analyses diagnosed in the same period were used as control. Diagnosis of CD was based on HLA-DQ2/8 typing, detection of celiac specific antibodies and of villous atrophy with increased counts of IEL on normal diet. Pts were further classified in RCDI or II depending on their clinical and histological response to a GFD and the presence of abnormal IEL. Results Twenty five adults were diagnosed with EATL on consensus review (median age 53 years [range 34-76], M/F ratio 12/13). Twenty five RCDI pts (median age 51 years [range 16-75], M/F ratio 6/19) and 20 RCDII pts (median age 62 years [range 29-81], M/F ratio 7/13) were used as control. A clinical history of CD was found in 17/20 (85%) evaluable EATL pts. Histological features of CD/RCD were seen in all cases (20/20) of EATL in which the mucosa adjacent to the tumor could be investigated (half of these were RCDII). Primary sites of EATL were small intestine (20/25), mesenteric lymph nodes (3/25), peritoneal nodules (1/25) and spleen (1/25). Phenotypic analysis showed that EATL cases were all WHO type I (25/25). ALK1 was constantly negative. IEL were CD3+ in all 70 cases. CD8 was normally expressed in all RCDI IEL and downregulated in all RCDII IEL and 35% of EATL. In all cases of EATL (25/25), CD30 was strongly expressed by all large tumor cells. In RCDI and II, CD30 was negative in most cases (∼90%), and was rarely expressed by dispersed atypical lymphocytes (IEL or in lamina propria) in some cases. TCRgamma genes were clonally rearranged in 11/14 (79%) EATL, 3/25 (12%) RCDI and 18/20 (90%) RCDII. Based on these results, we initiated in 2012 a pilot study combining BV with chemotherapy followed by autologous stem-cell transplantation (ASCT) as frontline treatment of EATL. Five pts have currently been treated. The associated chemotherapy regimen was IVE/MTX (Sieniawski M, Blood 2010) for the first two pts. After presentation at ASH 2012 Annual Meeting of preliminary results of a phase 1 study combining BV with CHP regimen as frontline treatment of systemic ALCL and other CD30-positive mature T–cell and NK–cell lymphomas (Fanale MA, Abstract #60), we replaced IVE/MTX by CHP regimen, and treated 3 other pts. The treatment was well tolerated, and the 5 pts reached CR and underwent ASCT. Conclusion CD30 is strongly expressed in EATL type I. Promising results of the combination of BV with CHP led us to plan a phase 2 study of BV and CHP followed by ASCT as frontline treatment of EATL. Disclosures: Off Label Use: Brentuximab vedotin was used in enteropathy-associated T-cell lymphoma (EATL).
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Verhagen, Johan, Norkhairin Yusuf, Emma L. Smith, et al. "Proinsulin peptide promotes autoimmune diabetes in a novel HLA-DR3-DQ2-transgenic murine model of spontaneous disease." Diabetologia 62, no. 12 (2019): 2252–61. http://dx.doi.org/10.1007/s00125-019-04994-8.
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Abstract Aims/hypothesis The molecular basis for the pathological impact of specific HLA molecules on autoimmune diseases such as type 1 diabetes remains unclear. Recent natural history studies in children have indicated a link between specific HLA genotypes and the first antigenic target against which immune responses develop. We set out to examine this link in vivo by exploring the diabetogenicity of islet antigens on the background of a common diabetes-associated HLA haplotype. Methods We generated a novel HLA-transgenic mouse model that expresses high-risk genes for type 1 diabetes (DRB1*03:01-DQA1*05:01-DQB1*02:01) as well as human CD80 under the rat insulin promoter and human CD4, on a C57BL/6 background. Adjuvanted antigen priming was used to reveal the diabetogenicity of candidate antigens and peptides. Results HLA-DR3-DQ2+huCD4+IA/IE−/−RIP.B7.1+ mice spontaneously developed autoimmune diabetes (incidence 46% by 35 weeks of age), accompanied by numerous hallmarks of human type 1 diabetes (autoantibodies against GAD65 and proinsulin; pancreatic islet infiltration by CD4+, CD8+ B220+, CD11b+ and CD11c+ immune cells). Disease was markedly accelerated and had deeper penetrance after adjuvanted antigen priming with proinsulin (mean onset 11 weeks and incidence 100% by 20 weeks post challenge). Moreover, the diabetogenic effect of proinsulin located to the 15-residue B29-C11 region. Conclusions/interpretation Our study identifies a proinsulin-derived peptide region that is highly diabetogenic on the HLA-DR3-DQ2 background using an in vivo model. This approach and the peptide region identified may have wider implications for future studies of human type 1 diabetes.
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Lim, D. R., D. Farina, W. Huang, and J. Zhu. "A181 ENDOSCOPIC BALLOON DILATION IS EFFECTIVE AND SAFE IN THE MANAGEMENT OF NSAID-INDUCED NON-ULCERATIVE GASTRIC OUTLET OBSTRUCTION." Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (2020): 48–50. http://dx.doi.org/10.1093/jcag/gwz047.180.
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Abstract Background We describe an unusual case of NSAID-induced gastric outlet obstruction (GOO) in the absence of malignancy or ulcers. This was successfully managed conservatively with drug withdrawal and serial endoscopic balloon dilation (EBD). Aims Case Report Methods Case Report and Literature Review Results A 58-year-old woman with 20-year history of daily Ketorolac use for osteoarthritis presented with iron deficiency anemia (IDA) of 58 g/L and post-prandial emesis for 2 months. There was no overt GI bleeding. Gastroscopy revealed severe erosive esophagitis and GOO with no ulcers. After a negative CT imaging ruled out extrinsic malignant compression, GOO was managed with EBD. Examination of the duodenum post-EBD revealed complete atrophy and scalloping. Focused biopsies reveal chronic gastritis, complete villous atrophy in the duodenum; ruled out H. Pylori, celiac disease, amyloidosis and dysplasia. EUS negative for infiltrative disease or regional adenopathy. Vitamin B12, anti-TTG I IgA, HLA DQ2/8 were normal. These findings made drug-induced enteropathy the top contender. PPI therapy was initiated and NSAID discontinued. Five serial EBD were performed over 4 months to 18mm. A pureed diet was tolerated after 2 dilations. Follow-up at 3 months showed partial recovery of enteropathy and pyloric stenosis. No adverse events were seen. The severe esophagitis was likely an erosive process secondary to reflux from GOO. Her IDA is likely multifactorial: Severe enteropathy and GOO may have led to chronic malabsorption; occult GI bleeding from erosions or ulcers that have healed may further contribute. Ketorolac could explain the enteropathy. COX-1 inhibition leads to decreased gastric cytoprotection. In rat models, COX-2 inhibition has been suggested to delay gastric healing and dysregulated immune response to food antigens in the small bowel [4–6]. NSAID-induced GOO almost always occur in the context of peptic ulcer disease [1,2]. A similar case [3] found pyloric stenosis in a 75-year old woman with esophagitis and ulcer-induced pyloric stenosis. They postulate that post ulcerative healing led to benign pyloric stenosis and explained the absence of ulcers. Historically, surgical intervention and stent placement have played a major role in the management of benign mechanical GOO. EBD has replaced surgical intervention as first line therapy [7] showing promising results beyond 3 months post EBD[8], sparing patients from surgery related morbidity. An algorithm has been suggested by us [Img 1] for the management of benign GOO. Conclusions We present an unusual case of NSAID-induced mechanical GOO and enteropathy. This case highlights these entities as rare but serious complications of chronic NSAID use. Management of benign mechanical GOO should be individualized. Prudence with prescribing NSAIDs to at risk populations is recommended. Funding Agencies None
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Ciccocioppo, R., A. Finamore, E. Mengheri, et al. "Tissue transglutaminase-specific HLA-DQ2 restricted T cell clones from peripheral blood of patients with coeliac disease." Digestive and Liver Disease 38 (April 2006): S76—S77. http://dx.doi.org/10.1016/s1590-8658(06)80200-8.
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Stepniak, Dariusz, L. Willemijn Vader, Yvonne Kooy, et al. "T-cell recognition of HLA-DQ2-bound gluten peptides can be influenced by an N-terminal proline at p-1." Immunogenetics 57, no. 1-2 (2005): 8–15. http://dx.doi.org/10.1007/s00251-005-0780-8.
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Viken, Helge D., Gunnar Paulsen, Sheila Drover, et al. "Influence on antibody recognition of amino acid substitutions in the cleft of HLA-DQ2 molecules suggestive evidence of peptide-dependent epitopes." Human Immunology 44, no. 2 (1995): 63–69. http://dx.doi.org/10.1016/0198-8859(95)00047-8.
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Weets, I., L. Kaufman, B. Van der Auwera, et al. "Seasonality in clinical onset of Type 1 diabetes in Belgian patients above the age of 10 is restricted to HLA-DQ2/DQ8-negative males, which explains the male to female excess in incidence." Diabetologia 47, no. 4 (2004): 614–21. http://dx.doi.org/10.1007/s00125-004-1369-8.
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Boucher, B. J. "?to: Weets I, Kaufman L, Van der Auwera B et al. (2004) Seasonality in clinical onset of Type 1 diabetes in Belgian patients above the age of 10 is restricted to HLA-DQ2/DQ8-negative males, which explains the male to female excess in incidence. Diabetologia 47:614?621." Diabetologia 47, no. 10 (2004): 1858. http://dx.doi.org/10.1007/s00125-004-1539-8.
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Murillo Saviano, José Alfredo, Willian Piedra Carvajal, Daniela Sequeira Calderón, Ellen Sylvie Sánchez Más, and Daniel Sandoval Loría. "Generalidades de Enfermedad Celiaca y abordaje diagnóstico." Revista Clínica Escuela de Medicina UCR-HSJD 9, no. 1 (2019). http://dx.doi.org/10.15517/rc_ucr-hsjd.v9i1.37367.
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 La enfermedad celiaca (EC), es una intolerancia permanente al gluten, con una prevalencia del 1%, la cual aumenta en personas con enfermedades autoinmunes, cromosomopatías, o familiares en primer grado con EC. Clínicamente puede cursar desde asintomática, hasta producir un síndrome de malabsorción florido con síntomas gastrointestinales y extra gastrointestinales, con afectación del estado nutricional. El diagnóstico se realiza basándose en la sospecha clínica, pruebas serológicas, estudios genéticos (HLA DQ2/8) y el Gold standar para el diagnóstico, el cual es la biopsia duodenal. El tratamiento una vez confirmado el diagnóstico, es mantener una dieta libre de gluten de por vida.
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Murillo Saviano, José Alfredo, Willian Piedra Carvajal, Daniela Sequeira Calderón, Ellen Sylvie Sánchez Más, and Daniel Andrés Sandoval Loría. "Generalidades de Enfermedad Celiaca y abordaje diagnóstico." Revista Clínica Escuela de Medicina UCR-HSJD 9, no. 2 (2019). http://dx.doi.org/10.15517/rc_ucr-hsjd.v9i2.37380.
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 La enfermedad celiaca (EC), es una intolerancia permanente al gluten, con una prevalencia del 1%, la cual aumenta en personas con enfermedades autoinmunes, cromosomopatías, o familiares en primer grado con EC. Clínicamente puede cursar desde asintomática, hasta producir un síndrome de malabsorción florido con síntomas gastrointestinales y extra gastrointestinales, con afectación del estado nutricional. El diagnóstico se realiza basándose en la sospecha clínica, pruebas serológicas, estudios genéticos (HLA DQ2/8) y el Gold standar para el diagnóstico, el cual es la biopsia duodenal. El tratamiento una vez confirmado el diagnóstico, es mantener una dieta libre de gluten de por vida.
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Muñiz-Castrillo, Sergio, Julien Jacques Hedou, Aditya Ambati, et al. "Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis." Brain, April 12, 2021. http://dx.doi.org/10.1093/brain/awab153.
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Abstract Limbic encephalitis (LE) with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leukocyte antigen (HLA), and CSF proteomic profiles. Patients with anti-AK5 LE were mostly men (20/26, 76.9%) of median age 66 years old (range 48-94). Predominant symptom was severe episodic amnesia in all patients, frequently associated with depression (17/25, 68.0%). Weight loss, asthenia, and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%), and increased Tau (11/14, 78.6%). Temporal lobe hyper-intensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably toward a severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with highest titres in nine CSF-serum paired samples. Temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T-cells, intense granzyme B expression, and abundant macrophages/microglia. HLA analysis in 11 patients showed a striking association with HLA-B*08:01 (7/11, 63.6%; OR = 13.4, 95% CI [3.8-47.4]), C*07:01 (8/11, 72.7%; OR = 11.0, 95% CI [2.9-42.5]), DRB1*03:01 (8/11, 72.7%; OR = 14.4, 95% CI [3.7-55.7]), DQB1*02:01 (8/11, 72.7%; OR = 13.5, 95% CI [3.5-52.0]), and DQA1*05:01 (8/11, 72.7%; OR = 14.4, 95% CI [3.7-55.7]) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR = 16.5, 95% CI [4.8-57.1]). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 controls and 10 cases with other more common non-paraneoplastic LE (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed, respectively, 31 and seven significantly up-regulated proteins in anti-AK5 LE, mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 LE result from a distinct T-cell mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy.
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Hughes, Michael S., Massimo Pietropaolo, Madhuri M. Vasudevan, Marco Marcelli, and Ha Nguyen. "Checking the Checkpoint Inhibitors: A Case of Autoimmune Diabetes After PD-1 Inhibition in a Patient with HIV." Journal of the Endocrine Society 4, no. 12 (2020). http://dx.doi.org/10.1210/jendso/bvaa150.
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Abstract Immune checkpoint inhibitor–associated diabetes mellitus (ICI-DM) is a known immune-related adverse event (irAE) following treatment with programmed cell death protein 1 (PD-1), with a reported 0.9% incidence. We hereby present the first case, to our knowledge, of ICI-DM following ICI use in a human immunodeficiency virus (HIV) patient. In this case, a 48-year-old man with HIV stable on highly active antiretroviral therapy (HAART) was diagnosed with Hodgkin lymphoma and initiated treatment with the PD-1 inhibitor nivolumab. His lymphoma achieved complete response after 5 months. However, at month 8, he reported sudden polydipsia and polyuria. Labs revealed a glucose level of 764 mg/dL and glycated hemoglobin A1c (HbA1c) of 7.1%. Low C-peptide and elevated glutamic acid decarboxylase 65 (GAD65) antibody levels confirmed autoimmune DM, and he was started on insulin. Major histocompatibility complex class II genetic analysis revealed homozygous HLA DRB1*03-DQA1*0501-DQB1*02 (DR3-DQ2), which is a known primary driver of genetic susceptibility to type 1 DM. Autoimmune DM has been reported as an ICI-associated irAE. However, patients with immunocompromising conditions such as HIV are usually excluded from ICI trials. Therefore, little is known about such irAEs in this population. In this case, risk of ICI-DM as an irAE was likely increased by several factors including family history, a high-risk genetic profile, islet-related immunologic abnormalities, active lymphoma, and HIV infection with a possible immune reconstitution event. Clinicians should maintain a high index of suspicion for development of irAEs associated with ICI, particularly as use of these therapies broadens. Thorough investigation for presence of higher-risk features should be conducted and may warrant inclusion of pre-therapy genetic and/or autoantibody screening.
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"Molecular modeling studies of the peptide binding groove of HLA-DQ2 and DQ6 (DQB1 *0603) associated with myasthenia gravis (MG)." Human Immunology 49 (January 1996): 17. http://dx.doi.org/10.1016/s0198-8859(96)89936-8.
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