HLA-DQ Research Articles

FRI271 A Case Of Autoimmune Polyglandular Syndrome Type 2 Presenting With Cardiac Symptoms

Abstract Disclosure: J. Lin: None. C. Lee: None. A.R. Crawford: None. C. Taub: None. Autoimmune polyglandular syndrome type 2 (APS 2) is characterized by the combination of autoimmune adrenal insufficiency with autoimmune primary hypothyroidism, and/or type 1 diabetes mellitus, as well as other autoimmune conditions. The estimated prevalence is reported to be 1.4-4.5 cases per 100,000 persons. Presenting symptoms are often nonspecific, leading to delayed diagnosis; however, manifestations can sometimes become rapidly life-threatening. Cardiac symptoms, rare but clinically significant, can be the first presentation for APS 2. 34 year old male with history of asthma presents with nausea and chest pain, found to have pericarditis that was complicated by pericardial tamponade and cardiogenic shock requiring emergent pericardiocentesis and mechanical support with veno-arterial extracorporeal membrane oxygenation. Stress dose steroids were given due to concern for fulminant myocarditis. His condition improved with glucocorticoid treatment, but the etiology of his acute decompensation was unclear. He completed the prednisone taper before discharge and was started on amiodarone for atrial flutter. He presented with recurrent symptoms a week later. Cardiac MRI showed pericarditis without myocarditis. PET scan showed pericardial inflammation without evidence of malignancy or vasculitis. Broad infectious workup including viral studies was negative. An extensive biochemical workup showed low serum aldosterone and high renin activity while on prednisone. Autoimmune workup was positive for 21-hydroxylase antibody, thyroid peroxidase antibody, and homozygous for celiac HLA DQ8, suggestive of APS 2. Patient was started on levothyroxine for subclinical hypothyroidism with TSH >20. Interleukin blockade with anakinra was initiated, and patient was discharged with 25mg of daily prednisone pending insurance authorization for anakinra. A month later, patient re-presented with pericarditis. Patient received stress dose steroids, and was started on fludrocortisone. Levothyroxine was stopped because of amiodarone induced thyrotoxicosis. Patient was discharged on a prednisone taper regimen, and anakinra was approved a month later. Few case reports have described the association between APS 2 with pericardial tamponade. In healthy patients presenting with unexplained pericarditis, autoimmunity should be considered as a differential diagnosis as it can rapidly become life-threatening requiring urgent intervention. It is important to recognize for these patients, they are at risk for recurrent pericarditis and cardiac tamponade. Presentation: Friday, June 16, 2023

Is There a Time and a Place for the Gluten-Free Diet in Potential Celiac Disease?

Potential celiac disease (PCD) is characterized by the absence of villous atrophy on duodenal biopsies (Marsh 0 or 1) despite positive celiac serology and HLA DQ2 or DQ8 heterodimers. Recent epidemiological studies report that PCD represents one fifth of the total CD diagnoses. Compared to patients with CD, the majority of adult patients with PCD show lower rates of nutrient deficiencies and extraintestinal symptoms at diagnosis. Recommending a gluten-free diet (GFD) to PCD patients depends on whether they have symptoms or not. A significant clinical improvement is reported by symptomatic patients, but for asymptomatic PCD, diet implementation is still a matter of debate. Some questions remain to be answered: does PCD serve as an intermediary phase leading to the progression of true CD? Is it reasonable to hypothesize that PCD and active CD represent different manifestations of the same condition? Is there a potential for both underdiagnosis and overdiagnosis of CD in those who may have the condition? Additional research is required to address these inquiries and ascertain the specific subset of people with potential progression to overt CD, as well as to determine the potential advantages of early implementation of a GFD for these individuals. The investigation of risk factors in CD warrants examination of variables such as the timing of diagnosis, the genetic profile, the extent of gluten exposure, and the composition of the microbiome.

HLA DQ protein changes the cell surface distribution pattern of HLA proteins as monitored by Förster resonance energy transfer and high-resolution electron microscopy.

Peptide presentation by MHC class I and MHC class II molecules plays important roles in the regulation of the immune response. One factor in these displays is the density of antigen, which must exceed a critical threshold for the effective activation of T cells. Nonrandom distribution of MHC class I and class II has already been detected at the nanometer level and at higher hierarchical levels. It is not clear how the absence and reappearance of some protein molecules can influence the nonrandom distribution. Therefore, we performed experiments on HLA II-deficient bare lymphocyte syndrome (BLS1) cells: we created a stable transfected cell line, tDQ6-BLS-1, and were able to detect the effect of the appearance of HLA-DQ6 molecules on the homo and heteroassociation of different cell surface molecules by comparing Förster resonance energy transfer (FRET) efficiency on transfected cells to that on nontransfected BLS-1 and JY human B-cell lines. Our FRET results show a decrease in homoassociation FRET between HLA I chains in HLA-DQ6-transfected tDQ6-BLS-1 cells compared with the parent BLS-1 cell line and an increase in heteroassociation FRET between HLA I and HLA II (compared with JY cells), suggesting a similar pattern of antigen presentation by the HLA-DQ6 allele. Transmission electron microscopy (TEM) revealed that both HLA class I and class II molecules formed clusters at higher hierarchical levels on the tDQ6-BLS-1 cells, and the de novo synthesized HLA DQ molecules did not intersperse with HLA class I islands. These observations could be important in understanding the fine tuning of the immune response.

Association between alleles, haplotypes, and amino acid variations in HLA class II genes and type 1 diabetes in Kuwaiti children.

Type 1 diabetes (T1D) is a complex autoimmune disorder that is highly prevalent globally. The interactions between genetic and environmental factors may trigger T1D in susceptible individuals. HLA genes play a significant role in T1D pathogenesis, and specific haplotypes are associated with an increased risk of developing the disease. Identifying risk haplotypes can greatly improve the genetic scoring for early diagnosis of T1D in difficult to rank subgroups. This study employed next-generation sequencing to evaluate the association between HLA class II alleles, haplotypes, and amino acids and T1D, by recruiting 95 children with T1D and 150 controls in the Kuwaiti population. Significant associations were identified for alleles at the HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci, including DRB1*03:01:01, DQA1*05:01:01, and DQB1*02:01:01, which conferred high risk, and DRB1*11:04:01, DQA1*05:05:01, and DQB1*03:01:01, which were protective. The DRB1*03:01:01~DQA1*05:01:01~DQB1*02:01:01 haplotype was most strongly associated with the risk of developing T1D, while DRB1*11:04-DQA1*05:05-DQB1*03:01 was the only haplotype that rendered protection against T1D. We also identified 66 amino acid positions across the HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes that were significantly associated with T1D, including novel associations. These results validate and extend our knowledge on the associations between HLA genes and T1D in Kuwaiti children. The identified risk alleles, haplotypes, and amino acid variations may influence disease development through effects on HLA structure and function and may allow early intervention via population-based screening efforts.

Unveiling the Etiopathogenic Spectrum of Hypophysitis: A Narrative Review.

Hypophysitis, a rare inflammatory disorder of the pituitary gland, has seen an uptick in reported cases in recent years. Our objective is to summarize the most recent research on the etiopathogenesis, molecular mechanisms, and genetics of both primary and secondary hypophysitis. Primary autoimmune hypophysitis (PAH): During the acute phase of the disease, the pituitary gland in enlarged due to the infiltration of T and B lymphocytes. The chronic phase is characterized by progressive and irreversible pituitary atrophy. APA may play a role in the management, diagnosis, and prognosis of PAH. Specific autoantibodies such as anti-GH, anti-PIT-1, and anti-T-PIT have been found in patients with hypophysitis and hypopituitarism. A recent study suggested that a mechanism of escaping clonal deletion and mounting an immune response against self antigens can explain the unusual nature of the immune response observed in PAH patients. A cytokine array shows the presence of gamma-interferon and interleukin-17. Patients carrying mutations in the PIT1 or PROP1 genes may present PAH. Individuals carrying the HLA DQ8 haplotype are four times more likely to develop PAH. Immune checkpoint inhibitors induce hypophysitis (IIHs): IIHs is an increasingly frequent toxicity of in patients on treatment with inhibitors targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1). ICIs inhibit the CTLA-4 pathway, leading to overactivation of T lymphocytes. The binding of PD-1/PD-L1 suppresses the activity of T cells, promotes the conversion of T-helpers into T-regulatory cells, and activates pro-survival signaling pathways in cancer cells. Cytokines play a crucial role in IIHs. B-cell infiltration has been observed in IIHs, suggesting that antibody-mediated pituitary injury may contribute. Genetic polymorphisms of CTLA-4 and PD-1 genes can increase the risk of IIHs. HLA alleles may also be involved in the onset of IIHs; this HLA association presents a possible alternative mechanistic hypothesis. IIHs may also be linked to a paraneoplastic syndrome triggered by ectopic expression of pituitary specific antigens. SARS-CoV-2-related hypophysitis: Recently, the literature has reported occurrences of hypophysitis associated with the SARS-CoV-2 virus; long COVID-19 may also present as infundibulo-neuro-hypophysitis. The virus enters the central nervous system because of its distinct interaction with angiotensin-converting enzyme receptors via spike proteins binding the capillary endothelium, and it directly damages the pituitary cells. The effect of SARS-CoV-2 can occur indirectly through inflammation and the release of cytokines. The exact mechanism remains ambiguous. The available data on endocrine complications associated with the SARS-CoV-2 vaccine are scant. Nonetheless, isolated cases of hypophysitis have been documented. Treatment of hypophysitis: Glucocorticoids are the cornerstone in managing primary hypophysitis, given their targeted action on inflammation. A better understanding of the etiopathogenesis and molecular mechanism of hypophysitis can lead to more effective and personalized treatment strategies.

The Combined Effect of Infant and Mother Secretor Status on Infant Susceptibility to Viral Gastroenteritis and Celiac Disease

Celiac disease is a prevalent autoimmune disorder with a rising incidence of 7.5% annually during the second half of the 20<sup>th</sup> century and the 21<sup>st</sup> century. Not all genetically susceptible individuals that carry the risk alleles HLA DQ2 and DQ8 go on to develop celiac disease, suggesting that there may be other environmental triggers that contribute to the development of celiac disease in genetically susceptible individuals. Gastroenteritis during infancy has been shown to be associated with increased risk of celiac disease. Secretor status, per the FUT2 genotype, and subsequent alterations in the microbiota, is associated with risk of gastroenteritis in infants. This review investigates the literature from January 2010 to June 2022 to determine the combined effect of secretor status and viral gastroenteritis on the development of celiac disease.<strong> </strong>Mothers with the secretor phenotype and infants with the non-secretor phenotype provided the most protection against particular strains of gastroenteritis and celiac disease. Both the maternal and infant secretor status, as well as the infant’s Lewis status and ABO blood group can influence the infant’s susceptibility to different viral strains, which cause gastroenteritis. Gastroenteritis caused by viral infections can damage intestinal epithelial cells, cause dysbiosis, and affect pro-inflammatory cytokines, which exacerbate celiac disease onset. Understanding the effect of secretor status and gastroenteritis on celiac disease may provide a novel approach to early screening and preventative strategies to reduce risk factors that contribute to the onset of celiac disease.

Celiac disease in children - diagnosis in light of the current 2020 ESPGHAN guidelines

Celiac disease is a chronic immune disorder of the small intestine that is triggered by the consumption of gluten in genetically predisposed individuals. The disease is difficult to diagnose and treat, and its incidence is increasing. It can have different symptoms and clinical manifestations in individuals. Diagnosis is usually based on the presence of specific antibodies and histopathological examination of biopsy specimens from the small intestine. The only effective treatment is a gluten-free diet for life. Diagnosis of celiac disease in children is mainly based on the presence of specific an- tibodies in the blood, such as antibodies to tissue transglutaminase (tTG), antibodies to endomysium (EMA) or deamidated gliadin peptides (DGP). In addition, genetic testing is also used in diagnosis to detect the presence of HLA DQ2 or DQ8 genes, which are often present in people with celiac disease. The final diagnosis of celiac disease is based on a combination of the results of these tests and the presence of characteristic lesions in the small intestine, which are detected during endoscopy and small bowel biopsy.

Antibody Profile, Gene Expression and Serum Cytokines in At-Risk Infants before the Onset of Celiac Disease

Immunological events that precede the development of villous atrophy in celiac disease (CeD) are still not completely understood. We aimed to explore CeD-associated antibody production (anti-native gliadin (AGA), anti-deamidated gliadin (DGP) and anti-tissue transglutaminase (anti-tTG)) in infants at genetic risk for CeD from the Italian cohorts of the PREVENT-CD and Neocel projects, as well as the relationship between antibody production and systemic inflammation. HLA DQ2 and/or DQ8 infants from families with a CeD case were followed from birth. Out of 220 at-risk children, 182 had not developed CeD by 6 years of age (CTRLs), and 38 developed celiac disease (CeD). The profiles of serum cytokines (INFγ, IL1β, IL2, IL4, IL6, IL10, IL12p70, IL17A and TNFα) and the expression of selected genes (FoxP3, IL10, TGFβ, INFγ, IL4 and IL2) were evaluated in 46 children (20 CeD and 26 CTRLs). Among the 182 healthy CTRLs, 28 (15.3%) produced high levels of AGA-IgA (AGA+CTRLs), and none developed anti-tTG-IgA or DGP-IgA, compared to 2/38 (5.3%) CeD infants (Chi Sq. 5.97, p = 0.0014). AGAs appeared earlier in CTRLs than in those who developed CeD (19 vs. 28 months). Additionally, the production of AGAs in CeD overlapped with the production of DGP and anti-tTG. In addition, gene expression as well as serum cytokine levels discriminated children who developed CeD from CTRLs. In conclusion, these findings suggest that the early and isolated production of AGA-IgA antibodies is a CeD-tolerogenic marker and that changes in gene expression and cytokine patterns precede the appearance of anti-tTG antibodies.

"Geographical distribution of risk genotypes in pediatric patients with celiac disease in Spain".

Celiac disease is strongly associated with HLA DQ, specifically with haplotypes. DRB1*03-DQA1*05:01/DQB1*02:01 (DQ2.5),DRB1*07-DQA1*02:01/DQB1*02:02 (DQ2.2), DRB1*11-DQA1*05:05/DQB1*03:01 (DQ7.5), and DRB1*04-DQA1*03:01/DQB1*03:02 (DQ8). The distribution of these risk haplotypes in patients with celiac disease is different in the geographical areas investigated. A high frequency of DRB1*07- DQA1*02:01/DQB1*02:02 (DQ2.2) and DRB1*11-DQA1*05:05/DQB1*03:01 (DQ7.5), has been described in Southern Europe. We analyzed 2102 confirmed CD cases with information on both DQB1* alelles and their distribution by geographical area in Spain. According to the presence of this haplotype in one or two chromosomes, the genotype is classified in: DQ2 homozygous, DQ2 heterozygous (cis or trans), DQ8 homozygous, DQ8/DQ2.5, DQ 2.2 homozygous and genotype known as "half DQ2". Two different patterns of risks related to CD were identified. In the Basque Country and Navarre, the Mediterranean Area (Aragon, Catalonia, Valencia, Balearic Islands, and Murcia), the South of Spain (Andalucía and Extremadura), and the Canary Islands, higher frequency of DQ2.5 trans, and more than 80% of DQ2.5/DQ2.2 homozygosis were described. The Cantabrian Coast (Cantabria, Asturias, and Galicia) and Central Areas (Castilla-León and Castilla-La Mancha) showed a higher percentage of DQ2.5/DQ2.5 homozygosis and a lower DQ2.5 in trans frequency, as in Northern Europe. Madrid has an intermediate model between the two described above. 17 cases (0.8%) did not carry any CD risk haplotypes.

Diagnostic challenges in children with celiac disease. A five-year experience with new guidelines in a General Pediatrics Department

Background. The clinical characteristics of patients with celiac disease cover a wide range of signs and symptoms. Our study aimed to describe the main clinical features and investigations performed on our celiac patients diagnosed in the past five years. Material and methods. We collected data from medical records of patients aged 0 to 18 years diagnosed with celiac disease. We included in the analysis patients newly diagnosed with celiac disease, in our department, between January 2017 and August 2022. Results. In this period, 30 children were diagnosed with celiac disease in our general pediatrics department. The mean age at diagnosis ± standard deviation was 6.3±4.2 years (median age=4.3 years). The period between onset of symptoms ranged between 3 months to 5 years (median=6 months). Twenty children (66%) had features of classical celiac disease. Thirteen/30 patients (43.3%) were found to have iron deficiency anemia at diagnosis. In 23/30 (76%) of the children, the values of the IgA-TGA were more than 10 times the upper limit of the normal values. Nineteen children were diagnosed between 2017 and 2019. Fifteen of these 19 patients (79%) were diagnosed based on positive levels of antibodies and duodenal biopsy samples showing Marsh 2 or 3 features, and 4/19 (21%) based on positive IgA-TGA and AEM and a genetic test showing HLA DQ2 and/or DQ8. Conclusions. Classical celiac disease remains the predominant phenotype in our patients. Adherence to new guidelines allowed in the past 2 years a diagnosis without histological examination of biopsy fragments in most of the patients.

HLA DQ2 and HLA DQ8 genetic evaluation in children with Type 1 Diabetes Mellitus and Celiac Disease

Objective: Celiac disease (CD) is an autoimmune disease, and other autoimmune diseases co-existence is very high, like type 1 diabetes mellitus (T1DM). Our study aimed to determine the genetic structure of HLADQ2 and HLADQ8 in pediatric patients with T1DM and CD. Materials and Methods: Our study was conducted retrospectively in patients aged 1-18 years with CD and T1DM, who were followed up in the Pediatric Endocrinology Outpatient Clinic in Adana, Turkey. Results: A total of 876 patient records with a T1DM diagnosis were reviewed, and the genetic testing of 41 patients with CD and T1DM was evaluated. In 27 of these 41 patients, genetic analysis was performed by the same method and could be evaluated. Of the cases, 12 (44.4%) were female and 15 (55.6%) were male. The mean follow-up duration for the patients was 3.12 ± 1.75 years. The current age of the patients was 12.7± 3.71 years. While 7 (25.9 %) patients were symptomatic, 20 (74.1%) patients were asymptomatic when diagnosed with CD. The highest rates of HLA DQ2 and HLA DQ8 were found in patients with T1DM and CD. Conclusion: In this study, we investigated, for the first time in our country, the HLA characteristics and clinical findings of a group of pediatric patients with both type 1 diabetes mellitus (T1DM) and celiac disease (CD). The rate of patients with HLA-DQA1* 05-DQB1 * 02-DQB1 *03:02 co-existence (HLA DQ2 and DQ8 co-positivity) was found to be as high as 40.7%, and this carrier was thought to be the riskiest group for T1DM and CD co-existence.

A19 INVESTIGATING MECHANISMS THAT DRIVE SYMPTOMS IN IRRITABLE BOWEL SYNDROME PATIENTS WITH PERCEIVED GLUTEN SENSITIVITY

Abstract Background Patients with irritable bowel syndrome (IBS) often report gastrointestinal symptoms after consuming wheat and gluten-containing foods. It is, however, unclear whether gluten is the main driver of symptoms, as other immunogenic peptides, such as amylase trypsin inhibitors (ATI), poorly digestible fiber (inulin, part of FODMAP) or even the nocebo effect may contribute to symptom generation. Purpose To evaluate whether whole wheat containing ATIs and/or purified gluten trigger gastrointestinal symptoms compared to nocebo in patients with IBS adopting a gluten-free diet (GFD). Method We conducted a double-blind, randomized, nocebo-controlled crossover study in adult IBS patients (Rome IV criteria) who previously perceived improvement of symptoms while on a GFD. The study was approved by the Hamilton Research Ethics Board (HiREB #4367). Participants were challenged for 7 days with whole wheat, purified gluten, and nocebo (gluten-free flour) added to low FODMAP cereal bars. Each challenge was followed by a 2-week washout. Patients remained on a GFD throughout the study, diet adherence was assessed by a dietitian and stool gluten immunogenic peptides (GIP; Biomedal). Gastrointestinal symptoms were assessed by IBS Symptom Severity Score (IBS-SSS); increases >50 points were considered a significant worsening. Blood samples were collected to assess immune markers and celiac (HLA DQ2, DQ8 and DQ7) genotype. Statistical comparisons used Friedman rank sum tests and paired Wilcoxon signed rank tests. Result(s) Twenty-nine IBS patients (27 female, mean age=42, SD=14.4 years) were enrolled in the study; 1 dropped. Similar proportions of patients reacted symptomatically to wheat (11/28, 39.3%), gluten (10/28, 35.7%) and nocebo (8/28, 28.6%). However, there was an overall significant increase in IBS symptoms after wheat (+39.5 on IBS-SSS; p=0.030) but not after gluten (+27.5; p=0.051) or nocebo (+5.5; p=0.236) challenges (Figure 1). Ten participants experienced IBS-SSS symptoms >175 during baseline and did not worsen further during the challenges. TNF-α trended from 1.35 pg/mL after nocebo, 1.47 pg/mL after gluten, to 1.57 pg/mL after wheat; however, this was not significant. Baseline adherence to a GFD was rated excellent in 19 (68%), good in 6 (21%), and fair in 3 (11%) participants. Median GIP levels were 0.584 µg/g after wheat, 0.432 µg/g after gluten, and 0.095 µg/g after nocebo; p<0.0001. Celiac predisposition genes were present in 19/24 participants (10/24 had DQ2, 2/24 had DQ8, and 9/24 had DQ7). Image Conclusion(s) IBS patients self-reporting wheat or gluten sensitivity had worse symptoms after whole wheat, but not purified gluten or nocebo challenge. However, similar proportions of IBS patients reacted to each intervention, suggesting that central mechanisms play an important role in symptom genesis. Furthermore, one third of patients had high symptoms during a GFD and did not react to wheat or gluten challenges, suggesting that other mechanisms are driving their IBS symptoms. Please acknowledge all funding agencies by checking the applicable boxes below CIHR, Other Please indicate your source of funding; Society for the Study of Celiac Disease (Nestle); Canadian Digestive Health Foundation Disclosure of Interest None Declared

Dysregulation of Gene Expression of Key Signaling Mediators in PBMCs from People with Type 2 Diabetes Mellitus.

Diabetes is currently the fifth leading cause of death by disease in the USA. The underlying mechanisms for type 2 Diabetes Mellitus (DM2) and the enhanced susceptibility of such patients to inflammatory disorders and infections remain to be fully defined. We have recently shown that peripheral blood mononuclear cells (PBMCs) from non-diabetic people upregulate expression of inflammatory genes in response to proteasome modulators, such as bacterial lipopolysaccharide (LPS) and soybean lectin (LEC); in contrast, resveratrol (RES) downregulates this response. We hypothesized that LPS and LEC will also elicit a similar upregulation of gene expression of key signaling mediators in (PBMCs) from people with type 2 diabetes (PwD2, with chronic inflammation) ex vivo. Unexpectedly, using next generation sequencing (NGS), we show for the first time, that PBMCs from PwD2 failed to elicit a robust LPS- and LEC-induced gene expression of proteasome subunit LMP7 (PSMB8) and mediators of T cell signaling that were observed in non-diabetic controls. These repressed genes included: PSMB8, PSMB9, interferon-γ, interferon-λ, signal-transducer-and-activator-of-transcription-1 (STAT1), human leukocyte antigen (HLA DQB1, HLA DQA1) molecules, interleukin 12A, tumor necrosis factor-α, transporter associated with antigen processing 1 (TAP1), and several others, which showed a markedly weak upregulation with toxins in PBMCs from PwD2, as compared to those from non-diabetics. Resveratrol (proteasome inhibitor) further downregulated the gene expression of these inflammatory mediators in PBMCs from PwD2. These results might explain why PwD2 may be susceptible to infectious disease. LPS and toxins may be leading to inflammation, insulin resistance, and thus, metabolic changes in the host cells.

A Genome-Wide Association Study Identified Novel Genetic Susceptibility Loci for Oral Cancer in Taiwan.

Taiwan has the highest incidence rate of oral cancer in the world. Although oral cancer is mostly an environmentally induced cancer, genetic factors also play an important role in its etiology. Genome-wide association studies (GWAS) have identified nine susceptibility regions for oral cancers in populations of European descent. In this study, we performed the first GWAS of oral cancer in Taiwan with 1529 cases and 44,572 controls. We confirmed two previously reported loci on the 6p21.33 (HLA-B) and 6p21.32 (HLA-DQ gene cluster) loci, highlighting the importance of the human leukocyte antigen and, hence, the immunologic mechanisms in oral carcinogenesis. The TERT-CLMPT1L locus on 5p15.33, the 4q23 ADH1B locus, and the LAMC3 locus on 9q34.12 were also consistent in the Taiwanese. We found two new independent loci on 6p21.32, rs401775 in SKIV2L gene and rs9267798 in TNXB gene. We also found two suggestive novel Taiwanese-specific loci near the TPRS1 gene on 8q23.3 and in the TMED3 gene on 15q25.1. This study identified both common and unique oral cancer susceptibility loci in the Taiwanese as compared to populations of European descent and shed significant light on the etiology of oral cancer in Taiwan.

P627 HLA DQA1*05 was not associated to primary non-response or loss of response to first anti-TNF in real world Inflammatory Bowel Disease patients.

Abstract Background Biologics have been a breakthrough in the management of patients with inflammatory bowel disease (IBD). However, we lack predictors of response to these drugs. A recent study has shown a significant association between HLA DQA*105 mutations and the development of loss of response to anti-TNF mediated by immunogenicity. The high quality of the study and the wide differences found, have led to its quick practical implementation in the choice of biological agent. However, the supporting evidence is limited in clinical practice. Methods Retrospective cohort study, carried out at the Miguel Servet Hospital, Zaragoza, Spain. We included IBD patients who had received anti-TNF therapy as first biologic and whose HLA DQA1*05 had been determined. Primary non-response and secondary failure (assessed by survival analysis) has been evaluated as well as safety outcomes. Results 199 IBD patients [161 (81%) Crohn′s disease (CD) 38 (19%) ulcerative colitis (UC)] were included. 42.4% had HLA DQA1*05 mutation and 60% received combination therapy with immunomodulators at the start of anti-TNF treatment. Median follow-up was 24 months (IQR 11-66). No statistically significant differences were found in primary non-response to anti-TNF (87,8% vs 12,2%, p = 0,825), depending on the presence or absence of HLA mutation. No differences in secondary loss of response according to HLA mutation in any of the analyses performed (full cohort, according to IBD or anti TNF type) were observed (Figure 1). Secondary loss of response has also been assessed according to the use or non-use of concomitant immunomodulator. Again, no differences were observed in this analysis (Figure 2). Multivariate analysis, like the univariate analyses, showed that the presence of the HLA-DQA1*05 mutation was not associated with a higher rate of secondary loss of response or shorter time to failure. In terms of safety, no significant differences were found in the rate of infusion reactions or serious adverse events between carrier and non-carrier patients. Conclusion In our real-life cohort of IBD patients treated for the first time with anti-TNF, the presence of the HLA-DQA1*05 mutation did not act as a predictor of response failure, either primary or secondary. The safety of anti-TNF treatment has also not been influenced by the mutation. More data is needed to incorporate HLA DQA1*05 determination into routine clinical practice as a key factor in individual decision making.

Juvenile Idiopathic Arthritis and Its HLA Association: A Study from Bangladesh

Background: HLA alleles may have association with overall JIA including specific sub-types. Determation of HLA DRB1, DPB1, DQA1, DQB1 and B27, may be helpful to diagnose JIA cases where diagnostic dilemma is present. The aim of the study was to find out the association of HLA alleles with JIA and its subtypes. Methods: This cross sectional study was conducted in the department of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, from April 2020 to March 2021. A total of 50 cases and 25 controls attending pediatric rheumatology clinic and pediatric OPD were enrolled in the study. Data were collected by a pre-designed questionnaire containing socio-demographic, clinical and laboratory parameters. HLA DR-B1, DQ-A1, DQ-B1 and B27 typing were done for the cases and controls from blood samples by polymerase chain reaction sequence specific primer (PCR-SSP) method. Data were analyzed by SPSS version 26. Frequency, percentage, chi square test and Fisher exact tests were done for statistical analysis. Results: HLA DR-B1_10 had significant positive association whereas HLA DR-B1_03 and B1_16 had negative association with overall JIA cases. Poly-articular JIA, oligo-articular JIA and ERA had association with HLA DRB1_01, B1_08 and B1_12 respectively. HLA DQA1-01 and A1_02 had positive association. However, DQ-A1_06 was negatively associated with JIA cases. Oligo JIA was positively associated with HLA DQ-A1_01, whereas poly JIA and ERA had association with A1_02. Though, HLA DQ_B1 had no association with overall JIA cases, analysis showed association of poly JIA with DQ-B1_04. Frequency of HLA DQ-B1_02 and 03 were higher among ERA cases, though not significant, but they had strong association with HLA B27. Conclusion: HLA associations were present with overall JIA and each sub-groups had different patterns of HLA associations including some protective roles.

Bone mineral density in Iranian children with celiac disease.

The current study aims to evaluate bone mineral density (BMD) in patients with celiac disease who were referred to the celiac clinic of Shahid Rahimi Hospital in Khorramabad, Iran, in 2020. Extraintestinal presentations of celiac disease are widespread and, if neglected, can be devastating. Osteoporosis, one of the extraintestinal manifestations of celiac disease, often remains undiagnosed until advanced stages and can impose a significant burden on patients with celiac and health systems. Nonetheless, the prevalence and characteristics of osteoporosis in celiac disease are unknown in Iran. This was a cross-sectional study at the celiac clinic of Shahid Rahimi Hospital in Khorramabad, Iran. Participants were 48 patients under 18 years diagnosed with Marsh II and Marsh III stages of celiac disease (who need to be on a gluten-free diet) at the pediatrics celiac clinic in 2020. All patients were recruited, completed a questionnaire, and had their blood biochemical parameters analyzed. Then their bone mineral density (BMD) was measured through dual-energy x-ray absorptiometry at the Asia Imaging Center in Khorramabad under the supervision of a radiologist and pediatric rheumatologist. The mean age of the children was 9.96±3.17 years. The minimum and maximum ages of the participants were 4 and 17 years, respectively. Of all 48 children who were included (48), 34 (70.8%) were female, and 14 (29.2%) were male. In the femoral region bone densitometry, 35.4% were normal, 41.7% had lower limit normal, and 22.9% had low bone density. In the lumbar region, 39.6% were normal, 25% were Lower limit normal, and 35.4% had low bone density. No significant correlation was found between age, sex, place of residence, Marsh stage, gluten-free diet, and bone densitometry in both lumbar and femoral regions. Nonetheless, we detected a statistically significant relationship between bone density in the lumbar region and two HLA types, namely HLA DQ8 and HLA DQ2/8 (P=0.016). The results of the current study provided further evidence that all children with advanced celiac disease should be screened for metabolic bone diseases. Besides those in Marsh II and Marsh III, patients in Marsh I stage should also be investigated for low bone mineral density.

What is the incidence of celiac disease in patients with microscopic colitis? Why are these two diseases related?

Although there are studies in the literature showing that celiac disease (CD) is more common in patients with microscopic colitis (MC), there are publications to the contrary. The pathophysiologies of both diseases are different from each other. To investigate the frequency of CD in MC patients, the different features of these 2 diseases, and the relationship between them. In our prospective and cross-sectional analytical study, the presence of CD was investigated in 90 patients diagnosed with MC by colonoscopy and biopsy due to chronic diarrhoea between September 2011 and December 2021. We detected MC in 102 (9.3%) of 1096 patients investigated for chronic diarrhoea. We detected CD in 1 (1.1%) of 90 patients with MC who participated in the study. Only 10% of the patients were positive for AGA IgA, 3.3% for EMA IgA, and 2.2% for Anti-TG2 IgA. There was no difference in autoantibody titre in treatment-responsive and treatment-resistant MC patients. HLA DQ2 was positive in 32.2% (n = 29) of the MC patients, and HLA DQ8 was found in 5.5% (n = 5). Intraepithelial lymphocyte increase was remarkable in the duodenal biopsies of MC patients who did not respond to treatment (40% vs. 11.4%; p = 0.007). We did not reach the conclusion that CD is more common in MC patients. An increase in IEL may also occur in the small intestine in patients with MC who do not respond to treatment.

Retracted: Study on the Relationship between Unexplained Recurrent Abortion and HLA-DQ Gene Polymorphism.

[This retracts the article DOI: 10.1155/2022/8005538.].

Gluten-sensitive enteropathy

Gluten sensitive enteropathy also known as Celiac disease, an autoimmune disorder which occurs in the presence of HLA DQ2 & HLA DQ8 gene in genetically susceptible individuals. Homoeopathy can direct the treatment constitutionally and therapeutically. Gliadin a derivative of gluten is modified by TTG which is seen as an antigen to the Antigen presenting cells. The enteropathy can also lead to failure to thrive.