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Arieke S B Kampstra, Jurgen van Heemst, Antonis K Moustakas, George K Papadopoulos, Tom W J Huizinga, René E M Toes
BACKGROUND: Presentation of citrullinated neo-epitopes by HLA-DRB1 molecules that carry the shared epitope (SE) sequence was proposed to explain the association between HLA and seropositive RA. Although it is shown that several HLA-DRB1-SE molecules display enhanced binding affinities for citrullinated ligands, the ability of other HLA molecules to present citrullinated epitopes has not been investigated in a systematic manner. To better understand the HLA-RA connection, we aimed to investigate if the enhanced capacity to present arginine-to-citrulline-converted peptides is unique for HLA-SE alleles...
November 3, 2016: Arthritis Research & Therapy
Isabelle Serr, Rainer W Fürst, Verena B Ott, Martin G Scherm, Alexei Nikolaev, Füsun Gökmen, Stefanie Kälin, Stephanie Zillmer, Melanie Bunk, Benno Weigmann, Nicole Kunschke, Brigitta Loretz, Claus-Michael Lehr, Benedikt Kirchner, Bettina Haase, Michael Pfaffl, Ari Waisman, Richard A Willis, Anette-G Ziegler, Carolin Daniel
Aberrant immune activation mediated by T effector cell populations is pivotal in the onset of autoimmunity in type 1 diabetes (T1D). T follicular helper (TFH) cells are essential in the induction of high-affinity antibodies, and their precursor memory compartment circulates in the blood. The role of TFH precursors in the onset of islet autoimmunity and signaling pathways regulating their differentiation is incompletely understood. Here, we provide direct evidence that during onset of islet autoimmunity, the insulin-specific target T-cell population is enriched with a C-X-C chemokine receptor type 5 (CXCR5)(+)CD4(+) TFH precursor phenotype...
October 25, 2016: Proceedings of the National Academy of Sciences of the United States of America
Janaína Guilhem Muniz, Vera Lucia Sdepanian, Ulysses Fagundes
Background: Celiac disease is a permanent intolerance induced by gluten, which is expressed by T-cell mediated enteropathy, and has a high prevalence in the general population. There is evidence of a strong genetic predisposition to celiac disease. Objective: To determine the prevalence of genetic markers HLA-DQ2 and HLA-DQ8 in blood donors from São Paulo and measure human recombinant tissue transglutaminase antibody IgA class in HLA-DQ2 and HLA-DQ8 positive donors...
October 2016: Arquivos de Gastroenterologia
Jan Petersen, Yvonne Kooy-Winkelaar, Khai Lee Loh, Mai Tran, Jeroen van Bergen, Frits Koning, Jamie Rossjohn, Hugh H Reid
In HLA-DQ8-associated celiac disease, TRAV26-2(+)-TRBV9(+) and TRAV8-3(+)-TRBV6(+) T cells recognize the immunodominant DQ8-glia-α1 epitope, whereupon a non-germline-encoded arginine residue played a key role in binding HLA-DQ8-glia-α1. Whether distinct T cell receptor (TCR) recognition modes exist for gliadin epitopes remains unclear. TCR repertoire analysis revealed populations of HLA-DQ8-glia-α1 and HLA-DQ8.5-glia-γ1 restricted TRAV20(+)-TRBV9(+) T cells that did not possess a non-germline-encoded arginine residue...
October 4, 2016: Structure
Tom van Gils, Tine van de Donk, Gerd Bouma, Foke van Delft, E Andra Neefjes-Borst, Chris J J Mulder
OBJECTIVE: Collagenous sprue (CS) is a rare form of small bowel enteropathy characterised by a thickened basement membrane and is, in most of the literature, reported as part of coeliac disease. Multiple treatment strategies are suggested in CS, but there is no standardised therapy. The aim of this series is to describe 4 cases of CS and to propose thioguanine (6-TG) treatment. DESIGN: We reviewed 4 cases of CS. Data were obtained from our prospective database of patients referred to our coeliac centre...
2016: BMJ Open Gastroenterology
Eric V Marietta, Joseph A Murray, David H Luckey, Patricio R Jeraldo, Abhinav Lamba, Robin Patel, Harvinder S Luthra, Ashutosh Mangalam, Veena Taneja
OBJECTIVE: The gut microbiome regulates host immune homeostasis. Rheumatoid arthritis (RA) is associated with intestinal dysbiosis. This study was undertaken to test the ability of a human gut-derived commensal to modulate immune response and treat arthritis in a humanized mouse model. METHODS: We isolated a commensal bacterium, Prevotella histicola, that is native to the human gut and has systemic immune effects when administered enterally. Arthritis-susceptible HLA-DQ8 mice were immunized with type II collagen and treated with P histicola...
December 2016: Arthritis & Rheumatology
Franca F Kirchberg, Katharina J Werkstetter, Olaf Uhl, Renata Auricchio, Gemma Castillejo, Ilma R Korponay-Szabo, Isabel Polanco, Carmen Ribes-Koninckx, Sabine L Vriezinga, Berthold Koletzko, M Luisa Mearin, Christian Hellmuth
OBJECTIVES AND STUDY: In the development of Celiac Disease (CD) both genetic and environmental factors play a crucial role. The Human Leukocyte Antigen (HLA)-DQ2 and HLA-DQ8 loci are strongly related to the disease and are necessary but not sufficient for the development of CD. Therefore, increasing interest lies in examining the mechanisms of CD onset from the early beginning. Differences in serum and urine metabolic profiles between healthy individuals and CD patients have been reported previously...
August 2016: Journal of Autoimmunity
Celia Escudero-Hernández, Amado Salvador Peña, David Bernardo
Celiac disease is the most common oral intolerance in Western countries. It results from an immune response towards gluten proteins from certain cereals in genetically predisposed individuals (HLA-DQ2 and/or HLA-DQ8). Its pathogenesis involves the adaptive (HLA molecules, transglutaminase 2, dendritic cells, and CD4(+) T-cells) and the innate immunity with an IL-15-mediated response elicited in the intraepithelial compartment. At present, the only treatment is a permanent strict gluten-free diet (GFD). Multidisciplinary studies have provided a deeper insight of the genetic and immunological factors and their interaction with the microbiota in the pathogenesis of the disease...
July 2016: Current Gastroenterology Reports
Sung-Hoon Moon, Jihun Kim, Mi-Young Kim, Do Hyun Park, Tae Jun Song, Sun A Kim, Sang Soo Lee, Dong Wan Seo, Sung Koo Lee, Myung-Hwan Kim
BACKGROUND/AIMS: The aim of this study was to establish a pathogenetic mechanism of pancreatitis in celiac disease and IgG4-related disease using gluten-sensitive human leukocyte antigen (HLA)-DQ8 transgenic mice. METHODS: Transgenic mice expressing HLA-DQ8 genes were utilized. Control mice were not sensitized but were fed gliadin-free rice cereal. Experimental groups consisted of gliadin-sensitized and gliadin-challenged mice; nonsensitized mice with cerulein hyperstimulation; and gliadin-sensitized and gliadinchallenged mice with cerulein hyperstimulation...
September 15, 2016: Gut and Liver
Savvas Polydorides, Eleni Michael, David Mignon, Karen Druart, Georgios Archontis, Thomas Simonson
This chapter describes the organization and use of Proteus, a multitool computational suite for the optimization of protein and ligand conformations and sequences, and the calculation of pK α shifts and relative binding affinities. The software offers the use of several molecular mechanics force fields and solvent models, including two generalized Born variants, and a large range of scoring functions, which can combine protein stability, ligand affinity, and ligand specificity terms, for positive and negative design...
2016: Methods in Molecular Biology
Isabelle Serr, Rainer W Fürst, Peter Achenbach, Martin G Scherm, Füsun Gökmen, Florian Haupt, Eva-Maria Sedlmeier, Annette Knopff, Leonard Shultz, Richard A Willis, Anette-Gabriele Ziegler, Carolin Daniel
Immune tolerance is executed partly by Foxp3(+)regulatory T (Treg) cells, which suppress autoreactive T cells. In autoimmune type 1 diabetes (T1D) impaired tolerance promotes destruction of insulin-producing β-cells. The development of autoantigen-specific vaccination strategies for Foxp3(+)Treg-induction and prevention of islet autoimmunity in patients is still in its infancy. Here, using human haematopoietic stem cell-engrafted NSG-HLA-DQ8 transgenic mice, we provide direct evidence for human autoantigen-specific Foxp3(+)Treg-induction in vivo...
2016: Nature Communications
Antonio Picarelli, Raffaele Borghini, Marco Di Tola, Mariacatia Marino, Caterina Urciuoli, Claudia Isonne, Marta Puzzono, Barbara Porowska, Gabriele Rumi, Silvia Lonardi, Marianna Salemme, Antonio Tiberti, Carmelo Rizzo, Giuseppe Donato, Vincenzo Villanacci
BACKGROUND: Nonceliac gluten sensitivity (NCGS) is an emergent condition, the framework of which is yet unclear, whereas the diagnosis is suggested only by gluten-dependent symptoms after excluding wheat allergy and celiac disease (CD). Our goal was to highlight intestinal, systemic, and oral alterations to clarify the NCGS pathogenesis and identify new diagnostic tools. STUDY: A total of 60 NCGS patients, 20 untreated CD, 20 treated CD, and 20 healthy volunteers were recruited...
March 11, 2016: Journal of Clinical Gastroenterology
S Dahal-Koirala, L F Risnes, A Christophersen, V K Sarna, K Ea Lundin, L M Sollid, S W Qiao
CD4+ T cells recognizing dietary gluten epitopes in the context of disease-associated human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 molecules are the key players in celiac disease pathogenesis. Here, we conducted a large-scale single-cell paired T-cell receptor (TCR) sequencing study to characterize the TCR repertoire for two homologous immunodominant gluten epitopes, DQ2.5-glia-α2 and DQ2.5-glia-ω2, in blood of celiac disease patients after oral gluten challenge. Despite sequence similarity of the epitopes, the TCR repertoires are unique but shared several overall features...
May 2016: Mucosal Immunology
Raymon Vijzelaar, Ellen van der Zwan, Adriaan van Gammeren, Rizkat Yilmaz, Alice Verheul, Ingrid van Hoogstraten, Ellen de Baar, Lianne Schrauwen, Wouter Kortlandt
BACKGROUND: Genotyping of HLA-DQ2.2, HLA-DQ2.5, and HLA-DQ8 is important in celiac disease (CD). The absence of these three genotypes has a strong negative predictive value. METHODS: We designed multiplex ligation-dependent probe amplification (MLPA) for the combined detection of HLA-DQ2.2, HLA-DQ2.5, and HLA-DQ8. The MLPA probe mix was validated against a set of 59 samples characterized by conventional techniques. RESULTS: The MLPA assay genotyped all 59 samples correctly when compared to the results obtained by PCR-SSCP/HD or PCR-SSO and PCR-SSP...
March 2016: Genetic Testing and Molecular Biomarkers
Lucila Arantes Cecilio, Mauro W Bonatto
BACKGROUND: Celiac disease is an enteropathy characterized by gluten sensitivity and broad clinical aspect. Has a multifactorial cause and depends on genetic, immunological and environmental factors for its development. The genetic influence is given mostly by the human leukocyte antigens HLA DQ2 and DQ8. AIM: To evaluate the prevalence of human leukocyte antigens DQ2 and DQ8 in three different groups: patients with celiac disease, first-degree relatives and the general population...
July 2015: Arquivos Brasileiros de Cirurgia Digestiva: ABCD, Brazilian Archives of Digestive Surgery
Xiaorong Wu, Erdem Tuzun, Shamsher S Saini, Jun Wang, Jing Li, Leopoldo Aguilera-Aguirre, Ruksana Huda, Premkumar Christadoss
Extraocular muscles (EOM) are preferentially involved in myasthenia gravis (MG) and acetylcholine receptor (AChR) antibody positive MG patients may occasionally present with isolated ocular symptoms. Although experimental autoimmune myasthenia gravis (EAMG) induced by whole AChR immunization closely mimics clinical and immunopathological aspects of MG, EOM are usually not affected. We have previously developed an EAMG model, which imitates EOM symptoms of MG by immunization of human leukocyte antigen (HLA) transgenic mice with α or γ-subunits of human AChR (H-AChR)...
December 2015: Immunology Letters
Frits Koning
Coeliac disease (CD) is a T cell mediated inflammatory disorder of the small intestine that affects approximately 1% of the population (1, 2). CD is triggered by gluten ingestion, proteins found in wheat, barley and rye. CD4(+) T cells specific for post-translationally modified gluten peptides bound to the disease-predisposing HLA-DQ2 or HLADQ8 molecules are typically found in patients with CD, explaining the strong association between these HLA-alleles and the occurrence of CD (1, 2). In addition, antibodies specific for modified gluten are also present in patients with CD, implying a role for B to T cell presentation (1)...
July 2015: Clinical and Experimental Rheumatology
Charlotte de Wolf, Ruurd van der Zee, Ineke den Braber, Tibor Glant, Bernard Maillère, Emmanuel Favry, Menno van Lummel, Frits Koning, Aad Hoek, Irene Ludwig, Willem van Eden, Femke Broere
OBJECTIVE: We previously showed that mycobacterial Hsp70-derived peptide B29 induced B29-specific Treg cells that suppressed experimental arthritis in mice via cross-recognition of their mammalian Hsp70 homologs. The aim of the current study was to characterize B29 binding and specific CD4+ T cell responses in the context of human major histocompatibility complex (MHC) molecules. METHODS: Competitive binding assays were performed to examine binding of peptide B29 and its mammalian homologs to HLA molecules...
March 2016: Arthritis & Rheumatology
Janet M Wenzlau, Lisa M Frisch, John C Hutton, Pamela R Fain, Howard W Davidson
Zinc transporter 8 autoantibodies (ZnT8A) were analyzed in sera from 1,504 subjects as part of the Type 1 Diabetes Genetics Consortium (T1DGC) Autoantibody Workshop. For these participants with type 1 diabetes (T1D), samples were collected within 3 years of T1D diagnosis. ZnT8A were detected in 862 subjects (57.3%), with the highest frequencies and median titers being associated with the shortest duration of disease. ZnT8A were present at similar frequencies in non-Hispanic whites, non-Hispanic blacks, and Hispanics, but significantly less prevalent in those of Asian ancestry...
October 2015: Diabetes Care
Anthony P Heaney, Brittany Sumerel, Raja Rajalingam, Marvin Bergsneider, William H Yong, Linda M Liau
IMPORTANCE: Lymphocytic hypophysitis (LH) is a poorly understood autoimmune disorder of the pituitary gland. Symptoms include headache, pituitary dysfunction, visual disturbances, and neurological deficits. The diagnosis can be made based on clinical and biochemical findings, but for atypical presentations, no circulatory diagnostic biomarkers exist, and a pituitary biopsy is necessary for diagnosis. OBJECTIVES: We used high-resolution human leukocyte antigen (HLA) screening assays to investigate a relationship between specific HLA markers and LH...
November 2015: Journal of Clinical Endocrinology and Metabolism
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