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Celiac.com 09/02/2008 - Thanks to a team of researchers based in Great Britain, doctors may soon have a powerful new diagnostic tool to help them in their efforts to combat the damage caused by celiac disease. Their new discovery concerns people with celiac disease who may also develop neurological disorders. The research team was made up of Marios Hadjivassiliou, MD, Pascale Aeschlimann, BSc, Alexander Strigun, MSc, David Sanders, MD, Nicola Woodroofe, PhD, and Daniel Aeschlimann, PhD. The team recently investigated the nature of gluten sensitivity by isolating a unique neuronal transglutaminase enzyme and examining whether it is the focus of the immune response in celiac patients with neurological dysfunction. About one in ten people with celiac disease also suffer from associated neurological disorders, mainly from a condition involving the cerebellum called gluten ataxia, and another involving the peripheral nerves called gluten neuropathy. For many people celiacs with gluten ataxia, their neurological problems are their sole symptom. Only about 1 out of 3 people with gluten ataxia and celiac disease will show classic intestinal damage when given a biopsy. This can make proper diagnosis difficult for them. Also, there’s presently no reliable way to predict which people with gluten intolerance might develop neurological problems. Most people familiar with celiac disease know that gastrointestinal discomfort is one of the most common symptoms. The antibody most commonly associated with such discomfort is called anti-transglutaminase 2 IgA. This is one of the main antibodies that doctors commonly look for when evaluating possible cases of celiac disease. Anti-TG2 antibodies are pretty much exclusive to people with celiac disease, and are associated with both untreated clinically symptomatic celiac disease, and with the latent form of the disease. This makes the presence of anti-TG2 antibodies an excellent diagnostic indicator of celiac disease. Anti-TG2, however, may not be the best indicator in every case of celiac disease. One example is in cases of dermatitis herpetiformis, which is an external skin reaction to gluten. Most people with dermatitis herpetiformis have a persistent itchy skin rash, and while the majority of cases show intestinal damage with a biopsy, patients rarely experience intestinal discomfort associated with classic celiac disease.1 There is also reliable data that point to a role that anti-TG3 plays in cases of dermatitis herpetiformis.2 This indicates that the nature of a given individual’s immune response may determine how celiac disease manifests itself within that individual. That hypothesis seems to be born out by the research team’s discovery that another antibody, called anti-transglutaminase 6 IgG and IgA response is widespread in gluten ataxia, completely outside of any intestinal symptoms. These antibodies are not found in healthy control patients or in patients with neurological conditions that had clear genetic causes. Both groups showed no anti-TG6 in their blood samples. The research team took blood samples from 20 patients with newly diagnosed celiac disease before the patients began a gluten-free diet. The team confirmed the presence of celiac disease with duodenal biopsy and made sure the patients had no patients had no evidence of neurological problems. The team then took blood samples from 34 patients with Gluten Ataxia, which they defined as otherwise sporadic idiopathic ataxia with positive IgG and/or IgA anti-gliadin antibodies. The also took samples from another17 patients with peripheral idiopathic neuropathy (PN) who tested positive for anti-gliadin antibodies. These 17 patients tested negative for anti-MAG and anti-GM1 and had no evidence of intestinal damage on biopsy. The team used three separate control groups. The first was a group with genetic ataxia, which included 18 patients with ataxia that was genetic in nature, or with a clear family history of autosomal dominant ataxia. The second control group of 14 patients included cases of diseases that were immune-mediated, but not tied to gluten-sensitivity (such as vasculitis, viral cerebellitis, paraneoplastic ataxia, GAD ataxia). Lastly, the team used blood samples from 19 healthy individuals as another control group. The research team used recombinant human transglutaminases to develop ELISA and inhibition assays with which they measured blood samples of patients with gluten sensitive gastrointestinal and neurological disorders, along with several control groups that included unrelated inherited or immune conditions, for the presence and specificity of autoantibodies. The team found that the blood samples of patients with celiac disease and gluten ataxia contain IgA and IgG class antibodies to TG6 that are not present in the healthy control patients or in patients with neurological conditions that had clear genetic causes. At present, doctors test for celiac disease by checking the HLA type, and looking for the presence of anti-gliadin and anti-transglutaminase 2 antibodies. The results of this study indicate that the presence of anti-transglutaminase 6 can help to pinpoint patients with gluten sensitivity that may be at risk of developing neurological disease. Forthcoming: Annals of Neurology Footnotes: 1. Marks J, Shuster S, Watson AJ. Small bowel changes in dermatitis herpetiformis. Lancet 1966; 2:1280-1282. 2. Sárdy M, Kárpáti S, Merkl B, Paulsson M, and Smyth N. Epidermal transglutaminase (TGase3) is the autoantigen of Dermatitis Herpetiformis. J Exp Med 2002; 195:747-757.

Celiac.com 03/09/2011 - A team of researchers recently identified a novel immunomodulatory gliadin peptide that triggers interleukin-8 release in a chemokine receptor CXCR3-dependent manner only in patients with celiac disease. The research team included Karen M. Lammers; Sunaina Khandelwal; Fatima Chaudhry; Debby Kryszak; Elaine L. Puppa; Vincenzo Casolaro; and Alessio Fasano. The same research team had previously reported that the chemokine receptor CXCR3 serves as a receptor for specific gliadin peptides that trigger zonulin release and increase in intestinal permeability. This mechanism plays an important role in the adverse immune reaction to gluten-containing grains that is central to the classic celiac disease response. To examine the role of CXCR3 in the immune response to gliadin, the researchers incubated peripheral blood mononuclear cells of both celiac patients and healthy controls with either pepsin-trypsin-digested gliadin or 11 α-gliadin synthetic peptides in the presence or absence of a blocking anti-CXCR3 monoclonal antibody. The team then analyzed supernatants for interleukin-6 (IL-6), IL-8, IL-10, IL-13, IP-10 (CXCL10), tumour necrosis factor-α and interferon-γ. Gliadin triggered cytokine production regardless of clinical condition. However, only small number of individuals showed IL-8 production. In those individuals, cells originating from white blood cells were the main source of IL-8 production. The team used one of a comprehensive panel of synthetic α-gliadin peptides to reproduce the induction of IL-8. They were able to cease the process by blocking CXCR3 before stimulation with either gliadin or this peptide in the celiac group, but not in the control group. This suggests that gliadin-induced IL-8 production is CXCR3-dependent only in people with celiac disease. Source: Immunology, Volume 132, Number 3, March 2011 , pp. 432-440(9)