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Celiac.com 06/03/2013 - Thrombophilias are defined as a group of inherited or acquired disorders that increase a person’s risk of developing thrombosis (abnormal “blood clotting”) in the veins or arteries. People with celiac disease may present with thromboembolic features that have multiple contributing factors, such as hyperhomocysteinemia, B12 andor folate deficiency, methylenetetrahydrofolate reductase mutations, and protein C and S deficiency due to vitamin K deficiency. However, there has been no research into how the well known thrombogenic factors, antiphosphatidylserine/prothrombin and antiprothrombin relate to celiac disease. A team of researchers recently studied the thrombophilic network of autoantibodies in celiac disease. The research team included Aaron Lerner1, Nancy Agmon-Levin, Yinon Shapira, Boris Gilburd, Sandra Reuter, Idit Lavi and Yehuda Shoenfeld. They are variously affiliated with Epidemiology and Community Medicine, and the Pediatric Gastroenterology and Nutrition Unit in the Carmel Medical Center of the B. Rappaport School of Medicine at the Technion-Israel institute of Technology in Haifa, Israel, with the Zabludowicz Center for Autoimmune Diseases at Sheba Medical Center in Tel-Ashomer, Israel, and with Aira e.v./Aesku.Kipp Institute in Wendelsheim, Germany. For their study, the team assessed blood autoantibody levels in 248 people, and then classified them into one of three groups. Group 1 included 70 children with confirmed celiac disease. They averaged 7.04 years of age (±4.3 years), with a male to female ratio of 1.06 to 1. Group 2 was a healthy control group that included 88 children, averaging 6.7 years of age (±4.17 years), with a male to female ratio 0.87 to 1. The team then compared the pediatric population to group 3, which included 90 adults who were family members (parents) of group 1 (age: 34.6 ±11.35 years, male to female ratio 1.2). The check antibodies using enzyme-linked immunosorbent assay. Results showed average optical density levels of serum antiphosphatidylserine/prothrombin immunoglobulin G antibodies of 32.4 ±19.4, 3.6 ±2.5 and 16.1 ±15.8 absorbance units in groups 1, 2 and 3 respectively (P less than 0.0001), with 45.7%, 0% and 7.8% of groups 1, 2 and 3 respectively positive for the antibody (P less than 0.01). Average optical density levels of serum antiphosphatidylserine/prothrombin immunoglobulin M antibodies were 14.2 ±8.7, 6.7 ±6.4 and 12.4 ±15.5 absorbance units in groups 1, 2 and 3 respectively (P less than 0.0001), with 7.1%, 3.4% and 9.9% of groups 1, 2 and 3 positive for the antibody. Average optical density levels of serum antiprothrombin and antiphospholipid immunoglobulin G antibodies were higher in groups 1 and 3 compared with 2 (P less than 0.005) and in groups 1 and 2 compared with 3 (P less than 0.01), respectively. Groups 1, 2 and 3 tested positive for antiphospholipid immunoglobulin G antibodies (groups 1 and 2 compared with 3) . Celiac disease blood samples contain a higher antiprothrombin immunoglobulin G level compared with controls. These results suggest that increased exposure of phospholipids or new epitopes representing autoantigens have their origins in the intestinal injury, endothelial dysfunction, platelet abnormality and enhanced apoptosis recently described in celiac disease. Those autoantibodies might play a pathogenic role in celiac-associated thrombophilia, and may also make good targets for possible preventive anticoagulant therapy. Source: BMC Medicine 2013, 11:89. doi:10.1186/1741-7015-11-89

Celiac.com 04/14/2014 - Exposure to stressful stimuli, such as inflammation, cause cells to up-regulate heat shock proteins (Hsp), which are highly conserved immunomodulatory molecules. Research points to Hsp involvement in numerous autoimmune diseases, including autoimmune bullous diseases and celiac disease. To better understand the role of Hsp in autoimmune bullous diseases, a research team conducted the first investigation of the humoral autoimmune response to Hsp40, Hsp60, Hsp70, and Hsp90 in patients with dermatitis herpetiformis (DH; n = 26), bullous pemphigoid (BP; n = 23), and pemphigus vulgaris (PV; n = 16), the first representing a cutaneous manifestation of celiac disease. The research team included Kasperkiewicz M1, Tukaj S, Gembicki AJ, Silló P, Görög A, Zillikens D, Kárpáti S. They are affiliated with the Department of Dermatology at the University of Lübeck in Lübeck, Germany. In patients with active BP and PV, serum levels of autoantibodies against these Hsp matched the healthy control subjects (n = 9-14), while circulating autoantibodies against Hsp60, Hsp70, and Hsp90 increased at the active disease stage of DH. Further analysis showed that in patients who adopt a gluten-free diet, these anti-Hsp autoantibodies decreased in relation to serum autoantibodies against epidermal and tissue transglutaminase during remission of skin lesions. Larger groups of patients must be studied to confirm these findings, but these results indicate that autoantibodies against Hsp60, Hsp70, and Hsp90 play a key role in the development and maintenance of DH, possibly also in the underlying celiac disease, and may be important in potentially undiscovered disease biomarkers. Source: Cell Stress Chaperones. 2014 Mar 19.

Celiac.com 11/01/2012 - Although most instances of gluten sensitivity manifest as a chronic, autoimmune disorder of the small intestine (celiac disease), around 10% of gluten sensitive patients suffer neurological symptoms. Usually these neurological symptoms accompany the more common intestinal issues, but some patients exhibit neurological symptoms exclusively. For this reason, it is thought that gluten-related symptoms in different parts of the body could be the result of autoimmune reactions to different members of the transglutaminase gene family. A recent lab study suggests that neurological gluten-related symptoms could be the result of an immune reaction to a particular neuronal enzyme known as TG6, and that this reaction occurs separate from other autoimmune reactions to gluten. Sera were collected from 6 groups: 20 newly diagnosed celiac disease patients (pre gluten-free diet) with no neurological symptoms, 34 gluten ataxia patients who tested positive for anti-gliadin antibodies, 17 peripheral idiopathic neuropathy patients, also positive for anti-gliadin antibodies, a control group of 18 genetic (non-gluten related) ataxia patients or individuals with clear family history of ataxia, a second control group of 14 patients with various immune-mediated but gluten-unrelated diseases and a third control group of 19 healthy individuals. Sera were tested through a series of protein analyses and enzyme-linked immunosorbent assays. In the celiac disease group, 18 of 20 patients tested positive for the TG2 autoantibody, with the remaining two testing postive for the TG3 or TG6 autoantibodies. 55% of celiac disease patients had multiple transglutaminase autoantibodies: 45% of all celiac disease patients had antibodies for both TG2 and TG3, 45% had antibodies for both TG2 and TG6, and 35% had antibodies for TG2, TG3 and TG6. Gluten ataxia patients were separated into two groups: those with intestinal symptoms (group GAE), and those without (group GAo). TG2 autoantibodies correlated well with intestinal symptoms: 12 of 15 in the GAE group tested positive for TG2 autoantibodies, while only 1 of 19 in the GAo group tested positive for them. TG3 autoantibody results were similar: group GAE results were comparable to the celiac disease group, while group GAo was no different from the control groups. In contrast, both gluten ataxia groups had similar results for TG6 autoantibodies. Overall prevalence of TG6 autoantibodies in the gluten ataxia group was 62%, compared to 45% in the celiac disease group. Inhibition studies showed that in group GAE (gluten ataxia with intestinal symptoms), autoantibodies reacted separately from one another, with TG2 and TG6 autoantibodies reacting independently of one another to their respective TG isozymes. This, along with the fact that some patients tested positive exclusively for TG6 would suggest that intestinal and neurological gluten-related symptoms are caused by separate immune reactions to different TG isozymes (TG2 and TG6, respectively). This is further supported by postmorten analysis of a gluten ataxia patient without intestinal symptoms, where TG6 deposits were found in the brain (TG6 could not be detected in a normal cerebellum). The findings of this study suggest that with more research, doctors may have another diagnostic tool in the form of TG6 autoantibody tests. This would help determine which patients with gluten sensitivity might be most at risk for developing neurological symptoms. Source: http://www.ncbi.nlm.nih.gov/pubmed/18825674

Celiac.com 10/29/2012 - Celiac disease with epilepsy and cerebral calcifications, also known as CEC, is a rare form of celiac disease that is accompanied by occipital epilepsy. Past studies have suggested that the neurological symptoms could be the result of a folate deficiency, as folate levels are typically low in patients suffering from CEC. However, a recent case report indicates that as with other neurological gluten-related diseases (such as gluten ataxia), there may be some correlation between CEC and TG6 autoantibodies, indicating that the disease is autoimmune in nature. The case study focuses on a four year old boy who suffered from 30+ minute long complex partial seizures every two to three days. He was given antiepileptic drugs (carbamazepine, sodium valproate, levetiracetam), but these only slightly helped reduce seizure frequency. After one year, MRI and CT scans revealed bilateral occipital calcifications over parieto-occipital regions of the brain. The patient also suffered from chronic diarrhea: endoscopy and biopsy confirmed villous atrophy and patient tested positive for antibodies associated with celiac disease. His folate levels were also markedly low. After being placed on a gluten-free diet, the patient's symptoms, including seizures, cleared within two weeks. After the seizures had ceased, the patient was given folate supplements, and taken off antiepileptic drugs. Gluten challenge caused a relapse of all symptoms. At the time of the report, the patient had been gluten-free and seizure-free for 18 months, and showed improved behavior and reading and writing abilities. Because the patient responded so well to gluten-free diet treatment before being given folate supplements and all symptoms resumed during gluten challenge, it would seem that the neurological symptoms of CEC are the result of immune mechanisms rather than vitamin deficiencies or malabsorption. Most CEC patients have low folate levels; folate deficiency was previously thought to play a causative role in the disease, but this case study brings that conclusion into question. Furthermore, the patient tested positive for TG6 autoantibodies, which are associated with gluten ataxia (another gluten-related disease with neurological symptoms, which are an autoimmune response). More studies are required, but this case study suggests that gluten ataxia is not the only gluten-related disease with autoimmune neurological manifestations. Source: http://www.ncbi.nlm.nih.gov/pubmed/22845673

Celiac.com 05/28/2012 - Two researchers recently conducted an assessment of the contribution of celiac disease autoantibodies to the disease process. The researchers were Katri Lindfors, of the Pediatric Research Center, University of Tampere & Tampere University Hospital and Katri Kaukinen, affiliated with both the School of Medicine, at the University of Tampere, and the Department of Gastroenterology & Alimentary Tract Surgery at Tampere University Hospital, both in Tampere, Finland. The protein transglutaminase 2 is a multifunctional protein that plays a role in cellular adhesion. Moreover, transglutaminase 2 has been identified as the auto-antigen in celiac disease, and in untreated celiac disease. In addition to being present in the serum, the transglutaminase 2-targeted autoantibodies are bound to their antigen in the basement membrane underlining the small-bowel mucosal epithelium. Furthermore, studies have shown that disease-specific transglutaminase 2-targeted autoantibodies have a range of biological effects on different cell types. By using Caco-2 intestinal epithelial cells, Lindfors and Kaukinen show that serum transglutaminase 2-targeted autoantibodies from untreated celiac patients inhibit the adhesion of these cells. These results offer an important direction for future research to improve the basic understanding of celiac disease pathogenesis, and especially how disease-specific autoantibodies function as the disease progresses. Source: Clin Immunol. 2012;8(2):151-154.