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T Cell Response Toward Tissue-and Epidermal-Transglutaminases in Coeliac Disease Patients Developing Dermatitis Herpetiformis.
Caproni, M, Capone, M, Rossi, MC, Santarlasci, V, Maggi, L, Mazzoni, A, Rossettini, B, Renzi, D, Quintarelli, L, Bianchi, B, et al
Frontiers in immunology. 2021;:645143
Abstract
The reason why only few coeliac patients develop the cutaneous manifestation of the disease, named dermatitis herpetiformis (DH), is still unknown. Epidermal transglutaminase (TG3) has been described as the main autoantigen of humoral immunity in DH but the mechanisms leading to this autoimmune response remain obscure. Here we characterized T cells from skin, gut and peripheral blood of DH and coeliac disease (CD) patients, evaluated the impact of the gluten-free diet on circulating T lymphocytes' phenotype and investigated antigen specific T cell response toward epidermal and tissue transglutaminase (TG2). DH patients showed an increased frequency of skin-derived T cells producing TNFα when compared to CD patients. Moreover, circulating T cells producing TNFα and IL-17A positively correlated with clinical score of skin disease activity and decreased after gluten-free diet. Finally, TG2 and TG3-specific T cells resulted more reactive to antigens stimulation in DH patients and showed cross reactivity toward the two autoantigens in both the group of patients. Our data suggest a role of TNFα and IL-17A producing cells in the development of DH and, for the first time, show the existence of a crossed T cell response toward the two transglutaminases isoforms, thus suggesting new insights on T cells role in skin damage.
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Poor Sensitivity of Fecal Gluten Immunogenic Peptides and Serum Antibodies to Detect Duodenal Mucosal Damage in Celiac Disease Monitoring.
Laserna-Mendieta, EJ, Casanova, MJ, Arias, Á, Arias-González, L, Majano, P, Mate, LA, Gordillo-Vélez, CH, Jiménez, M, Angueira, T, Tébar-Romero, E, et al
Nutrients. 2020;(1)
Abstract
A lifelong gluten-free diet (GFD) is the only current treatment for celiac disease (CD), but strict compliance is complicated. Duodenal biopsies are the "gold standard" method for diagnosing CD, but they are not generally recommended for disease monitoring. We evaluated the sensitivity and specificity of fecal gluten immunogenic peptides (GIPs) to detect duodenal lesions in CD patients on a GFD and compared them with serum anti-tissue transglutaminase (tTG) IgA antibodies. A prospective study was conducted at two tertiary centers in Spain on a consecutive series of adolescents and adults with CD who maintained a long-lasting GFD. Adherence to a GFD and health-related quality of life were scored with validated questionnaires. Mucosal damage graded according to the Marsh-Oberhüber classification (Marsh 1/2/3) was used as the reference standard. Of the 97 patients included, 27 presented duodenal mucosal damage and 70 had normal biopsies (Marsh 0). The sensitivity (33%) and specificity (81%) of GIPs were similar to those provided by the two assays used to measure anti-tTG antibodies. Scores in questionnaires showed no association with GIP, but an association between GIPs and patients' self-reported gluten consumption was found (p = 0.003). GIP displayed low sensitivity but acceptable specificity for the detection of mucosal damage in CD.
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Comparison of DNA methylation profiles from saliva in Coeliac disease and non-coeliac disease individuals.
Hearn, NL, Chiu, CL, Lind, JM
BMC medical genomics. 2020;(1):16
Abstract
BACKGROUND Coeliac disease (CD) is a autoimmune disease characterised by mucosal inflammation in the small intestine in response to dietary gluten. Genetic factors play a key role with CD individuals carrying either the HLA-DQ2 or HLA-DQ8 haplotype, however these haplotypes are present in half the general population making them necessary but insufficient to cause CD. Epigenetic modifications, including DNA methylation that can change in response to environmental exposure could help to explain how interactions between genes and environmental factors combine to trigger disease development. Identifying changes in DNA methylation profiles in individuals with CD could help discover novel genomic regions involved in the onset and development of CD. METHODS The Illumina InfiniumMethylation450 Beadchip array (HM450) was used to compare DNA methylation profiles in saliva, in CD and non-CD affected individuals. CD individuals who had been diagnosed at least 2 years previously; were on a GFD; and who were currently asymptomatic; were compared to age and sex-matched non-CD affected healthy controls. Bisulphite pyrosequencing was used to validate regions found to be differentially methylated. These regions were also validated in a second larger cohort of CD and non-CD affected individuals. RESULTS Methylation differences within the HLA region at HLA-DQB1 were identified on HM450 but could not be confirmed with pyrosequencing. Significant methylation differences near the SLC17A3 gene were confirmed on pyrosequencing in the initial pilot cohort. Interestingly pyrosequencing sequencing of these same sites within a second cohort of CD and non-CD affected controls produced significant methylation differences in the opposite direction. CONCLUSION Altered DNA methylation profiles appear to be present in saliva in CD individuals. Further work to confirm whether these differences are truly associated with CD is needed.
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Sucrosomial Iron Supplementation in Anemic Patients with Celiac Disease Not Tolerating Oral Ferrous Sulfate: A Prospective Study.
Elli, L, Ferretti, F, Branchi, F, Tomba, C, Lombardo, V, Scricciolo, A, Doneda, L, Roncoroni, L
Nutrients. 2018;(3)
Abstract
Patients with celiac disease (CD) frequently suffer from iron deficiency anemia (IDA) and may benefit from iron supplementation. However, intolerance to iron sulfate and duodenal atrophy could reduce the efficacy of this supplementation. This study evaluated the efficacy of a new sucrosomial iron formulation in patients with CD. Consecutive patients with CD and IDA were divided into two groups: patients with a known intolerance to iron sulfate were treated with sucrosomial iron (30 mg of iron/day), while those receiving iron supplementation for the first time were assigned to iron sulfate (105 mg of iron/day). Forty-three patients were enrolled (38 females, mean age 49 ± 9 years). After a follow-up of 90 days both groups showed an increase in Hb levels compared to baseline (+10.1% and +16.2% for sucrosomial and sulfate groups, respectively), and a significant improvement in all iron parameters, with no statistical difference between the two groups. Patients treated with sucrosomial iron reported a lower severity of abdominal symptoms, such as abdominal and epigastric pain, abdominal bloating, and constipation, and a higher increase in general well-being (+33% vs. +21%) compared to the iron sulfate group. Sucrosomial iron can be effective in providing iron supplementation in difficult-to-treat populations, such as patients with CD, IDA, and known intolerance to iron sulfate.
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Adherence to the Gluten-free Diet and Health-related Quality of Life in an Ethnically Diverse Pediatric Population With Celiac Disease.
Mager, DR, Marcon, M, Brill, H, Liu, A, Radmanovich, K, Mileski, H, Nasser, R, Alzaben, A, Carroll, MW, Yap, J, et al
Journal of pediatric gastroenterology and nutrition. 2018;(6):941-948
Abstract
OBJECTIVES Celiac disease (CD) is an autoimmune disease that requires lifelong adherence to a gluten-free diet (GFD). Adherence to the GFD in childhood may be poor and adversely influence health-related quality of life (HRQOL). The study purpose was to determine sociodemographic and socioeconomic factors influencing adherence to the GFD and HRQOL in a multiethnic cohort of youth with CD. METHODS A multisite (Edmonton, Hamilton, Toronto) study examining child-parent HRQOL in youth with CD (n = 243) and/or mild gastrointestinal complaints (GI-CON; n = 148) was conducted. Sociodemographic (age, child-parental age/education/ethnicity/place of birth), anthropometric (weight, height, body mass index), disease (diagnosis, age at diagnosis, duration, Marsh score, serology), household characteristics (income, family size, region, number of children/total household size), HRQOL (Peds TM/KINDL and Celiac Disease DUX), GI Complaints (PedsQL: Gastrointestinal Symptom Scale) and gluten intake were measured. RESULTS Younger age (<10 years), non-Caucasian ethnicity (parent/child), and presence of GI symptoms were associated with the highest rates of adherence to the GFD in CD children (P < 0.05). CD children (parent/child) had higher HRQOL (average, composite domains) than GI-CON (P < 0.05), but CD children were comparable to healthy children. Lack of GI symptoms, non-Caucasian ethnicity and age (<10 years) were associated with increased HRQOL in composite/average domains for CD (P < 0.05). CONCLUSIONS Child-parent perceptions of HRQOL in a multiethnic population with CD are comparable to healthy reference populations, but significantly higher than in parent/child GI-CON. Adherence to the GFD in ethnically diverse youth with CD was related to GI symptoms, age of the child, and ethnicity of the parent-child.
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Immunological indicators of coeliac disease activity are not altered by long-term oats challenge.
Cooper, SE, Kennedy, NP, Mohamed, BM, Abuzakouk, M, Dunne, J, Byrne, G, McDonald, G, Davies, A, Edwards, C, Kelly, J, et al
Clinical and experimental immunology. 2013;(3):313-8
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Abstract
Coeliac disease is a gluten-sensitive enteropathy that develops in genetically susceptible individuals. The disease exhibits many features of an autoimmune disorder. These include the production of highly specific anti-endomysial autoantibodies directed against the enzyme tissue transglutaminase. It is well accepted that wheat-, barley- and rye-based foods should be excluded in the gluten-free diet. Although several studies report that oats ingestion is safe in this diet, the potential toxicity of oats remains controversial. In the current study, 46 coeliac patients ingested oats for 1 year and were investigated for a potential immunogenic or toxic effect. Stringent clinical monitoring of these patients was performed and none experienced adverse effects, despite ingestion of a mean of 286 g of oats each week. Routine histological analysis of intestinal biopsies showed improvement or no change in 95% of the samples examined. Furthermore, tissue transglutaminase expression in biopsy samples, determined quantitatively using the IN Cell Analyzer, was unchanged. Employing immunohistochemistry, oats ingestion was not associated with changes in intraepithelial lymphocyte numbers or with enterocyte proliferation as assessed by Ki-67 staining. Finally, despite the potential for tissue transglutaminase to interact with oats, neither endomysial nor tissue transglutaminase antibodies were generated in any of the patients throughout the study. To conclude, this study reaffirms the lack of oats immunogenicity and toxicity to coeliac patients. It also suggests that the antigenic stimulus caused by wheat exposure differs fundamentally from that caused by oats.
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Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials.
Siegel, M, Garber, ME, Spencer, AG, Botwick, W, Kumar, P, Williams, RN, Kozuka, K, Shreeniwas, R, Pratha, V, Adelman, DC
Digestive diseases and sciences. 2012;(2):440-50
Abstract
BACKGROUND Celiac disease is the most common hereditary autoimmune disease in humans. The only treatment option for non-refractory celiac disease patients is adherence to a strict life-long gluten-free diet, which often fails to normalize small bowel histology. ALV003 is a mixture of two proteases that degrades gluten and is in clinical development as an oral therapy for patients with celiac disease. AIMS The safety, tolerability, and activity of ALV003 were assessed in two phase 1 clinical trials. METHODS In study 1 (N = 28) the study drug was administered in the fasted state; in study 2 (N = 53) the study drug was administered together with a gluten-containing meal. Both studies were single-dose, single-blind, placebo-controlled, cross-over trials. ALV003 was dosed at escalating dose levels by cohort (100, 300, 900, and 1,800 mg) and gastric samples were aspirated using a nasogastric tube. Adverse events, serum drug levels, and anti-drug antibody titers were measured. Gastric samples were assessed for ALV003 enzymatic activity over time (gastric pharmacokinetics) and gluten degradation (gastric pharmacodynamics). RESULTS All doses were well tolerated, and no serious adverse events or allergic reactions were observed. Gastric aspirates collected 30 min following a meal showed that 100 and 300 mg ALV003 degraded 75 ± 10% (N = 8) and 88 ± 5% (N = 8), respectively, of one gram of wheat bread gluten. CONCLUSIONS ALV003 is an orally active protease that appears to be stable in the fed stomach and degrades dietary gluten in this compartment. Single doses of oral ALV003 were not associated with serious adverse reactions.
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Antitissue transglutaminase antibodies in acute coronary syndrome: an alert signal of myocardial tissue lesion?
Di Tola, M, Barillà, F, Trappolini, M, Palumbo, HF, Gaudio, C, Picarelli, A
Journal of internal medicine. 2008;(1):43-51
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Abstract
BACKGROUND AND AIM Antitransglutaminase, previously considered identical to antiendomysial in coeliac sprue (CS), have been reported in end-stage heart failure. To clarify the above-mentioned data, we evaluated these antibodies in a cohort of cardiological patients with respect to troponin I, creatine kinase (CK), MB fraction creatine kinase (CK-MB mass) and myoglobin. METHODS Forty-one patients with acute coronary syndrome (ACS), 39 with dilated cardiomyopathy (DCM), 45 with CS and 58 blood donors (BDs) were evaluated. Antitransglutaminase and antiendomysial antibodies were tested in serum of the patients being studied. RESULTS High-positive antitransglutaminase values were found in CS, whilst low-positive values were also found in ACS and DCM. In patients at the second ACS, antibody levels were higher than in those at the first cardiac event. In patients with infarct Q, antitransglutaminase were higher than those in infarct non-Q, in which antibody levels were higher than those in unstable angina. A correlation between antitransglutaminase and troponin I, CK, CK-MB mass and myoglobin was found. Finally, antibody levels rose to reach a peak at 30 days from the cardiac event, whereas after further 150 days, approached the values of BDs. Antiendomysial were detectable only in CS. CONCLUSIONS Data highlight that antitransglutaminase can occur in cardiological patients, and that these antibodies are related to the severity/extent of the myocardial tissue lesion. This feature suggests a loss of specificity for antitransglutaminase in CS. Furthermore, the possibility of employing these antibodies in the long-term follow-up of ACS, could become an object of interesting discussion.
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Dietary treatment of gluten neuropathy.
Hadjivassiliou, M, Kandler, RH, Chattopadhyay, AK, Davies-Jones, AG, Jarratt, JA, Sanders, DS, Sharrack, B, Grünewald, RA
Muscle & nerve. 2006;(6):762-6
Abstract
We studied the effect of a gluten-free diet in patients with idiopathic sensorimotor axonal neuropathy and circulating antigliadin antibodies. Consecutive patients underwent baseline neurophysiological assessment and were offered a gluten-free diet. Those who went on the diet formed the intention-to-treat group and those who did not were the control group. Repeat neurophysiological assessment and subjective evaluation of neuropathy symptoms were performed at 1 year. A total of 35 patients participated in the study, with 25 patients going on the diet and 10 not doing so. There was a significant difference in the change of sural sensory action potentials (pre-defined primary endpoint), with evidence of improvement in the intention-to-treat group and deterioration in the control group. Subjective change in neuropathy symptoms also showed significant differences, with patients in the intention-to-treat group reporting improvement and those in the control group reporting deterioration. Gluten-free diet may thus be a useful therapeutic intervention for patients with gluten neuropathy.
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Growth and adult height in atypical coeliac patients, with or without growth hormone deficiency.
Salardi, S, Cacciari, E, Volta, U, Santoni, R, Ragni, L, Elleri, D, Cicognani, A, Vaira, D
Journal of pediatric endocrinology & metabolism : JPEM. 2005;(8):769-75
Abstract
OBJECTIVE To evaluate the effect of a gluten-free diet on growth and adult height, when available, in coeliac children without gastrointestinal symptoms. PATIENTS AND METHODS Sixty-one coeliac children without gastro-intestinal symptoms were included in the study. The age at diagnosis was 9.50 +/- 3.3 years. Thirty-eight had short stature at diagnosis (< 10th percentile) and 23 had normal stature. Thirty-seven reached adult height. RESULTS After beginning the diet an increase in growth velocity was seen in 30 patients (responders) (20 with initial short stature), while in 31 patients (18 with short stature) there was no catch-up growth (non-responders). Bone age at diagnosis was significantly more delayed in the responders than in the non-responders. Target height was significantly higher in children with normal stature at diagnosis than those with short stature. Growth hormone (GH) deficiency was found and confirmed after 6-12 months of diet in 12 of the 38 patients (32%) with short stature. In the group of the 30 'short' patients who attained final height, target height was attained or improved in 12 patients (40%): in eight of the 16 (50%) responders and in four of the 14 (29%) non-responders; in eight (all responders) out of 22 (36%) without GH deficiency, and in four out of eight (50%) patients with GH deficiency treated with GH (all non-responders). CONCLUSIONS In children in whom coeliac disease is diagnosed because of short stature, a gluten-free diet will be successful if at diagnosis there is a delay of bone age and in the first year of diet there is an evident catch-up growth. When this does not occur, i.e. in half of the patients (18 out of 38), it may be because of an associated and transient GH deficiency. In these patients a period of GH replacement therapy as well as a gluten-free diet may improve their final height.