Debby Kryszak

Natural history of celiac disease autoimmunity in a USA cohort followed since 1974

Abstract Background. The natural history and the possible changes of celiac disease (CD) prevalence over time are still unclear. Objectives. 1) To establish whether loss of tolerance to gluten may occur at any age; 2) to investigate possible changes of CD prevalence over time; and 3) to investigate CD-related co-morbidities. Methods. We analyzed 3,511 subjects with matched samples from 1974 (CLUE I) and 1989 (CLUE II). To avoid a selection bias regarding survival, we also screened 840 CLUE I participants who deceased after the 1974 survey. Outcome measure. CD autoimmunity (positivity to auto-antibodies) over time. Results. CD autoimmunity was detected in seven subjects in 1974 (prevalence 1:501) and in an additional nine subjects in 1989 (prevalence 1:219). Two cases of CD autoimmunity were found among the 840 subjects deceased after CLUE I. Compared to controls, untreated CD subjects showed increased incidence of osteoporosis and associated autoimmune disorders, but they did not reach statistical significance. Conclusions. During a 15-year period CD prevalence increased 2-fold in the CLUE cohort and 5-fold overall in the US since 1974. The CLUE study demonstrated that this increase was due to an increasing number of subjects that lost the immunological tolerance to gluten in their adulthood.

Identification of a novel immunomodulatory gliadin peptide that causes interleukin-8 release in a chemokine receptor CXCR3-dependent manner only in patients with coeliac disease

The autoimmune enteropathy, coeliac disease (CD), is triggered by ingestion of gluten‐containing grains. We recently reported that the chemokine receptor CXCR3 serves as a receptor for specific gliadin peptides that cause zonulin release and subsequent increase in intestinal permeability. To explore the role of CXCR3 in the immune response to gliadin, peripheral blood mononuclear cells from both patients with CD and healthy controls were incubated with either pepsin‐trypsin‐digested gliadin or 11 α‐gliadin synthetic peptides in the presence or absence of a blocking anti‐CXCR3 monoclonal antibody. Supernatants were analysed for interleukin‐6 (IL‐6), IL‐8, IL‐10, IL‐13, IP‐10 (CXCL10), tumour necrosis factor‐α and interferon‐γ. Gliadin broadly induced cytokine production irrespective of the clinical condition. However, IL‐8 production occurred only in a subgroup of individuals and cells of the phagocytic lineage were the main source. Induction of IL‐8 was reproduced by one of a comprehensive panel of synthetic α‐gliadin peptides and was abrogated when CXCR3 was blocked before stimulation with either gliadin or this peptide in the CD group but not in the control group, suggesting that gliadin‐induced IL‐8 production was CXCR3‐dependent gliadin induced IL‐8 production only in CD.

65 Mucosal Duodenal Tissue From Gluten-Sensitive Patients Do Not Have Increased Expression of IgA B Cell Switch Markers

(heterozygous state,10%), R202Q (heterozygous state, 3%) and R202Q + M694V mutations (3%). GI motility was assessed in the asymptomatic phase by functional ultrasonography (changes of gastric antral areas and gallbladder volumes; 5.0 MHz ClarUs©, Telemed device) and H2-breath test (orocecal transit time by Lactofan®, FAN-GmbH, DE and Italchimici, Italy). Measurements were taken at 5-15 min intervals in the fasting state and during 270 min postprandially after a 200ml liquid meal formula (Nutridrink®, Nutricia added with 10g lactulose). A group of 142 agesexBMI-matched healthy subjects served as control (M:F=67:75, age 38±1 yrs). Results. Acute attacks (1 day mean duration), had a frequency of <1 (48%), 2 (22%) and ≥3 (13%) episodes/mo. Symptoms included abdominal pain and fever (44%), joint pain (22%), fever alone (9%), fatigue (4%), erysipelas-like erythema (4%) or none (17%). Although the mean age at symptom onset was 19.2±8.4 yrs, FMF was only diagnosed after 15.4±9.7 yrs. Compared to control, FMF patients had comparable fasting antral areas (3.3±0.2 vs. 3.2±0.1 cm2), but increased max postprandial area (14.1±0.4 vs. 11.6±0.2 cm2, P<0.000001), residual postprandial area (4.3±0.2 vs. 3.5±0.1 cm2, P<0.001) and longer half emptying time (43.2±1.2 vs. 26.6±0.5 min, P<0.000001). Gallbladder vol. in FMF and control was comparable during fasting (19.8±2.1 vs. 22.4±0.5 ml) and postprandially (residual 5.4±0.4 vs. 5.5±0.2 ml), with a trend of increased percent residual volume (28.9±1.6 FMF vs. 24.8±0.7 % in controls, P=0.059). Gallbladder emptying time was comparable in FMF and control (23.2±1.7 FMF vs. 21.0±0.5 min). OCTT was longer in FMF (132.3±10.5 vs. 99.5±1.6 min, P<0.000001). All FMF patients responded to colchicine therapy 1 mg/day p.o. Conclusions. In a novel cluster of FMF patients, the final diagnosis of FMF is consistently delayed. Patients with FMF exhibit impairedmotorfunction in the GI tract but not in the gallbladder. Our study of GI motility provides additional clues on the natural history of this rare disorder before and after therapy.

64 Elevated Levels of Neuronal Tissue Transglutaminase (tTG)6 in AGA-IgA Positive Schizophrenic Subjects

Background: Celiac disease is an immune-mediated reaction to gluten, presenting with diarrhea, weight loss, abdominal complaints and a range of less common associated neurologic and psychiatric symptoms. Evidence of a link between schizophrenia and celiac disease dates back as far as 1961. A theory for this association presented by Dohan was that gluten serves as an environmental trigger in individuals predisposed to schizophrenia. This theory was supported by two series of ecologic data: the first showed that the prevalence of schizophrenia was decreased during periods of low grain consumption and the second comparative study showing that the prevalence of schizophrenia was lower in geographic areas of low grain consumption. Recent data from Denmark show elevated prevalence of celiac disease in cases of schizophrenia and in their relatives. Aims: To evaluate the prevalence of antibodies against neuronal transglutaminase (tTG)6 in tTG2 positive schizophrenia subjects. Methods: Intestinal anti-tTG 2, anti-gliadin IgA, anti-gliadin IgG and anti-endomysium antibodies (EMA) were assayed in 1401 schizophrenic patients who were part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and 900 controls. Neuronal anti-tTG6 antibodies were tested in those schizophrenic patients that were positive for anti-tTG2 antibodies and in matched controls with a ratio1 patient: 2 controls. Results: Prevalence of EMA-positive schizophrenia subjects was much lower (1:280) compared to the prevalence of anti-tTG2 antibodies (1:19). Of the 74 schizophrenic subjects that tested positive for anti-tTG2 antibodies, 36 tested positive for anti-tTG6 antibodies as well (prevalence 1:2), compared to 7 tTG6 positive subjects among the 148 controls (prevalence 1:21). Conclusions: Our preliminary observations suggest that the discrepancy between positive EMA and tTG2 antibodies that we observed among schizophrenic patients can be related to the concomitant presence of neuronal anti-tTG6 antibodies. Schizophrenic patients with elevated tTG2 are 10 times more likely to test positive for tTG6 as compared to age and gender matched controls. These results point to a possible role of tTG6 as a biomarker of gluten sensitivity among schizophrenic patients.