Masked bolus gluten challenge low in FODMAPs implicates nausea and vomiting as key symptoms associated with immune activation in treated coeliac disease

Background In patients with coeliac disease, FODMAPs in gluten-containing foods, and participant anticipation of a harmful ('nocebo') effect, may contribute to acute symptoms after gluten challenge. Aim To establish acute gluten-specific symptoms linked to immune activation in coeliac disease Methods We included 36 coeliac disease patients on a gluten-free diet receiving placebo in the RESET CeD trial. Double-blind, bolus vital wheat gluten (similar to 6-g gluten protein) and sham challenges low in FODMAPs were consumed 2 weeks apart. Assessments included daily Coeliac Disease Patient Reported Outcome (CeD PRO) symptom scores (0-10), adverse events and serum interleukin-2 (baseline and 4 hours). Results Median CeD PRO score for nausea increased most (sham: 0 vs gluten: 5.5; P < .001). Apart from tiredness (1 vs 4, P = .005) and headache (0 vs 2, P = .002), changes in other symptoms were small or absent. Only nausea increased significantly in occurrence with gluten (11% vs 69%, P < .001). Without nausea, only tiredness and flatulence were common after gluten. Nausea (6% vs 61%, P < .001; median onset: 1:34 hours) and vomiting (0% vs 44%, P < .001; 1:51 hours) were the only adverse events more common with gluten than sham. Interleukin-2 was always below the level of quantitation (0.5 pg/mL) at baseline, and after sham. Interleukin-2 was elevated after gluten in 97% of patients (median fold-change: 20), and correlated with severity of nausea (r(s) = .49, P = .0025) and occurrence of vomiting (P = .0005). Conclusions Nausea and vomiting are relatively specific indicators of acute gluten ingestion, and correlate with immune activation. IBS-like symptoms without nausea are unlikely to indicate recent gluten exposure

Evaluation of a DLA-79 allele associated with multiple immune-mediated diseases in dogs

Immune-mediated diseases are common and life-threatening disorders in dogs. Many canine immune-mediated diseases have strong breed predispositions and are believed to be inherited. However, the genetic mutations that cause these diseases are mostly unknown. As many immune-mediated diseases in humans share polymorphisms among a common set of genes, we conducted a candidate gene study of 15 of these genes across four immune-mediated diseases (immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, immune-mediated polyarthritis (IMPA), and atopic dermatitis) in 195 affected and 206 unaffected dogs to assess whether causative or predictive polymorphisms might exist in similar genes in dogs. We demonstrate a strong association (Fisher’s exact p = 0.0004 for allelic association, p = 0.0035 for genotypic association) between two polymorphic positions (10 bp apart) in exon 2 of one allele in DLA-79, DLA-79*001:02, and multiple immune-mediated diseases. The frequency of this allele was significantly higher in dogs with immune-mediated disease than in control dogs (0.21 vs. 0.12), and ranged from 0.28 in dogs with IMPA to 0.15 in dogs with atopic dermatitis. This allele has two non-synonymous substitutions (compared to the reference allele, DLA-79*001:01) resulting in F33L and N37D amino acid changes. These mutations occur in the peptide binding pocket of the protein, and based upon our computational modeling studies are likely to affect critical interactions with the peptide N-terminus. Further studies are warranted to confirm these findings more broadly, and to determine the specific mechanism by which the identified variants alter canine immune system function