Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

Background : 5‐aminosalicylic acid (5‐ASA) has been associated with renal complications in inflammatory bowel disease. Renal function is typically monitored using serum creatinine; however, significant disease may predate increases in creatinine. Aims : To identify whether markers of early renal disease (urinary albumin, α‐1‐microglobulin [α‐1‐M] and N‐acetyl‐β‐D‐glucosaminidase [NAG], and serum cystatin C) are useful in the assessment of renal function in inflammatory bowel disease patients receiving 5‐ASA. Methods : Twenty‐one patients with a new diagnosis of inflammatory bowel disease were investigated. Samples were taken at diagnosis, and at 3‐monthly intervals after the commencement of 5‐ASA, for 1 year. Results : Mean creatinine clearance was 100 mL/min and did not change following treatment. Inflammatory bowel disease was not associated with albuminuria. Urinary N‐acetyl‐β‐D‐glucosaminidase and α‐1‐microglobulin at diagnosis were increased in 10 (48%) and 11 (52%) patients, respectively: treatment was not associated with consistent changes in urinary protein excretion. There was a significant correlation between cystatin C and creatinine clearance both at diagnosis (r=–0.533, P=0.0275) and combining the initial and follow‐up data (r=–0.601, P < 0.01), but not between creatinine and creatinine clearance (P > 0.05). Conclusions : Tubular proteinuria is an extra‐intestinal manifestation of inflammatory bowel disease irrespective of 5‐ASA treatment. Tubular proteins are not useful predictors of an adverse renal response to 5‐ASA. Serum cystatin C may be an improved marker of glomerular filtration rate in this setting.

Background: Peptides from a-gliadins have been used to characterise the immunodominant coeliac toxic epitope. A peptide corresponding to amino acid residues 57-73 of A-gliadin causes peripheral blood mononuclear cells from coeliac patients to secrete interferon c (IFN-c); gluten specific small intestinal T cell clones proliferate in response to peptides corresponding to residues 57-68 and 62-75 of a-gliadins. We wished to investigate whether a peptide corresponding to residues 56-75 of a-gliadins exacerbates coeliac disease in vivo. Methods: Four adults with coeliac disease, all of whom were on a gluten free diet, underwent three challenges. Peptic-tryptic gliadin (PTG 1 g) served as a positive control. The test peptide and a negative control peptide were studied on separate occasions. The peptides were instilled into the duodenum and biopsies were taken before the infusion, and two, four, and six hours after commencing the infusions, using a Quinton hydraulic multiple biopsy capsule. Biopsy specimens were assessed blindly for villus height to crypt depth ratio (VH:CD), enterocyte cell height (ECH), and intraepithelial lymphocyte (IEL) count. We used the Mann-Whitney U test, with 95% confidence intervals, for statistical analysis. Results: VH:CD and ECH fell, and IEL increased significantly 4-6 hours after commencing infusions with both PTG and the test peptide in all subjects. The negative control peptide caused no significant changes to villus morphology, enterocyte height, or IEL count in any patient. Conclusion: We have confirmed that the putative immunodominant epitope, a peptide corresponding to residues 56-75 of a-gliadins, exacerbates coeliac disease in vivo.

Background: Coeliac disease (CD) is an enteropathy mediated by gluten specific T cells which secrete interferon γ (IFN-γ) when stimulated by gluten peptides presented by HLA-DQ2 or DQ8 molecules. Residues 62-75 of α 2 gliadin have been proposed as the immunodominant epitope in the majority of CD patients. Deamidation by tissue transglutaminase (tTG) of the glutamine (Q) at position 65 to glutamic acid (E) is essential for T cell stimulation. Aims: To investigate the antigenicity of this peptide and to establish whether its T cell activating properties can be downregulated by the formation of altered peptide ligands. Patients: Individuals with known CD. Methods: Peptide G4 corresponding to α 2 gliadin residues 62-75, Q-E65 and analogues, substituting each amino acid, except E65, in turn for alanine residues, were synthesised. Small intestinal biopsies were obtained from patients. Biopsies were cultured overnight with a peptic/tryptic digest of gliadin (PTG). Lymphocytes were cultured and restimulated with tTG treated PTG. A T cell line was cloned and clones tested for stimulation and IFN-γ production in response to G4 and its analogues. Results: Some high activity clones were isolated with, for example, a stimulation index (SI) of 15 to G4 and secreting 327 pg/ml of IFN-γ. Substitution of amino acids at several positions abolished or downregulated stimulation and IFN-γ production. Conclusions: Peptide G4 is highly immunogenic. Certain amino acid substitutions in peptide G4 abolish T cell reactivity while others are partial agonists which may have potential in immunomodulation in this condition.