Parallels between Pathogens and Gluten Peptides in Celiac Sprue

Pathogens are exogenous agents capable of causing disease in susceptible organisms. In celiac sprue, a disease triggered by partially hydrolyzed gluten peptides in the small intestine, the offending immunotoxins cannot replicate, but otherwise have many hallmarks of classical pathogens. First, dietary gluten and its peptide metabolites are ubiquitous components of the modern diet, yet only a small, genetically susceptible fraction of the human population contracts celiac sprue. Second, immunotoxic gluten peptides have certain unusual structural features that allow them to survive the harsh proteolytic conditions of the gastrointestinal tract and thereby interact extensively with the mucosal lining of the small intestine. Third, they invade across epithelial barriers intact to access the underlying gut-associated lymphoid tissue. Fourth, they possess recognition sequences for selective modification by an endogenous enzyme, transglutaminase 2, allowing for in situ activation to a more immunotoxic form via host subversion. Fifth, they precipitate a T cell–mediated immune reaction comprising both innate and adaptive responses that causes chronic inflammation of the small intestine. Sixth, complete elimination of immunotoxic gluten peptides from the celiac diet results in remission, whereas reintroduction of gluten in the diet causes relapse. Therefore, in analogy with antibiotics, orally administered proteases that reduce the host's exposure to the immunotoxin by accelerating gluten peptide destruction have considerable therapeutic potential. Last but not least, notwithstanding the power of in vitro methods to reconstitute the essence of the immune response to gluten in a celiac patient, animal models for the disease, while elusive, are likely to yield fundamentally new systems-level insights

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets 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 4,261 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 signalling and cytokine-cytokine pathways, for which relevant therapies exist

The effects of a preassessment clinic on nonattendance rates for day-case colonoscopy

Background and Study Aims: Nonattendance for colonoscopy contributes to an increase in the waiting lists for this procedure. Preassessment clinics routinely run for a number of day-patient surgical procedures have been shown to reduce nonattendance rates by enhancing patient understanding. This study aimed to determine prospectively whether preassessing patients booked for colonoscopy would lead to a reduction in the nonattendance rate. Patients and Methods: Nonattendance rates for colonoscopy were assessed in consecutive 9-month periods. During the first period all patients were mailed appointments for colonoscopy with dietary and purgative bowel preparation instructions. During the second period, patients who had never previously undergone a colonoscopic examination were invited to attend a preassessment clinic, while patients who had attended for colonoscopy in the past were sent appointments and purgative instructions in the post. Results: 344 colonoscopies were booked in the first 9-month period and 350 in the second, of which 195 were preassessed, Overall, 60 patients did not attend for colonoscopy during the first 9-month period (17.4%), and 40 (11.4%; P &lt;0.05) did not attend during the second period of study. During the second 9 months only six (3.1%) of the 195 preassessed patients did not attend for colonoscopy, in comparison with 34 (22%; P &lt;0.0001) of the 155 patients not preassessed. Conclusions: By running a limited preassessment clinic for patients due for colonoscopy, we have shown a significant reduction in the nonattendance rate. If all patients were to attend for preassessment, nonattendance rates for colonoscopy might be reduced to that seen in our preassessment group (3.1%)