Autophagie und Stress des Endoplasmatischen Reticulums koordinieren protektive Interleukin-22-Signale im intestinalen Epithel.

Inflammatory bowel diseases (IBD) are playing a more and more important socioeconomic role due to increasing incidences. However, the detailed pathophysiology is not fully understood, yet. This is reflected by the yet unsatisfactory treatment efficiency of even the most modern drugs under development. Genetic factors, environmental triggers, lifestyle and microbial signals are interactively contributing to the development of IBD. Coding variants of the IBD risk genes ATG16L1 and XBP1 have been associated with defective autophagy, deregulation of endoplasmic reticulum (ER) function and impaired pathogen clearance. IL-22 is a barrier protective cytokine by inducing regeneration and antimicrobial responses in the intestinal mucosa. Here, we show that XBP1 and ATG16L1 critically orchestrates beneficial IL-22 signalling in intestinal epithelium. IL-22 stimulation physiologically leads to transient ER stress, intracellular release of dsDNA and subsequent activation of the cGAS-STING pathway. Loss of ATG16L1 exacerbates IL-22-induced ER stress and augments STING-dependent IFN-I responses in IECs. IFN-I amplifies epithelial TNFα production downstream of IL-22 and leads to necroptotic cell death. In vivo, IL-22 treatment in Atg16l1ΔIEC mono- and Atg16l1ΔIEC/Xbp1ΔIEC double knockout mice potentiates endogenous ileal inflammation and causes widespread necroptotic epithelial cell death, which can be partially rescued by neutralising the IFN-I signalling using anti-IFNAR antibodies. Under conditions of chronic intestinal inflammation and with clear genetic “hits” to the autophagic and ER stress machinery like in human IBD, however, such a fate of IL-22 signals may crucially contribute to a vicious circle of tissue damage and inflammation

Case report: Induction and maintenance of steroid-free remission with vedolizumab in a case of steroid-dependent autoimmune pancreatitis

Autoimmune pancreatitis responds well to corticosteroids in most instances. Additional immunosuppression or low-dose maintenance steroids may be necessary upon relapse. There is limited data on alternative strategies when these regiments fail or cause adverse reactions. We report a case of a middle-aged woman with autoimmune pancreatitis in whom tapering of prednisolone below the dose of 25mg per day resulted in relapse of symptoms and long-term steroid use led to development of steroid induced hyperglycaemia. Induction and maintenance of steroid-free remission was ultimately successful under vedolizumab therapy. Remission has been stable for over one year with reduced need for antidiabetic intervention. This is the first reported case of treatment of refractory autoimmune pancreatitis with vedolizumab. It highlights the overlap of immunological mechanisms within inflammatory diseases of the digestive tract and how knowledge of biological data can inform treatment decisions for individual cases. The demonstrated efficacy of vedolizumab and low risk of severe side effects warrant further investigation into its use in autoimmune pancreatitis

Long-range epidemic spreading with immunization

We study the phase transition between survival and extinction in an epidemic process with long-range interactions and immunization. This model can be viewed as the well-known general epidemic process (GEP) in which nearest-neighbor interactions are replaced by Levy flights over distances r which are distributed as P(r) ~ r^(-d-sigma). By extensive numerical simulations we confirm previous field-theoretical results obtained by Janssen et al. [Eur. Phys. J. B7, 137 (1999)].Comment: LaTeX, 14 pages, 4 eps figure

Esophageal Carcinoma Histology Affects Perioperative Morbidity Following Open Esophagogastrectomy

Background. Esophagectomy for esophageal cancer is being practiced routinely with favorable results at many centers. We sought to determine if tumor histology is a powerful surrogate marker for perioperative morbidity. Methods. Seventy three consecutive patients managed operatively were reviewed from our prospectively maintained database. Results. Adenocarcinoma (AC) was present in 52 (71%) and squamous cell (SCC) in 21 (29%). The use of neoadjuvant therapy was similar for the AC (34.62%) and SCC (42.86%) groups. The SCC group had a higher incidence of prior pulmonary disease than the AC group (23.8% versus 5.8%, resp.; P = .03). SCC patients were more likely to have a prolonged ICU stay than AC patients (P = .004) despite similar complication rates, EBL, and prognostic nutritional index. The SCC group did, however, experience higher grades of complications (P = .0053). Conclusions. Presence of SCC was the single best predictor of prolonged ICU stay and more severe complications as defined by this study. Only a past history of pulmonary disease was different between the two histologic subgroups