Framework for interpretation of trypsin-antitrypsin imbalance and genetic heterogeneity in pancreatitis

Abstract

Early intracellular premature trypsinogen activation was interpreted as the key initiator of pancreatitis. When the balance in the homeostasis of trypsin and antitrypsin system is disequilibrated, elevated aggressive enzymes directly attack the pancreatic tissue, which leads to pancreatic destruction and inflammation. However, trypsin alone is not enough to cause complications in pancreatitis, which may play a crucial role in modulating signaling events in the initial phase of the disease. NFκB activation is the major inflammatory pathway involved in the occurrence and development of pancreatitis and it can be induced by intrapancreatic activation of trypsinogen. Synthesis of trypsinogen occurs in endoplasmic reticulum (ER), and ER stress is an important early acinar cell event. Components of ER stress response are known to be able to trigger cell death as well as NFκB signaling cascade. The strongest evidence supporting the trypsin-centered theory is that gene mutations, which lead to the generation of more trypsin, or reduce the activity of trypsin inhibitors or trypsin degradation, are associated with pancreatitis. Thus, trypsin–antitrypsin imbalance may be the first step leading to pancreatic autodigestion and inducing other pathways. Continued experimental studies are necessary to determine the specific relationships between trypsin–antitrypsin imbalance and genetic heterogeneity in pancreatitis. In this article, we review the latest advances that contributed to the understanding of the basic mechanisms behind the occurrence and development of pancreatitis with a focus on the interpretation of trypsin–antitrypsin imbalance and their relationships with other inflammation pathways. We additionally highlight genetic predispositions to pancreatitis and possible mechanisms associated with them.

Clinical and pathological characteristics of IgG4‑related interstitial lung disease

“…Obliterative vasculitis and a high level of α-1-AT expression were also observed in the patients enrolled in the present study. Fibrosis and vasculitis induced by trypsin-antitrypsin imbalance have been reported in immune systemic disorders, including inflammatory bowel disease ( 22 ) and hepatic fibrosis ( 23 ), and as a key initiator in IgG4-related pancreatitis ( 24 ). In addition, it has been observed that mutations in protease serine 1 cause ectopic trypsinogen activation, and calcitonin gene-associated peptide-β splice region pathogenic variants may lead to plasma cell neurotropic enrichment, inducing obliterative vasculitis and perineural inflammation in the pancreas in type 1 AIP ( 6 , 25 ).…”