MZB1 Modulates Inflammatory Severity in Severe Acute Pancreatitis through an IgA-Associated Intestinal Barrier Axis.

Severe acute pancreatitis (SAP) is characterized by excessive inflammatory responses that critically influence disease severity and systemic complications. Although innate immune activation has been extensively studied in SAP, the contribution of adaptive humoral immunity to inflammatory modulation during disease progression remains incompletely understood. In this study, we performed longitudinal single-cell RNA sequencing of peripheral blood mononuclear cells from patients with mild and severe acute pancreatitis to characterize immune alterations across disease stages. We observed dynamic immune remodeling, including increased engagement of B cell-associated humoral immune programs during later stages of severe disease. Among these changes, expression of the endoplasmic reticulum-resident protein MZB1 was prominently associated with plasma cell differentiation and immunoglobulin-related transcriptional activity. To investigate the functional relevance of MZB1, we employed genetic mouse models of experimental pancreatitis. Loss of MZB1 was associated with exacerbated pancreatic inflammation, impaired IgA production, and compromised intestinal barrier integrity. Together, these findings suggest that MZB1-associated humoral immune responses contribute to modulation of inflammatory severity in severe acute pancreatitis by supporting IgA-dependent intestinal barrier integrity and limiting secondary macrophage-driven inflammation.