Fire in the belly: A scoping review of the immunopathological mechanisms of acute pancreatitis

Abstract

Introduction: Acute pancreatitis (AP) is characterised by an inflammatory response that in its most severe form can cause a systemic dysregulated immune response and progression to acute multi-organ dysfunction. The pathobiology of the disease is unclear and as a result no targeted, disease-modifying therapies exist. We performed a scoping review of data pertaining to the human immunology of AP to summarise the current field and to identify future research opportunities.

Methods: A scoping review of all clinical studies of AP immunology was performed across multiple databases. Studies were included if they were human studies of AP with an immunological outcome or intervention.

Results: 205 studies met the inclusion criteria for the review. Severe AP is characterised by significant immune dysregulation compared to the milder form of the disease. Broadly, this immune dysfunction was categorised into: innate immune responses (including profound release of damage-associated molecular patterns and heightened activity of pattern recognition receptors), cytokine profile dysregulation (particularly IL-1, 6, 10 and TNF-α), lymphocyte abnormalities, paradoxical immunosuppression (including HLA-DR suppression and increased co-inhibitory molecule expression), and failure of the intestinal barrier function. Studies including interventions were also included. Several limitations in the existing literature have been identified; consolidation and consistency across studies is required if progress is to be made in our understanding of this disease.

Conclusions: AP, particularly the more severe spectrum of the disease, is characterised by a multifaceted immune response that drives tissue injury and contributes to the associated morbidity and mortality. Significant work is required to develop our understanding of the immunopathology of this disease if disease-modifying therapies are to be established.

Keywords: acute pancreatitis (AP); human; immune dysregulation; immunodeficiency; immunopathology; scoping review.

Figure 1

PRISMA flow diagram of study screening and selection. Adapted from The PRISMA 2020 statement: an updated guideline for reporting systematic reviews (9).

Figure 2

Summary of the current understanding of the immunopathogenesis of severe acute pancreatitis (SAP). The initial pancreatic injury can be instigated by a variety of noxious stimuli; acinar cell injury releases damage-associated molecular patterns (DAMPs). DAMPs are recognised by pattern-recognition receptors (PRR), which activate tissue and peripheral blood leukocytes and triggers the inflammatory cytokine release. The sequelae include alterations in lymphocyte phenotype, paradoxical hallmarks of immunosuppression, and a systemic inflammatory syndrome of endothelial dysfunction. Increased vascular permeability that causes distributory shock and multi-organ failure also occurs. Local and systemic factors induce failure of the intestinal barrier, promoting bacterial translocation. The relative immunodeficiency and increased intestinal permeability significantly increase the risk of secondary infectious complications.