What is the autoantigen in Primary Sclerosing Cholangitis (PSC)?

Autoantigens in Primary Sclerosing Cholangitis (PSC)

The primary autoantigen in PSC has not been definitively identified, but the most frequently detected autoantibodies are atypical perinuclear anti-neutrophil cytoplasmic antibodies (atypical p-ANCA), which target components of the nuclear envelope rather than the typical cytoplasmic targets in vasculitis.

Autoantibody Profile in PSC

Atypical p-ANCA

• Present in 26-96% of PSC patients 1
• Unlike classical p-ANCA in vasculitis (which target myeloperoxidase), the "atypical" p-ANCA in PSC:
  • Targets components of the nuclear envelope 1
  • Retains perinuclear staining pattern even after formaldehyde fixation (unlike classical p-ANCA) 1
  • Is also found in ulcerative colitis (60-87%) and Crohn's disease (5-25%) 1

Other Common Autoantibodies in PSC

• Anti-nuclear antibodies (ANA): Found in 8-77% of patients 1
• Smooth muscle antibodies (SMA): Present in up to 83% of patients 1
• Anticardiolipin antibodies: Correlate with disease severity and Mayo risk score 2

Specific Antigenic Targets

Neutrophil-Related Targets

• Bactericidal/permeability-increasing protein (BPI): Antibodies found in 46% of PSC patients 3
• Cathepsin G: Antibodies present in 23% of patients 3
• Lactoferrin: Antibodies detected in 22% of patients 3

Biliary Epithelial Cell Targets

• Autoantibodies against biliary epithelial cells (BECs) are found in 63% of PSC patients 4
• These antibodies predominantly react with cytokine-stimulated BECs (90% of cases) 4
• PSC sera recognize a specific 40 kDa protein band on BEC membranes 4
• PDZK1 (PDZ domain containing 1) has been identified as a potential autoantigen in 9% of PSC patients 5
• IgA autoantibodies against biliary epithelial cells are present in a majority of PSC patients and correlate with faster disease progression 6

Clinical Relevance of Autoantibodies

• Antibodies to BPI and cathepsin G are associated with cirrhosis 3
• Antibodies to lactoferrin are more frequent in PSC patients with concurrent ulcerative colitis 3
• Anticardiolipin antibodies correlate with disease severity and histological stage 2
• IgA autoantibodies against BECs are associated with faster progression to clinical endpoints (death or liver transplantation) 6

Diagnostic Implications

• Despite their prevalence, these autoantibodies lack diagnostic specificity for PSC 1
• Routine autoantibody screening is not required to establish a diagnosis of PSC 1
• The diagnosis of PSC is primarily based on cholestatic liver biochemistry and typical cholangiographic features 1
• Testing for autoantibodies may be relevant when suspecting PSC-AIH overlap syndrome 1

Key Points for Clinicians

• No single pathognomonic autoantigen has been identified for PSC
• Atypical p-ANCA is the most common autoantibody but lacks specificity
• Multiple autoantibodies are often present simultaneously (81% of patients have ≥3 autoantibodies) 2
• The presence of specific autoantibodies may help identify clinical subsets of PSC with different prognoses
• Diagnosis should rely on cholangiographic features and exclusion of secondary causes rather than autoantibody testing