Pathogenic insights into immune-mediated sclerosing cholangiopathies From autoantibody formation to cholangiocellular defence mechanisms

In immune-mediated cholestatic liver diseases bile flow is impaired due to biliary tree damage induced or perpetuated by an excessive immune-response often against self-antigens. Primary sclerosing cholangitis (PSC) and IgG4-related cholangitis (IRC) are characterized by inflammation and consequent sclerosing (scarring) of the bile ducts, which leads to cirrhosis and need for liver transplantation when inadequately treated. To arrive at new, increasingly selective treatment strategies that slow down disease progression, it is important to understand the potentially disrupted underlying regulatory mechanisms in cholangiocytes.
This thesis focusses on identifying protective machinery and autoantigens in cholangiocytes, and investigates the potentially pathogenic role of autoantibodies against these targets in PSC and IRC.
We found that: 1) The ion transporters SLC9A1, SLC26A2 and SLC26A6 protect cholangiocytes from toxic bile acids and may be transcriptionally regulated by peroxisome proliferator-activated receptors. 2) Individuals with PSC and IRC have autoantibodies against carbonic anhydrase (CA) enzymes, which catalyse the reaction CO₂ + H₂O ⇌ HCO₃- + H⁺. In particular, anti-CA5B autoantibodies are highly prevalent and functionally inhibit the human enzyme. 3) Individuals with IRC possess autoantibodies against laminin 511, an extracellular matrix protein substantially secreted by cholangiocytes that enhances barrier function and protects against T cell-induced barrier dysfunction. Notably, the autoantigens galectin-3 and prohibitin 1 do not have clear protective functions in cholangiocytes.
This suggests that certain – but not all – autoantibodies in PSC and IRC may disrupt protective mechanisms of cholangiocytes comprising: HCO₃- production and secretion, a sensory component, and epithelial barrier tightness, collectively termed the “cholangiocyte defence triangle”.