Differential Pathways Orchestrate Plasma-Cell Infiltration in Liver Autoimmunity Diseases

Plasma cells (PCs) are frequently infiltrating livers from autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). However, the molecular pathway(s) implicated remain largely undefined.

A retrospective in situ study was performed to assess the cells and molecules involved in PC chemotactism and survival. Relevant in vitro assays were conducted to confirm the activity of the identified molecules.

We found that myeloid cells producing the PC survival factor a proliferation-inducing ligand (APRIL) were present in livers from both diseases. Notably, APRIL density both at the level of producing cells and tissue retention of their secreted product correlated with PC accumulation in portal tracts from AIH but not PBC. PCs from AIH livers expressed the B-cell maturation antigen and CD138 as the APRIL (co)receptors. Consequently, AIH liver PCs responded to APRIL stimulation with an increase in vitro survival. We further identified IL-16 produced by infiltrating lymphocytes as a chemokine involved in PC recruitment. IL-16 expression also correlated with PC accumulation in portal spaces from AIH but again not from PBC. Follow-up biopsies in AIH showed that treatment expectedly reduced PC density and affected in a similar way the density of APRIL-producing cells. Notably, the density of secreted APRIL was less affected. Finally, the density of IL-16-producing cells was not affected.

Our data show that PC infiltration and persistence is under the guidance of different pathways in AIH and PBC. In AIH, treatment leaves the PC chemotactism pathway unaffected, while partly downregulating the survival pathway.