Autoantigen-selected B cells are bystanders in spontaneous T cell-driven experimental autoimmune hepatitis

Abstract

Autoreactive B cells are considered pathogenic drivers in many autoimmune dis-eases; however, it is not clear whether autoimmune B cells are invariably patho-genic or whether they can also arise as bystanders of T cell-driven autoimmunepathology. Here, we studied the B cell response in an autoantigen- and CD4+Tcell-driven model of autoimmune hepatitis (AIH), the Alb-iGP_Smarta mouse inwhich expression of a viral model antigen (GP) in hepatocytes and its recognitionby GP-specific CD4+T cells causes spontaneous AIH-like disease. T cell-drivenAIH in Alb-iGP_Smarta mice was marked by autoantibodies and hepatic infiltra-tion of plasma cells and B cells, particularly of isotype-switched memory B cells,indicating antigen-driven selection and activation. Immunosequencing of B cellreceptor repertoires confirmed B cell expansion selectively in the liver, which wasmost likely driven by the hepatic GP model antigen, as indicated by branched net-works of connected sequences and elevated levels of IgG antibodies toGP. However, intrahepatic B cells did not produce increased levels of cytokinesand their depletion with anti-CD20 antibody did not alter the CD4+T cellresponse in Alb-iGP_Smarta mice. Moreover, B cell depletion did not preventspontaneous liver inflammation and AIH-like disease in Alb-iGP_Smarta mice. Inconclusion, selection and isotype-switch of liver-infiltrating B cells was dependenton the presence of CD4+T cells recognizing liver antigen. However, recognitionof hepatic antigen by CD4+T cells and CD4+T cell-mediated hepatitis was notdependent on B cells. Thus, autoreactive B cells can be bystanders and need notbe drivers of liver inflammation in AIH.