Immune profiling links autoimmune hepatitis to human herpesvirus 6 and relaxin receptor antigens

Autoimmune hepatitis (AIH) is a severe, chronic disease where IgG elevation and autoantibody profile are defining features. However, linking autoantibodies to AIH pathogenesis remains elusive. We employed phage-display immunoprecipitation sequencing and uncovered a novel humoral signature specific to AIH. Embedded within this signature were antibodies against the known AIH autoantigen SLA/LP and novel reactivities to disco-interacting protein 2 homolog A (DIP2A), and the relaxin family peptide receptor 1 (RXFP1). Fine mapping of the DIP2A epitope revealed preferential enrichment for a nearly identical 9-amino acid sequence derived from the U27 protein of human herpesvirus 6 (HHV6). Preincubation with the HHV6 epitope blocked DIP2A binding, consistent with cross-reactivity. AIH patients positive for anti-DIP2A had higher titers of HHV6 IgG, suggestive of reactivation. AIH patients had antibodies against the antifibrotic receptor, RXFP1, which inhibited relaxin-2 signaling in an IgG-dependent manner. These data provide evidence for a novel serological profile in AIH, linking HHV6 reactivation anti-RXFP1 antibodies to disease pathogenesis.