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

## TL;DR

Autoimmune hepatitis is linked to antibodies against a herpesvirus and a relaxin receptor, suggesting a new path to understanding the disease.

## Contribution

The study identifies a novel autoantibody signature in autoimmune hepatitis, linking it to human herpesvirus 6 and the relaxin receptor.

## Key findings

- Autoantibodies in AIH patients target DIP2A and RXFP1, with cross-reactivity to human herpesvirus 6.
- Anti-RXFP1 antibodies inhibit relaxin-2 signaling, potentially promoting fibrosis.
- HHV6 IgG titers are higher in AIH patients with anti-DIP2A antibodies, suggesting viral reactivation.

## Abstract

Patients with autoimmune hepatitis have a unique autoantibody signature, yielding clues about disease pathophysiology, including evidence for cross-reactivity with a common herpesvirus, human herpesvirus 6, and antibodies targeting the antifibrotic relaxin receptor with potential to promote fibrosis progression.

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.