Immune profiling links autoimmune hepatitis to human herpes virus 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 Immunoprecipitation-Sequencing (PhIP-seq) 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 herpes virus 6 (HHV-6). Pre-incubation with the HHV-6 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 anti-fibrotic receptor, RXFP1, which inhibited re..., DNA libraries were barcoded and amplified, gel purified, and subjected to Next-Generation Sequencing on an Illumina NextSeq or NovaSeq Instruments (Illumina, San Diego, CA). Sequencing reads from raw fastq files were aligned to the reference library using RAPSearch2, and RPK was calculated. This data is uploaded here., , # PhIP-Seq in Autoimmune Hepatitis

[https://doi.org/10.5061/dryad.kh18932hj](https://doi.org/10.5061/dryad.kh18932hj)

## Description of the data and file structure

Two files have been uploaded: 

1\) \"AIH PhIP-Seq Phaser Epitope Scanning.csv\" - this file contains the peptide level PhIP-seq data generated in deep mutational scanning experiments using a selected PhIP-seq library for epitope mapping. Raw sequencing were aligned to the input PhIP-seq library using RAPSearch2, and then RPK were calculated, and uploaded in this csv file. 

2\) \"AIH PhIP Seq Experimental Data.csv\" - this file contains the peptide level PhIP-seq data generated in the AIH and control patient PhIP-seq experiments using a phage display library spanning the entire human proteome. Raw sequencing were aligned to the input PhIP-seq library using RAPSearch2, and then RPK were calculated, and uploaded in this csv file. 

### Files and variables

#### File: AIH_PhIP-Seq_Phaser_Epitope_Scanning.csv

**Description:** Ph..., We confirm that all participants provided explicit consent for their de-identified data to be shared in the public domain. All personal identifiers, including names, contact information, and any other data that could reasonably be used to identify individual participants, have been removed or anonymized. Any remaining data have been generalized or aggregated as needed to prevent re-identification. This ensures that the dataset is fully de-identified and safe for public use.