Klepper Arielle, Asaki James, Kung Andrew F, Vazquez Sara E, Bodansky Aaron, Mitchell Anthea, Mann Sabrina A, Zorn Kelsey, Avila-Vargas Isaac, Kari Swathi, Tekeste Melawit, Castro Javier, Lee Briton, Duarte Maria, Khalili Mandana, Yang Monica, Wolters Paul, Price Jennifer, Perito Emily, Feng Sandy, Maher Jacquelyn J, Lai Jennifer C, Weiler-Normann Christina, Lohse Ansgar W, DeRisi Joseph, Tana Michele
Department of Medicine, University of California, San Francisco, USA.
UCSF Liver Center.
medRxiv. 2024 Oct 29:2023.06.12.23291297. doi: 10.1101/2023.06.12.23291297.
Autoimmune hepatitis (AIH) is a severe disease characterized by elevated immunoglobin levels. However, the role of autoantibodies in the pathophysiology of AIH remains uncertain.
Phage Immunoprecipitation-Sequencing (PhIP-seq) was employed to identify autoantibodies in the serum of patients with AIH ( = 115), compared to patients with other liver diseases (metabolic associated steatotic liver disease (MASH) = 178, primary biliary cholangitis (PBC), = 26, or healthy controls, = 94).
Logistic regression using PhIP-seq enriched peptides as inputs yielded a classification AUC of 0.81, indicating the presence of a predictive humoral immune signature for AIH. Embedded within this signature were disease relevant targets, including SLA/LP, the target of a well-recognized autoantibody in AIH, disco interacting protein 2 homolog A (DIP2A), and the relaxin family peptide receptor 1 (RXFP1). The autoreactive fragment of DIP2A was a 9-amino acid stretch nearly identical to the U27 protein of human herpes virus 6 (HHV-6). Fine mapping of this epitope suggests the HHV-6 U27 sequence is preferentially enriched relative to the corresponding DIP2A sequence. Antibodies against RXFP1, a receptor involved in anti-fibrotic signaling, were also highly specific to AIH. The enriched peptides are within a motif adjacent to the receptor binding domain, required for signaling and serum from AIH patients positive for anti-RFXP1 antibody was able to significantly inhibit relaxin-2 singling. Depletion of IgG from anti-RXFP1 positive serum abrogated this effect.
These data provide evidence for a novel serological profile in AIH, including a possible functional role for anti-RXFP1, and antibodies that cross react with HHV6 U27 protein.
自身免疫性肝炎（AIH）是一种以免疫球蛋白水平升高为特征的严重疾病。然而，自身抗体在AIH病理生理学中的作用仍不确定。
采用噬菌体免疫沉淀测序（PhIP-seq）技术，对115例AIH患者血清中的自身抗体进行鉴定，并与其他肝病患者（代谢相关脂肪性肝病（MASH）178例、原发性胆汁性胆管炎（PBC）26例或健康对照94例）进行比较。
以PhIP-seq富集肽为输入进行逻辑回归分析，分类AUC为0.81，表明存在AIH的预测性体液免疫特征。该特征中包含与疾病相关的靶点，包括SLA/LP（AIH中一种公认自身抗体的靶点）、盘状相互作用蛋白2同源物A（DIP2A）和松弛素家族肽受体1（RXFP1）。DIP2A的自身反应性片段是一个9个氨基酸的序列，与人类疱疹病毒6（HHV-6）的U27蛋白几乎相同。该表位的精细定位表明，相对于相应的DIP2A序列，HHV-6 U27序列优先富集。针对参与抗纤维化信号传导的受体RXFP1的抗体对AIH也具有高度特异性。富集的肽位于与受体结合域相邻的基序内，该基序是信号传导所必需的，来自抗RXFP1抗体阳性的AIH患者的血清能够显著抑制松弛素-2信号传导。从抗RXFP1阳性血清中去除IgG可消除这种效应。
这些数据为AIH的一种新的血清学特征提供了证据，包括抗RXFP1可能的功能作用以及与HHV6 U27蛋白交叉反应的抗体。
