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Novel autoantibody targets identified in patients with autoimmune hepatitis (AIH) by PhIP-Seq reveals pathogenic insights
Autoimmune hepatitis (AIH) is a severe autoimmune disease, characterized by the presence of autoantibodies. However, the role of autoantibodies in the pathophysiology of AIH remains uncertain. Here, we employed Phage Immunoprecipitation-Sequencing (PhIP-Seq) to identify novel autoantibodies in AIH....
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312872/ https://www.ncbi.nlm.nih.gov/pubmed/37398174 http://dx.doi.org/10.1101/2023.06.12.23291297 |
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author | Klepper, Arielle Kung, Andrew Vazquez, Sara E. Mitchell, Anthea Mann, Sabrina 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 Weiler-Normann, Christina Lohse, Ansgar W DeRisi, Joseph Tana, Michele |
author_facet | Klepper, Arielle Kung, Andrew Vazquez, Sara E. Mitchell, Anthea Mann, Sabrina 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 Weiler-Normann, Christina Lohse, Ansgar W DeRisi, Joseph Tana, Michele |
author_sort | Klepper, Arielle |
collection | PubMed |
description | Autoimmune hepatitis (AIH) is a severe autoimmune disease, characterized by the presence of autoantibodies. However, the role of autoantibodies in the pathophysiology of AIH remains uncertain. Here, we employed Phage Immunoprecipitation-Sequencing (PhIP-Seq) to identify novel autoantibodies in AIH. Using these results, a logistic regression classifier was able to predict which patients had AIH, indicating the presence of a distinct humoral immune signature. To further investigate the autoantibodies most specific to AIH, significant peptides were identified relative to a broad array of controls (298 patients with non-alcoholic fatty liver disease (NAFLD), primary biliary cholangitis (PBC), or healthy controls). Top ranked autoreactive targets included SLA, the target of a well-recognized autoantibody in AIH, and disco interacting protein 2 homolog A (DIP2A). The autoreactive fragment of DIP2A shares a 9-amino acid stretch nearly identical to the U27 protein of HHV-6B, a virus found in the liver. In addition, antibodies against peptides derived from the leucine rich repeat N-terminal (LRRNT) domain of the relaxin family peptide receptor 1 (RXFP1) were highly enriched and specific to AIH. The enriched peptides map to a motif adjacent to the receptor binding domain, which is required for RXFP1 signaling. RXFP1 is a G protein-coupled receptor that binds relaxin-2, an anti-fibrogenic molecule shown to reduce the myofibroblastic phenotype of hepatic stellate cells. Eight of nine patients with antibodies to RXFP1 had evidence of advanced fibrosis (F3 or greater). Furthermore, serum from AIH patients positive for anti-RFXP1 antibody was able to significantly inhibit relaxin-2 signaling in the human monocytic cell line, THP1. Depletion of IgG from anti-RXFP1 positive serum abrogated this effect. These data provide supporting evidence that HHV6 plays a role in the development of AIH and point to a potential pathogenic role for anti-RXFP1 IgG in some patients. Identification of anti-RXFP1 in patient serum may enable risk stratification of AIH patients for fibrosis progression and lead to the development of novel strategies for disease intervention. |
format | Online Article Text |
id | pubmed-10312872 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-103128722023-07-01 Novel autoantibody targets identified in patients with autoimmune hepatitis (AIH) by PhIP-Seq reveals pathogenic insights Klepper, Arielle Kung, Andrew Vazquez, Sara E. Mitchell, Anthea Mann, Sabrina 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 Weiler-Normann, Christina Lohse, Ansgar W DeRisi, Joseph Tana, Michele medRxiv Article Autoimmune hepatitis (AIH) is a severe autoimmune disease, characterized by the presence of autoantibodies. However, the role of autoantibodies in the pathophysiology of AIH remains uncertain. Here, we employed Phage Immunoprecipitation-Sequencing (PhIP-Seq) to identify novel autoantibodies in AIH. Using these results, a logistic regression classifier was able to predict which patients had AIH, indicating the presence of a distinct humoral immune signature. To further investigate the autoantibodies most specific to AIH, significant peptides were identified relative to a broad array of controls (298 patients with non-alcoholic fatty liver disease (NAFLD), primary biliary cholangitis (PBC), or healthy controls). Top ranked autoreactive targets included SLA, the target of a well-recognized autoantibody in AIH, and disco interacting protein 2 homolog A (DIP2A). The autoreactive fragment of DIP2A shares a 9-amino acid stretch nearly identical to the U27 protein of HHV-6B, a virus found in the liver. In addition, antibodies against peptides derived from the leucine rich repeat N-terminal (LRRNT) domain of the relaxin family peptide receptor 1 (RXFP1) were highly enriched and specific to AIH. The enriched peptides map to a motif adjacent to the receptor binding domain, which is required for RXFP1 signaling. RXFP1 is a G protein-coupled receptor that binds relaxin-2, an anti-fibrogenic molecule shown to reduce the myofibroblastic phenotype of hepatic stellate cells. Eight of nine patients with antibodies to RXFP1 had evidence of advanced fibrosis (F3 or greater). Furthermore, serum from AIH patients positive for anti-RFXP1 antibody was able to significantly inhibit relaxin-2 signaling in the human monocytic cell line, THP1. Depletion of IgG from anti-RXFP1 positive serum abrogated this effect. These data provide supporting evidence that HHV6 plays a role in the development of AIH and point to a potential pathogenic role for anti-RXFP1 IgG in some patients. Identification of anti-RXFP1 in patient serum may enable risk stratification of AIH patients for fibrosis progression and lead to the development of novel strategies for disease intervention. Cold Spring Harbor Laboratory 2023-06-27 /pmc/articles/PMC10312872/ /pubmed/37398174 http://dx.doi.org/10.1101/2023.06.12.23291297 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Klepper, Arielle Kung, Andrew Vazquez, Sara E. Mitchell, Anthea Mann, Sabrina 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 Weiler-Normann, Christina Lohse, Ansgar W DeRisi, Joseph Tana, Michele Novel autoantibody targets identified in patients with autoimmune hepatitis (AIH) by PhIP-Seq reveals pathogenic insights |
title | Novel autoantibody targets identified in patients with autoimmune hepatitis (AIH) by PhIP-Seq reveals pathogenic insights |
title_full | Novel autoantibody targets identified in patients with autoimmune hepatitis (AIH) by PhIP-Seq reveals pathogenic insights |
title_fullStr | Novel autoantibody targets identified in patients with autoimmune hepatitis (AIH) by PhIP-Seq reveals pathogenic insights |
title_full_unstemmed | Novel autoantibody targets identified in patients with autoimmune hepatitis (AIH) by PhIP-Seq reveals pathogenic insights |
title_short | Novel autoantibody targets identified in patients with autoimmune hepatitis (AIH) by PhIP-Seq reveals pathogenic insights |
title_sort | novel autoantibody targets identified in patients with autoimmune hepatitis (aih) by phip-seq reveals pathogenic insights |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312872/ https://www.ncbi.nlm.nih.gov/pubmed/37398174 http://dx.doi.org/10.1101/2023.06.12.23291297 |
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