Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus
- PMID: 29593104
- PMCID: PMC5918293
- DOI: 10.1126/scitranslmed.aan2306
Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus
Abstract
The earliest autoantibodies in lupus are directed against the RNA binding autoantigen Ro60, but the triggers against this evolutionarily conserved antigen remain elusive. We identified Ro60 orthologs in a subset of human skin, oral, and gut commensal bacterial species and confirmed the presence of these orthologs in patients with lupus and healthy controls. Thus, we hypothesized that commensal Ro60 orthologs may trigger autoimmunity via cross-reactivity in genetically susceptible individuals. Sera from human anti-Ro60-positive lupus patients immunoprecipitated commensal Ro60 ribonucleoproteins. Human Ro60 autoantigen-specific CD4 memory T cell clones from lupus patients were activated by skin and mucosal Ro60-containing bacteria, supporting T cell cross-reactivity in humans. Further, germ-free mice spontaneously initiated anti-human Ro60 T and B cell responses and developed glomerular immune complex deposits after monocolonization with a Ro60 ortholog-containing gut commensal, linking anti-Ro60 commensal responses in vivo with the production of human Ro60 autoantibodies and signs of autoimmunity. Together, these data support that colonization with autoantigen ortholog-producing commensal species may initiate and sustain chronic autoimmunity in genetically predisposed individuals. The concept of commensal ortholog cross-reactivity may apply more broadly to autoimmune diseases and lead to novel treatment approaches aimed at defined commensal species.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Conflict of interest statement
Figures
![Fig. 1](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5918293/bin/nihms959857f1.gif)
![Fig. 2](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5918293/bin/nihms959857f2.gif)
![Fig. 3](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5918293/bin/nihms959857f3.gif)
![Fig. 4](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5918293/bin/nihms959857f4.gif)
![Fig. 5](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5918293/bin/nihms959857f5.gif)
![Fig. 6](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5918293/bin/nihms959857f6.gif)
![Fig. 7](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5918293/bin/nihms959857f7.gif)
![Fig. 8](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5918293/bin/nihms959857f8.gif)
Comment in
-
Bacterial orthologues of Ro60 trigger disease.Nat Rev Rheumatol. 2018 Jun;14(6):322. doi: 10.1038/s41584-018-0008-6. Nat Rev Rheumatol. 2018. PMID: 29691493 No abstract available.
-
Molecular (Me)micry?Cell Host Microbe. 2018 May 9;23(5):576-578. doi: 10.1016/j.chom.2018.04.012. Cell Host Microbe. 2018. PMID: 29746828
Similar articles
-
Immune responses to Ro60 and its peptides in mice. I. The nature of the immunogen and endogenous autoantigen determine the specificities of the induced autoantibodies.J Exp Med. 1999 Feb 1;189(3):531-40. doi: 10.1084/jem.189.3.531. J Exp Med. 1999. PMID: 9927515 Free PMC article.
-
Evidence for multiple shared antigenic determinants within Ro60 and other lupus-related ribonucleoprotein autoantigens in human autoimmune responses.J Immunol. 2005 Dec 1;175(11):7669-77. doi: 10.4049/jimmunol.175.11.7669. J Immunol. 2005. PMID: 16301677
-
Spreading of the immune response from 52 kDaRo and 60 kDaRo to calreticulin in experimental autoimmunity.Lupus. 1998;7(1):7-11. doi: 10.1191/096120398678919606. Lupus. 1998. PMID: 9493142
-
The Ro 60 kDa autoantigen comes into focus: interpreting epitope mapping experiments on the basis of structure.Autoimmun Rev. 2006 Jul;5(6):367-72. doi: 10.1016/j.autrev.2005.10.004. Epub 2005 Nov 15. Autoimmun Rev. 2006. PMID: 16890888 Review.
-
Ro60 and Y RNAs: structure, functions, and roles in autoimmunity.Crit Rev Biochem Mol Biol. 2019 Apr;54(2):133-152. doi: 10.1080/10409238.2019.1608902. Epub 2019 May 14. Crit Rev Biochem Mol Biol. 2019. PMID: 31084369 Free PMC article. Review.
Cited by
-
Emerging role of gut microbiota in autoimmune diseases.Front Immunol. 2024 May 3;15:1365554. doi: 10.3389/fimmu.2024.1365554. eCollection 2024. Front Immunol. 2024. PMID: 38765017 Free PMC article. Review.
-
Appraising SARS-CoV-2 infections after full mRNA COVID-19 vaccination in patients with systemic lupus erythematosus (SLE).Clin Immunol Commun. 2022 Dec;2:54-56. doi: 10.1016/j.clicom.2022.03.002. Epub 2022 Mar 10. Clin Immunol Commun. 2022. PMID: 38620676 Free PMC article.
-
Activated B-Cells enhance epitope spreading to support successful cancer immunotherapy.Front Immunol. 2024 Mar 19;15:1382236. doi: 10.3389/fimmu.2024.1382236. eCollection 2024. Front Immunol. 2024. PMID: 38571942 Free PMC article. Review.
-
Potential clinical implications of molecular mimicry-induced autoimmunity.Immun Inflamm Dis. 2024 Feb;12(2):e1178. doi: 10.1002/iid3.1178. Immun Inflamm Dis. 2024. PMID: 38415936 Free PMC article. Review.
-
The gut microbiome in systemic lupus erythematosus: lessons from rheumatic fever.Nat Rev Rheumatol. 2024 Mar;20(3):143-157. doi: 10.1038/s41584-023-01071-8. Epub 2024 Feb 6. Nat Rev Rheumatol. 2024. PMID: 38321297 Review.
References
-
- Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, Harley JB. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349:1526–1533. - PubMed
-
- Sontheimer RD, McCauliffe DP, Zappi E, Targoff I. Antinuclear antibodies: Clinical correlations and biologic significance. Adv Dermatol. 1992;7:3–52. discussion 53. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- K08 AI095318/AI/NIAID NIH HHS/United States
- UL1 RR024139/RR/NCRR NIH HHS/United States
- T32 AI007019/AI/NIAID NIH HHS/United States
- T32 GM007223/GM/NIGMS NIH HHS/United States
- F32 ES026227/ES/NIEHS NIH HHS/United States
- P30 DK079310/DK/NIDDK NIH HHS/United States
- R01 GM073863/GM/NIGMS NIH HHS/United States
- T32 AR007016/AR/NIAMS NIH HHS/United States
- R01 AI118855/AI/NIAID NIH HHS/United States
- P30 AR053495/AR/NIAMS NIH HHS/United States
- R25 GM104553/GM/NIGMS NIH HHS/United States
- T32 AI007210/AI/NIAID NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials