A Predictive Autoantibody Signature in Multiple Sclerosis

Zamecnik, Colin R.; Sowa, Gavin M.; Abdelhak, Ahmed; Dandekar, Ravi; Bair, Rebecca; Wade, Kristen J.; Bartley, Christopher M.; Tubati, Asritha; Gomez, Refujia; Fouassier, Camille; Gerungan, Chloe; Alexander, Jessica; Wapniarski, Anne E.; Loudermilk, Rita P.; Eggers, Erica L.; Zorn, Kelsey C.; Ananth, Kirtana; Jabassini, Nora; Mann, Sabrina A; Ragan, Nicholas R; Santaniello, Adam; Henry, Roland G.; Baranzini, Sergio E.; Zamvil, Scott S.; Bove, Riley; Guo, Chu-Yueh; Gelfand, Jeffrey M.; Cuneo, Richard; Büdingen, H.-Christian von; Oksenberg, Jorge R.; Cree, Bruce A.C.; Hollenbach, Jill A.; Green, Ari J.; Wallin, Mitchell T.; DeRisi, Joseph L.; Wilson, Michael R.

doi:10.1101/2023.05.01.23288943

Cited by 6 publications

(10 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, we demonstrate the direct translatability of our results to autoimmunity in MS, one of the most common autoimmune diseases 26 . The recent study by Zamecnik et al 26 detailed an auto-antibody profile in ∼8% of MS cases, believed to stem from EBV-induced molecular mimicry.…”

Section: Discussionsupporting

confidence: 53%

“… A) Frequency of EBV mimicry (defined as EBV 8mers with ≤1 (left) or ≤2 mismatches (right)) in autoantibody targets in MS patients pre and post diagnosis. Dotted lines show the rate of peptides with an EBV mimic for auto-antibodies found in either in no participannt, in healthy controls, or in the previously identified IC Cluster (Zamecnik et al 26 ). B) Left: Peptide sequences of the top non-IC Cluster and most frequent post MS diagnosis auto-antibodies.…”

Section: Resultsmentioning

confidence: 96%

“…Data was retrieved from Zamecnik et al 2023 26 . Reads per 100,000 (rpK) were used to calculate FC for each peptides of MS patients based on the control mean and distribution separately for the pre-diagnosis and post-diagnosis timepoint.…”

Section: Analysis Of Phip-seq Autoantibodiesmentioning

confidence: 99%

“…Finally, we sought to evaluate whether our viral mimics could explain auto-antibodies in a pathological autoimmune disease. Due to the strong epidemiological association between multiple sclerosis (MS) and EBV 33 , we leveraged the recently generated data from Zamecnik et al 26 to further evaluate how linear mimicry may play a role in the MS autoimmune pathophysiology. Previously, Zamecnik et al 26 screened for auto-antibodies against the human proteome using Phip-seq, a technique used to identify auto-antibodies against 49 AA long linear peptides from the human proteome.…”

Section: Molecular Mimicry Explains Portions Of the Multiple Sclerosi...mentioning

confidence: 99%

“…Due to the strong epidemiological association between multiple sclerosis (MS) and EBV 33 , we leveraged the recently generated data from Zamecnik et al 26 to further evaluate how linear mimicry may play a role in the MS autoimmune pathophysiology. Previously, Zamecnik et al 26 screened for auto-antibodies against the human proteome using Phip-seq, a technique used to identify auto-antibodies against 49 AA long linear peptides from the human proteome. The authors found that approximately 8% of MS patients will have an auto-antibody signature that contains a motiff found in EBV's Envelope Glyocprotein M and BRRF2, with this signature refered to as an immunogenic cluster (IC Cluster).…”

Section: Molecular Mimicry Explains Portions Of the Multiple Sclerosi...mentioning

confidence: 99%

See 4 more Smart Citations

Molecular Mimicry as a Mechanism of Viral Immune Evasion and Autoimmunity

Maguire,

Wang,

Ramasamy

et al. 2024

Preprint

View full text Add to dashboard Cite

Mimicry of host protein structures ("molecular mimicry") is a common mechanism employed by viruses to evade the host's immune system. To date, studies have primarily evaluated molecular mimicry in the context of full protein structural mimics. However, recent work has demonstrated that short linear amino acid (AA) molecular mimics can elicit cross-reactive antibodies and T-cells from the host, which may contribute to development and progression of autoimmunity. Despite this, the prevalence of molecular mimics throughout the human virome has not been fully explored. In this study, we evaluate 134 human infecting viruses and find significant usage of linear mimicry across the virome, particularly those in the herpesviridae and poxviridae families. Furthermore, we identify that proteins involved in cellular replication and inflammation, those expressed from autosomes, the X chromosome, and in thymic cells are over-enriched in viral mimicry. Finally, we demonstrate that short linear mimicry from Epstein-Barr virus (EBV) is significantly higher in auto-antibodies found in multiple sclerosis patients to a greater degree than previously appreciated. Our results demonstrate that human-infecting viruses frequently leverage mimicry in the course of their infection, point to substantial evolutionary pressure for mimicry, and highlight mimicry's important role in human autoimmunity. Clinically, our findings could translate to development of novel therapeutic strategies that target viral infections linked to autoimmunity, with the goal of eliminating disease-associated latent viruses and preventing their reactivation.

show abstract

Section: Discussionsupporting

confidence: 53%

Section: Resultsmentioning

confidence: 96%

Section: Analysis Of Phip-seq Autoantibodiesmentioning

confidence: 99%

Section: Molecular Mimicry Explains Portions Of the Multiple Sclerosi...mentioning

confidence: 99%

Section: Molecular Mimicry Explains Portions Of the Multiple Sclerosi...mentioning

confidence: 99%

See 3 more Smart Citations

Molecular Mimicry as a Mechanism of Viral Immune Evasion and Autoimmunity

Maguire,

Wang,

Ramasamy

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Herpes viral infection and the multiple sclerosis prodrome: is HHV-6A infection a second hit?

Cree

2023

Brain

View full text Add to dashboard Cite

show abstract

Novel autoantibody targets identified in patients with autoimmune hepatitis (AIH) by PhIP-Seq reveals pathogenic insights

Klepper

Kung

Vazquez

et al. 2023

Preprint

View full text Add to dashboard Cite

While the identification of autoantigens remains a critical challenge in understanding and treating autoimmune diseases, the role of autoantibodies in the pathophysiology of autoimmune hepatitis (AIH) is uncertain. To better characterize the antigenic landscape of AIH, we employed Phage Immunoprecipitation-Sequencing (PhIP-Seq) to identify novel autoantibodies specific to patients. Using these results, a logistic regression classifier was able to predict which patients had AIH, relative to healthy controls indicating the presence of a distinct humoral immune signature. To further investigate the autoantibodies most specific to AIH, significant peptides were identified with >98% specificity relative to a broad array of controls (298 patients with NAFLD, PBV, or healthy controls). Top ranked autoreactive targets included anti-SLA, a well-recognized autoantibody in AIH, and a second hit to disco interacting protein 2 homolog A (DIP2A). The autoreactive fragment of DIP2A shares a nearly identical 8 amino acid stretch with the U27 protein of HHV-6, a virus known to reside in the liver. Finally, peptides derived from the 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, 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 THP1 cells relative to anti-RXFP1 negative control serum, while depletion of IgG abrogated this effect. These data demonstrate that PhIP-Seq is a powerful discovery tool, capable of identifying known and novel autoantibody targets in AIH, lending additional supporting evidence that HHV6 may play a role in the development of AIH, and pointing 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.

show abstract

A Predictive Autoantibody Signature in Multiple Sclerosis

Cited by 6 publications

References 70 publications

Molecular Mimicry as a Mechanism of Viral Immune Evasion and Autoimmunity

Molecular Mimicry as a Mechanism of Viral Immune Evasion and Autoimmunity

Herpes viral infection and the multiple sclerosis prodrome: is HHV-6A infection a second hit?

Novel autoantibody targets identified in patients with autoimmune hepatitis (AIH) by PhIP-Seq reveals pathogenic insights

Contact Info

Product

Resources

About