Bidirectional causal relationships between antibody-mediated immune responses and autoimmune diseases: Insights from Mendelian randomization analysis

Autoimmune diseases like systemic lupus erythematosus (SLE) and multiple sclerosis (MS) involve intricate interactions between immune responses and genetic factors, and this study aimed to explore the causal and bidirectional relationships between antibody-mediated immune responses and these diseases to deepen understanding of their mechanisms. A bidirectional 2-sample Mendelian randomization (MR) approach was used, with genetic variants as instrumental variables; antibody data were obtained from the UK Biobank, and autoimmune disease data from the FinnGen database. Generalized summary data-based MR and complementary MR methods were applied to ensure robust results, and Bonferroni-adjusted thresholds were used to address multiple testing. The results showed that elevated levels of Epstein-Barr virus EBNA-1 and ZEBRA antibodies were associated with a reduced risk of SLE, while higher human herpesvirus 7 U14 antibody levels increased SLE risk; for MS, higher Epstein-Barr virus EBNA-1 antibody levels were linked to an increased risk. Bidirectional analyses revealed that autoimmune diseases such as SLE and MS also affect antibody levels, indicating a complex 2-way interaction. This study identifies the bidirectional relationships between antibody-mediated immune responses and autoimmune diseases, notes that pathogen-specific antibody levels can act as protective or risk factors depending on the disease, and provides new insights into the immunopathogenesis of SLE and MS as well as potential directions for therapeutic intervention.

• Publication year

  2026

• Venue

  Medicine

• Publication date

  2026-01-02

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1097/MD.0000000000047013PMID 41496099PMCID 12778236
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2021cited by this paper
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  2020cited by this paper
• Factorial Mendelian randomization: using genetic variants to assess interactions

  2019cited by this paper
• 'Mendelian randomization': an approach for exploring causal relations in epidemiology.

  2017cited by this paper
• Interpreting findings from Mendelian randomization using the MR-Egger method

  2017cited by this paper
• Progressive multiple sclerosis: from pathogenic mechanisms to treatment.

  2016cited by this paper
• Human autoimmune diseases: a comprehensive update

  2015cited by this paper
• Low intrathecal immune response of anti-EBNA-1 antibodies and EBV DNA from multiple sclerosis patients.

  2011cited by this paper
• Human herpesvirus 6 and 7 reactivation and disease activity in multiple sclerosis.

  2011cited by this paper
• Diagnosis and therapy of autoimmune hepatitis.

  2009cited by this paper
• Aberrant Epstein-Barr viral infection in systemic lupus erythematosus.

  2009cited by this paper
• Plasma Titers of Antibodies against Epstein-Barr Virus BZLF1 and Risk of Multiple Sclerosis

  2007cited by this paper
• Consistent dissection of the protein interaction network by combining global and local metrics Genome

  2007cited by this paper
• Mendelian randomization: a new approach to studying epidemiology in ESRD.

  2006cited by this paper
• Epstein-Barr virus and molecular mimicry in systemic lupus erythematosus

  2006cited by this paper
• Epstein-Barr virus infection induces lupus autoimmunity.

  2006influential reference
• [Mendelian randomization].

  2005cited by this paper
• Association between clinical disease activity and Epstein–Barr virus reactivation in MS

  2000cited by this paper
• A pilot study on the antibodies to HHV-6 variants and HHV-7 in CSF of MS patients.

  1999cited by this paper
• Diagnosis of Epstein-Barr virus-related diseases.

  1996influential reference
• Statistical Methods in Medical Research Mendelian Randomization as an Instrumental Variable Approach to Causal Inference Mendelian Randomization as an Instrumental Variable Approach to Causal Inference

  year unknowncited by this paper

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