ArticleArthritis research & therapy2021
Cross-reactivity of IgM anti-modified protein antibodies in rheumatoid arthritis despite limited mutational load.
Article in Arthritis research & therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 22 citations in OpenAlex.
- Anti-Modified Protein Antibodies in Rheumatoid Arthritis: Pathogenic, Protective, or Passive Bystander?Immunological reviews · 2026Review
- Therapeutic IgG- and IgM-specific proteases disarm the acetylcholine receptor autoantibodies that drive myasthenia gravis pathology.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Regulators and Conductors of Immunity: Natural Immune System in Health and Autoimmunity.International journal of molecular sciences · 2025Review
- Smoking as a risk factor for rheumatoid arthritis: predominant association with IgA autoantibodies - comprehensive analysis of anti-modified protein antibodies with smoking and genetic risk factors in rheumatoid arthritis.Arthritis research & therapy · 2025Article
- Acetylated bacterial proteins as potent antigens inducing an anti-modified protein antibody response.RMD open · 2024Article
- The peculiar features, diversity and impact of citrulline-reactive autoantibodies.Nature reviews. Rheumatology · 2024Review
- Autoimmunity to stromal-derived autoantigens in rheumatoid ectopic germinal centers exacerbates arthritis and affects clinical response.The Journal of clinical investigation · 2024Article
- Autoreactive B cells in rheumatoid arthritis include mainly activated CXCR3+ memory B cells and plasmablasts.JCI insight · 2023Article
- TLR7 and IgM: Dangerous Partners in Autoimmunity.Antibodies (Basel, Switzerland) · 2023Review
- From risk to chronicity: evolution of autoreactive B cell and antibody responses in rheumatoid arthritis.Nature reviews. Rheumatology · 2022Review
- The current status of anti-citrullinated protein antibodies and citrullinated protein-reactive B cells in the pathogenesis of rheumatoid arthritis.Molecular biology reports · 2022Review
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Authors and funding
17 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAnti-modified protein antibodies (AMPA) targeting citrullinated, acetylated and/or carbamylated self-antigens are hallmarks of rheumatoid arthritis (RA). Although AMPA-IgG cross-reactivity to multiple post-translational modifications (PTMs) is evident, it is unknown whether the first responding B cells, expressing IgM, display similar characteristics or if cross-reactivity is crucially dependent on somatic hypermutation (SHM). We now studied the reactivity of (germline) AMPA-IgM to further understand the breach of B cell tolerance and to identify if cross-reactivity depends on extensive SHM. Moreover, we investigated whether AMPA-IgM can efficiently recruit immune effector mechanisms.
methodsPolyclonal AMPA-IgM were isolated from RA patients and assessed for cross-reactivity towards PTM antigens. AMPA-IgM B cell receptor sequences were obtained by single cell isolation using antigen-specific tetramers. Subsequently, pentameric monoclonal AMPA-IgM, their germline counterparts and monomeric IgG variants were generated. The antibodies were analysed on a panel of PTM antigens and tested for complement activation.
resultsPentameric monoclonal and polyclonal AMPA-IgM displayed cross-reactivity to multiple antigens and different PTMs. PTM antigen recognition was still present, although reduced, after reverting the IgM into germline. Valency of AMPA-IgM was crucial for antigen recognition as PTM-reactivity significantly decreased when AMPA-IgM were expressed as IgG. Furthermore, AMPA-IgM was 15- to 30-fold more potent in complement-activation compared to AMPA-IgG.
conclusionsWe provide first evidence that AMPA-IgM are cross-reactive towards different PTMs, indicating that PTM (cross-)reactivity is not confined to IgG and does not necessarily depend on extensive somatic hypermutation. Moreover, our data indicate that a diverse set of PTM antigens could be involved in the initial tolerance breach in RA and suggest that AMPA-IgM can induce complement-activation and thereby inflammation.
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