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Chronic inflammation drives epididymal tertiary lymphoid structure formation and autoimmune fertility disorders in mice

Author

Listed:
  • Maia L. Elizagaray

    (Massachusetts General Hospital and Harvard Medical School)

  • Ferran Barrachina

    (Massachusetts General Hospital and Harvard Medical School)

  • Maria C. Avenatti

    (Massachusetts General Hospital and Harvard Medical School)

  • Isinsu Bastepe

    (Massachusetts General Hospital and Harvard Medical School)

  • Angela Chen

    (Massachusetts General Hospital and Harvard Medical School)

  • Ainize Odriozola

    (Massachusetts General Hospital and Harvard Medical School
    University of the Basque Country (UPV/EHU)
    Bizkaia Health Research Institute
    MEPRO Medical Reproductive Solutions)

  • Oluchi Ukairo

    (Massachusetts General Hospital and Harvard Medical School)

  • Vanina G. Da Ros

    (Massachusetts General Hospital and Harvard Medical School
    Ciudad Autónoma de Buenos Aires)

  • Kiera Ottino

    (Massachusetts General Hospital and Harvard Medical School)

  • Nerea Subiran

    (University of the Basque Country (UPV/EHU)
    Bizkaia Health Research Institute
    MEPRO Medical Reproductive Solutions)

  • Maria A. Battistone

    (Massachusetts General Hospital and Harvard Medical School)

Abstract

Gaps in knowledge about the epididymal mucosa contribute to the prevalent classification of male idiopathic infertility. Inflammatory triggers, such as infections and autoimmunity, can breach immune privilege, induce anti-sperm antibody (ASA) production, and impair fertility. However, the mechanisms governing ASA production are poorly characterized. Here, using a murine model of epididymitis induced by regulatory T cell (Treg) depletion, we show that the disruption of immunotolerance leads to chronic autoimmunity characterized by the presence of ASA, and distinct testicular and epididymal immune landscapes. These inflammatory features impair sperm function, contribute to epididymal damage, and drive subfertility. Treg depletion induces the formation of tertiary lymphoid structures (TLS) within the epididymis, as indicated by the presence of B and T cell clusters, fibroblasts, and high endothelial venules. Similar autoantibody responses were detected in the seminal plasma of infertile patients, suggesting conserved mechanisms. Thus, we provide an in-depth analysis of immune cell dynamics and TLS during epididymitis, offering insights for the development of precision-targeted therapies for fertility disorders, as well as the identification of new contraceptive strategies.

Suggested Citation

  • Maia L. Elizagaray & Ferran Barrachina & Maria C. Avenatti & Isinsu Bastepe & Angela Chen & Ainize Odriozola & Oluchi Ukairo & Vanina G. Da Ros & Kiera Ottino & Nerea Subiran & Maria A. Battistone, 2025. "Chronic inflammation drives epididymal tertiary lymphoid structure formation and autoimmune fertility disorders in mice," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63514-y
    DOI: 10.1038/s41467-025-63514-y
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    References listed on IDEAS

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    1. John W. Hickey & Winston R. Becker & Stephanie A. Nevins & Aaron Horning & Almudena Espin Perez & Chenchen Zhu & Bokai Zhu & Bei Wei & Roxanne Chiu & Derek C. Chen & Daniel L. Cotter & Edward D. Espli, 2023. "Organization of the human intestine at single-cell resolution," Nature, Nature, vol. 619(7970), pages 572-584, July.
    2. Jean-Ju Chung & Betsy Navarro & Grigory Krapivinsky & Luba Krapivinsky & David E. Clapham, 2011. "A novel gene required for male fertility and functional CATSPER channel formation in spermatozoa," Nature Communications, Nature, vol. 2(1), pages 1-12, September.
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