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

Maia L. Elizagaray, Ferran Barrachina, Maria C. Avenatti, Isinsu Bastepe, Angela Chen, Ainize Odriozola, Oluchi Ukairo, Vanina G. Da Ros, Kiera Ottino, Nerea Subiran and Maria A. Battistone ()
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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
Oluchi Ukairo: Massachusetts General Hospital and Harvard Medical School
Vanina G. Da Ros: Massachusetts General Hospital and Harvard Medical School
Kiera Ottino: Massachusetts General Hospital and Harvard Medical School
Nerea Subiran: University of the Basque Country (UPV/EHU)
Maria A. Battistone: Massachusetts General Hospital and Harvard Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63514-y

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