Autoimmune regulator deficiency causes sterile epididymitis and infertility characterized by infiltration of iron-laden macrophages

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B643
Abstract ID: 5374

Presenting Author:
Soo Hyun Ahn , Research Associate Professor at Michigan State Univ. Col. of Vet. Med.

Abstract:

Men with Autoimmune Polyglandular Syndrome Type 1 (APS-1), a disease caused by a mutation in the gene encoding Autoimmune regulator (Aire), can suffer infertility, but the mechanism is not known. Using transgenic animals and a novel mass spectrometry to detect trace elements (LA-ICP-TOF-MS), we set out to determine the role of immune cells in male infertility using a mouse model of APS-1. We generated a transgenic mouse line with targeted mutations in Aire (AireKO) alone, or in both Aire and Rag1 (AireKORag1KO) using CRISPR/Cas9 on the Balb/c background. The resulting AireKO males were almost completely infertile compared to WT and AireKORag1KO males. All AireKO males (n=10) had epididymitis characterized by fibrosis and infiltration of T and B cells and macrophages as early as 8 weeks of age. LA-ICP-TOF-MS showed increased iron concentration in the interstitium that co-registered with F4/80+ macrophages using structural similarity index matrix. Immune cell infiltration, fibrosis, or iron-laden macrophages were absent in AIREKORAG1KO mice. Our results reveal the importance of Aire-mediated immune tolerance in preservation of fertility and suggest that in the absence of Aire, autoreactive T and B lymphocytes target the epididymis and promote inflammation that ultimately results in fibrosis. Further studies will reveal the specific role of lymphocytes in causing these changes, and the significance of iron deposition in fibrosis development.