Autoimmune epididymoorchitis is essential to the pathogenesis of male-specific spondylarthritis in HLA-B27-transgenic rats

Joel D Taurog, Claudia Rival, Leonie M. Van Duivenvoorde, Nimman Satumtira, Martha L. Dorris, Margaret Sun, John M. Shelton, James A Richardson, Franklin K Hamra, Robert E Hammer, Kenneth S K Tung

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Abstract

Objective Male rats transgenic for HLA-B27 and human β2- microglobulin (hβ2m) spontaneously develop epididymoorchitis (EO) preceding the development of spondylarthritis (SpA). In the specific B27/hβ2m-transgenic rat cross-strain (21-3 × 382-2)F 1, only the males develop SpA, and neither sex develops gut inflammation. This study was undertaken to determine whether EO and SpA in male (21-3 × 382-2)F1 rats are causally related. In addition, the primary characteristics of EO in this rat arthritis model were assessed. Methods Male B27/hβ2m-transgenic (21-3 × 382-2)F1 rats underwent bilateral, unilateral, or sham epididymoorchiectomy between ages 36 and 125 days. The castrated rats were given testosterone replacement. Alternatively, the 21-3 and 283-2 transgene loci were crossed with a transgene inducing aspermatogenesis. Rats were observed for the development of EO, arthritis, and spondylitis. Results In unmanipulated transgenic rats, inflammation was first evident in the ductuli efferentes (DE; ducts linking the rete testis to epididymis) as early as age 30 days. The inflammation was initially neutrophilic, and later became granulomatous. Antisperm and anti-testis cell antibodies appeared in the rat serum after age 70 days. Cells infiltrating the testes were predominantly CD4+ T cells and CD68+ or CD163+ macrophages. Quantitative polymerase chain reaction of the DE, epididymis, and testis showed elevations in the levels of interferon-γ, interleukin-10 (IL-10), and IL-17A. In addition, levels of IL-12A, IL-22, IL-23A, and IL-23 receptor were found to be elevated in the DE. Remarkably, castration of the rats before age 91 days completely prevented the subsequent onset of arthritis and spondylitis, as did transgene-induced azospermia. Conclusion Autoimmune EO develops spontaneously in HLA-B27/hβ2m-transgenic (21-3 × 283-2)F1 rats at age 30 days, the age when antigen-positive meiotic germ cells first exit the testis. Persistent testicular inflammation and/or antigenic stimulation are essential prerequisites for the subsequent development of SpA. Thus, dysregulated innate immunity at immune-privileged sites may be an essential mechanism triggering the onset of SpA.

Original languageEnglish (US)
Pages (from-to)2518-2528
Number of pages11
JournalArthritis and rheumatism
Volume64
Issue number8
DOIs
StatePublished - Aug 1 2012

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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