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

作者:Taurog Joel D*; Rival Claudia; van Duivenvoorde Leonie M; Satumtira Nimman; Dorris Martha L; Sun Margaret; Shelton John M; Richardson James A; Hamra F Kent; Hammer Robert E; Tung Kenneth S K
来源:Arthritis and Rheumatism, 2012, 64(8): 2518-2528.
DOI:10.1002/art.34480

摘要

Objective Male rats transgenic for HLAB27 and human beta 2-microglobulin (h beta 2m) spontaneously develop epididymoorchitis (EO) preceding the development of spondylarthritis (SpA). In the specific B27/h beta 2m-transgenic rat cross-strain (21-3 x 382-2)F1, 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 x 382-2)F1 rats are causally related. In addition, the primary characteristics of EO in this rat arthritis model were assessed. Methods Male B27/h beta 2m-transgenic (21-3 x 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 antitestis 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-gamma, 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 HLAB27/h beta 2mtransgenic (21-3 x 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.

  • 出版日期2012-8