TY - JOUR
T1 - Autoimmune epididymoorchitis is essential to the pathogenesis of male-specific spondylarthritis in HLA-B27-transgenic rats
AU - Taurog, Joel D
AU - Rival, Claudia
AU - Van Duivenvoorde, Leonie M.
AU - Satumtira, Nimman
AU - Dorris, Martha L.
AU - Sun, Margaret
AU - Shelton, John M.
AU - Richardson, James A
AU - Hamra, Franklin K
AU - Hammer, Robert E
AU - Tung, Kenneth S K
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
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U2 - 10.1002/art.34480
DO - 10.1002/art.34480
M3 - Article
C2 - 22488218
AN - SCOPUS:84864440555
SN - 0004-3591
VL - 64
SP - 2518
EP - 2528
JO - Arthritis and rheumatism
JF - Arthritis and rheumatism
IS - 8
ER -