Autoimmune epididymoorchitis is essential to the pathogenesis of male-specific spondylarthritis in HLA–B27–transgenic rats
Article first published online: 27 JUL 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 8, pages 2518–2528, August 2012
How to Cite
Taurog, J. D., Rival, C., van Duivenvoorde, L. M., Satumtira, N., Dorris, M. L., Sun, M., Shelton, J. M., Richardson, J. A., Hamra, F. K., Hammer, R. E. and Tung, K. S. K. (2012), Autoimmune epididymoorchitis is essential to the pathogenesis of male-specific spondylarthritis in HLA–B27–transgenic rats. Arthritis & Rheumatism, 64: 2518–2528. doi: 10.1002/art.34480
- Issue published online: 27 JUL 2012
- Article first published online: 27 JUL 2012
- Accepted manuscript online: 5 APR 2012 11:47AM EST
- Manuscript Accepted: 20 MAR 2012
- Manuscript Received: 9 OCT 2011
- NIH. Grant Numbers: R01-AR-38319, R01-AI-41236
- Arthritis Foundation
- EMBO. Grant Number: ASTF 202.00-2010
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)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 × 382-2)F1 rats are causally related. In addition, the primary characteristics of EO in this rat arthritis model were assessed.
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.
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.
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.