title: Autoimmune epididymoorchitis is essential to the pathogenesis of male-specific spondylarthritis in HLA-B27-transgenic rats.
abstract: OBJECTIVE
  Male rats transgenic for HLA-B27 and human β(2) -microglobulin (hβ(2) m) spontaneously develop epididymoorchitis (EO) preceding the development of spondylarthritis (SpA). In the specific B27/hβ(2) m-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)F(1)  rats are causally related. In addition, the primary characteristics of EO in this rat arthritis model were assessed.
  
  
  METHODS
  Male B27/hβ(2) m-transgenic (21-3 × 382-2)F(1)  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.
  
  
  CONCLUSIONS
  Autoimmune EO develops spontaneously in HLA-B27/hβ(2) m-transgenic (21-3 × 283-2)F(1)  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.
authors.affiliation: Rheumatic Diseases Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8884, USA. joel.taurog@utsouthwestern.edu
authors.forename: Joel D
authors.initials: JD
authors.lastname: Taurog
authors.forename: Claudia
authors.initials: C
authors.lastname: Rival
authors.forename: Leonie M
authors.initials: LM
authors.lastname: van Duivenvoorde
authors.forename: Nimman
authors.initials: N
authors.lastname: Satumtira
authors.forename: Martha L
authors.initials: ML
authors.lastname: Dorris
authors.forename: Margaret
authors.initials: M
authors.lastname: Sun
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: F Kent
authors.initials: FK
authors.lastname: Hamra
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.forename: Kenneth S K
authors.initials: KS
authors.lastname: Tung
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000150:complications* / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004822:Epididymis / Q000378:metabolism / Q000601:surgery; D004823:Epididymitis / Q000150:complications* / Q000276:immunology; D005260:Female; D015796:HLA-B27 Antigen / Q000235:genetics*; D007113:Immunity, Innate / Q000276:immunology; D008297:Male; D009920:Orchitis / Q000150:complications* / Q000276:immunology; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012727:Sex Characteristics; D025241:Spondylarthritis / Q000209:etiology* / Q000235:genetics* / Q000276:immunology; D013737:Testis / Q000378:metabolism / Q000601:surgery; D019076:Transgenes / Q000235:genetics
chemical_list: D016207:Cytokines; C512808:DAZL protein, rat; D015796:HLA-B27 Antigen; D016601:RNA-Binding Proteins