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.

CONCLUSION:

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: Joel D Taurog, Claudia Rival, Leonie M van Duivenvoorde, Nimman Satumtira, Martha L Dorris, Margaret Sun, John M Shelton, James A Richardson, F Kent Hamra, Robert E Hammer, Kenneth S K Tung
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 64 Issue 8 Pg. 2518-28 (Aug 2012) ISSN: 1529-0131 [Electronic] United States
• PMID: 22488218 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 by the American College of Rheumatology.

Chemical References

• Cytokines
• DAZL protein, rat
• HLA-B27 Antigen
• RNA-Binding Proteins

Topics

• Animals
• Autoimmune Diseases (complications, immunology)
• Cytokines (metabolism)
• Disease Models, Animal
• Epididymis (metabolism, surgery)
• Epididymitis (complications, immunology)
• Female
• HLA-B27 Antigen (genetics)
• Immunity, Innate (immunology)
• Male
• Orchitis (complications, immunology)
• Phenotype
• RNA-Binding Proteins (genetics)
• Rats
• Rats, Sprague-Dawley
• Rats, Transgenic
• Sex Characteristics
• Spondylarthritis (etiology, genetics, immunology)
• Testis (metabolism, surgery)
• Transgenes (genetics)