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

Joel D Taurog, Claudia Rival, Leonie M. Van Duivenvoorde, Nimman Satumtira, Martha L. Dorris, Margaret Sun, John M. Shelton, James A Richardson, Franklin K Hamra, Robert E Hammer, Kenneth S K Tung

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2518-2528
Number of pages11
JournalArthritis and Rheumatism
Volume64
Issue number8
DOIs
StatePublished - Aug 2012

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Spondylarthritis
Transgenic Rats
HLA-B27 Antigen
Testis
Transgenes
Inflammation
Arthritis
Spondylitis
Epididymis
Rete Testis
Interleukin-23
Interleukin-17
Castration
Innate Immunity
Germ Cells
Interleukin-10
Interferons
Testosterone
Macrophages
T-Lymphocytes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Autoimmune epididymoorchitis is essential to the pathogenesis of male-specific spondylarthritis in HLA-B27-transgenic rats. / Taurog, Joel D; Rival, Claudia; Van Duivenvoorde, Leonie M.; Satumtira, Nimman; Dorris, Martha L.; Sun, Margaret; Shelton, John M.; Richardson, James A; Hamra, Franklin K; Hammer, Robert E; Tung, Kenneth S K.

In: Arthritis and Rheumatism, Vol. 64, No. 8, 08.2012, p. 2518-2528.

Research output: Contribution to journalArticle

Taurog, Joel D ; Rival, Claudia ; Van Duivenvoorde, Leonie M. ; Satumtira, Nimman ; Dorris, Martha L. ; Sun, Margaret ; Shelton, John M. ; Richardson, James A ; Hamra, Franklin K ; Hammer, Robert E ; Tung, Kenneth S K. / Autoimmune epididymoorchitis is essential to the pathogenesis of male-specific spondylarthritis in HLA-B27-transgenic rats. In: Arthritis and Rheumatism. 2012 ; Vol. 64, No. 8. pp. 2518-2528.
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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 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.",
author = "Taurog, {Joel D} and Claudia Rival and {Van Duivenvoorde}, {Leonie M.} and Nimman Satumtira and Dorris, {Martha L.} and Margaret Sun and Shelton, {John M.} and Richardson, {James A} and Hamra, {Franklin K} and Hammer, {Robert E} and Tung, {Kenneth S K}",
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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

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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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