Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Autoimmunity to Sperm and Testicular Antigens Precedes Onset of Spondyloarthritis in HLA-B27/Hu-2-Microglobulin Transgenic Rats.
Taurog1, Joel D., Rival3, Claudia, Dorris2, Martha, Satumtira2, Nimman, Sun3, Margaret, Tung3, Kenneth S. K.
In all lines of rats transgenic (TG) for HLA-B27 and human b2m that develop spondyloarthritis (SpA), epididymo-orchitis (EO) develops in nearly all males. In the B27/Hub2m TG (21-3×283-2)F1 rats (A&R 54:1317, 2006), in which only males develop SpA, EO is evident as scrotal swelling at a median age of 100 d, which is 50 d and 90 d, respectively, before the median time of onset of arthritis and spondylitis,. We have previously found that castration (i.e., bilateral resection of testis and epididymis) by 91 d of age prevents subsequent SpA (A&R 60s:1168, 2009). Here, we sought to investigate the pathogenesis of the EO and to characterize the autoimmune response to sperm and testis antigens.
B27/Hub2m TG 21-3×283-2 F1 males underwent either castration, unilateral castration, or sham castration between ages 36 d and 125 d. Castrated rats were given testosterone replacement. Rats were observed for > 300 d for EO, arthritis, and spondylitis. Resected tissue was examined for histopathology and by immunohistology. Serum was examined for anti-sperm and anti-testis cell antibodies by IF and ELISA.
As a rule, inflammation was first evident in the ductuli efferentes (DE, small ducts that link the rete testis to the epididymis) adjacent to the testis. As early as age 36 d, focal periductal neutrophils and mononuclear cells were detected, some penetrating the basal lamina. By 62 d, there was extensive mononuclear cell granulomatous inflammation in the DE. This was more severe by age 77 d, when aspermatogenesis was evident, coinciding with the appearance of anti-sperm and anti-testis cell antibodies in serum. Rats castrated after onset of orchitis showed a decline in these antibodies, even when arthritis developed later.
Immunohistological examination identified massive infiltration of activated macrophages and activated T cells surrounding the granulomatous lesions in the testis, but not elsewhere. In addition, granular deposition of rat IgG, presumed to reflect immune complexes, were deposited at the periphery of the seminiferous tubules. Indirect IF showed that the serum autoantibodies bind to antigens in the testis cell cytoplasm, sperm acrosome, and sperm tail. Thus both T cell and antibody-mediated mechanisms participate in the autoimmune EO, but the T cell-mediated processes appear first and are primary.
The B27/Hub2m transgenes initiate characteristic T cell-mediated inflammation in the ductus efferentes that becomes granulomatous. Orchitis appears later, coinciding with the appearance of anti-sperm and anti-testis cell antibodies in serum, presumably as a result of an ongoing autoimmune response to sperm and other testicular antigens. As previously shown, bilateral castration prevented subsequent development of SpA if carried out before the age of onset of arthritis, even if advanced EO was already present. The data therefore suggest that the process of prolonged inflammation and antigenic stimulation within the testis and epididymis is an essential precursor of SpA in (21-3×283-2) F1 B27/Hub2m TG rats. More generally, persistent autoimmune inflammation in one site seems linked causally to autoimmunity targeting a second site.
To cite this abstract, please use the following information:
Taurog, Joel D., Rival, Claudia, Dorris, Martha, Satumtira, Nimman, Sun, Margaret, Tung, Kenneth S. K.; Autoimmunity to Sperm and Testicular Antigens Precedes Onset of Spondyloarthritis in HLA-B27/Hu-2-Microglobulin Transgenic Rats. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1448