Epididymo-orchitis: basic aspects

JACOBO PV; GUAZZONE VA; PÉREZ CV; THEAS MS; LUSTIG L

Atenas

Congreso; VI Congreso Europeo de Andrología; 2010

Academia Europea de Andrología

Infection and inflammation of the male genital tract are a frequent cause or co-factor of male fertility disorders. Epididymoorchitis is mainly attributable to specific pathogens (Gram negative or positive bacteria, Mycoplasma and viruses) but also may originate as an autoimmune reaction to sperm antigens. Vas deferens retrograde innoculation of Escherichia coli induces epididymitisin rats. In this in vivo modelepididymal immune and epithelial cells express functional Toll like receptor (TLR)4 which upon recognition of LPS from E. coli can induce a specific signaling cascade that results in NFkapa-B activation. Also, it was recently demonstrated in vitro that testicular macrophages and Sertoli cells express TLRs which interacting with uropathogenic E. coli use alternative signalling pathways preventing pro-inflammatory cytokine secretion. Although early andadequate antimicrobial treatment eradicates the pathogen, nonbacterial inflammation may induce tissue damage and autoimmune reactions to sperm antigens, compromising fertility. Experimental autoimmune orchitis (EAO) and epididymitis can be elicited in mice or rats by immune-manipulation such as day-3 thymectomy or by active immunization with testis homogenate and adjuvants. Epididymitis has also been induced in mice by active immunization with testicular germ cells followed by vasectomy, a procedure which facilitates germ cell leakage into the interstitium inducing a sperm autoimmune reaction. In EAO rats, histopathology shows interstitial lympho-mononuclear cell infiltrates in the testis and epididymis and apoptosis and severe germ cell sloughing in the seminiferous tubules. We previously demonstrated that during the development of EAO, numerous dendritic cells (DC), macrophages and T cells (CD4+ and CD8+) infiltrate the testis. Our recent data on DC from testicular draining lymph node of rats with orchitis showing up-regulation of MHC class II and IL-12p35 mRNA and their capacity to induce proliferation of T cells in vitro suggest thatDC are mature, able to present antigens to T cells and to stimulate an autoimmune response against testicular antigens. The expression of T-bet and RORgamma-t as well as TNF-alpha, IFN-gamma, and IL-17 showed a Th1 and Th17 profile of the autoimmune response in EAO suggesting a role of both cell lineages in tissue inflammation. These cytokines may also be involved in the alteration of blood testis barrier permeability and in the variations of cell adhesion molecule expression and localization at the seminiferous tubules that we detected in rats with EAO. Concomitantly with the presence of Teffector subsets in the testes of rats with EAO we observed a significant increase in the number of regulatory T cells (Treg) Foxp3+ (CD4+ and CD8+). By in vitro functional studies we demonstrated that Treg CD4+ CD25+Foxp3+ are able to suppress proliferation of T cells stimulated with spermatic antigens and also express TGF-beta1. Although Treg subsets are actively accumulated into the testis they fail to suppress inflammation in EAO rats. It is possible that these cells are outnumbered by the even more vigorously expanding Teffector subset. Factors present in the inflamed testis might limit the efficacy of Tregs to abrogate the inflammatory process that results in aspermatogenesis and infertility.