Pathomechanisms of autoimmune orchitis

C RIVAL, VA GUAZZONE, MS THEAS, L LUSTIG

Giessen, Alemania

Workshop; 4th International Workshop of Molecular Andrology; 2005

TESTICULAR CELL INTERACTIONS IN AUTOIMMUNE ORCHITIS Vanesa A. Guazzone, Claudia Rival, Mar¨ªa S. Theas and Livia Lustig Center for Research in Reproduction, School of Medicine, University of Buenos Aires, Argentina Testicular antigens expressed in haploid germ cells appear after puberty when immunocompetence is already established. However, the normal testis has the ability to tolerate these autoantigens. Certain stimuli such as inflammation, infections or trauma can overwhelm control mechanisms and induce a testicular autoimmune disease with infertility. We developed an experimental model of autoimmune orchitis (EAO) in rats by active immunization with spermatic antigens and adjuvants characterized by an interstitial lymphomononuclear cell infiltrate and severe damage of seminiferous tubules (ST). Although the pathogenic role of CD4+ T cells has been established in EAO, the behaviour of other immune cells of the testis has been little explored. The number of ED2+ and ED1+ cells (resident macrophages and monocytes recently arrived from circulation, respectively) significantly increased in the testicular interstitium of rats with EAO compared to controls (C) and correlated with the degree of tubular damage. The early increase of macrophage inflammatory protein (MIP-1¦Á) concentration in the conditioned media of testicular macrophages (CMTM) of rats with EAO, compared to C, as well as the increase of monocyte chemoattractant protein-1 (MCP-1) in the late phase of the disease suggest a temporal variation and a selective role of these chemokines in the recruitment of mononuclear cells to the testis. The content of IL-6 and TNF¦Á (ELISA) in the CMTM of rats with EAO was significantly higher compared to C. We demonstrated that IL-6 and TNF¦Á added to cultures of ST segments induce germ cell apoptosis. In vitro results and the increased number of IL6R+ and TNFR1+ germ cells of rats with EAO suggest that both cytokines are involved in the induction of germ cell apoptosis in EAO. The increased caspase 8 and 9 activity and cytochrome c release indicated that germ cell apoptosis in EAO occurs through the extrinsic and mitochondrial pathways. Our results suggest that in EAO macrophages change their immunosuppressor profile to an inflammatory profile by secreting chemokines that attract lymphomonocytes to the testis, as well as cytokines, such as IL-6 and TNF¦Á. Acting together with other local factors as Fas L, they trigger germ cell apoptosis.