Antígenos prostáticos como posibles blanco de la respuesta autoinmune en enfermedades humanas y modelos experimentales

• Autores: Motrich, Rubén Dario
• Año de publicación: 2007
• Idioma: español castellano
• Tipo de recurso: tesis doctoral
• Colaborador/a o director/a de tesis: Rivero, Virginia Elena; Daniotti, José Luis; Juncos Allende, Luis Isaías; Riera, Clelia María; Giambartolomei, Guillermo Hernán
• Materia: Autoinmunidad; Antígeno prostático específico; Vesiculas seminales; Modelo experimental; Prostatitis; Semen; Próstata
• Institución: Universidad Nacional de Córdoba

Tesis (Dr. en Ciencias Químicas) - - Universidad Nacional de Córdoba. Facultad de Ciencias Químicas, 2007.
Fil: Motrich, Rubén Dario. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina.
Fil: Motrich, Rubén Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigación en Bioquímica Clínica e Inmunología; Argentina.
The prostate is a male accessory gland whose main function is to secrete several substances that compose seminal plasma. The latter has many roles being the principal one to constitute the optimal medium for sperm survival, and many other ones, such as being a defense barrier against male urogenital infections and exerting complex effects in the female genital tract for achieving a pregnancy. The prostate is not only important because of its physiology but also for its pathology. It is a key target of several and very prevalent diseases in the clinical practice. Benign prostate hypertrophy, prostate cancer and prostate inflammation or prostatitis are the more common diseases affecting the prostate. Prostatitis accounts for the 10% of visits in the uro!ogy clinic and Chronic Non Bacteria! Prostatitis or Chronic Pelvic Pain Syndrome (Prostatitis NIH-III) represents 90% of them. CPPS is an inf!ammatory condition of the prostate gland without any apparent cause. Many hypotheses have been postu!ated to exp!ain its etiology: cryptic infections, autoimmunity against prostate antigens, a neurogenic mechanism, etc. In addition, the information regarding the relationship between chronic prostatitis and male infertility is very scarce. The litt!e information about prostate pathology and its consequences is due, at least in part, to the lack of experimental animal modeis. Taking all these data into account, the aim of this thesis project was to assess the possible autoimmune etiology of CPPS, its consequences and to advance in the development and study of adequate animal mode!s that mirror human pathology. A group of patients with an established diagnosis of CPPS was analyzed and an autoimmune response against prostate antigens was evidenced in 34% of patients. They showed the presence of IFN-y secreting !ymphocytes ab!e to activate, proliferate and secrete high leve!s of IFN-y when they were stimulated with different prostate antigens in vitro. These inflammatory response was evidenced sistemically (peripheral bl000d mononuclear cel!s) as well as loca!ly by the finding of elevated leveis of pro-imflammatory cytokines, such as IFN-y, TNF-a and IL-10, in seminal plasma. Besides, striking abnormalities in the semen quality of these patients was evidenced suggesting a link between chronic prostatitis and a decreased semen quality. Later on and with the aim of advancing on understanding the immunopathogenic underlying mechanisms, the experimental model of autoimmune prostatitis deve!oped in NOD mice was studied. Prostate antigens immunized animals deve!oped a strong cellular and humoral immune response against prostate and it was accompanied by a strong infiltration and tissue damage. This autoimmune response against prostate antigens showed a marked bias to a Thl profile. The findings in this animal model reproduced what it was previously found in human disease, which supports its validity as an experimental model for CPPS. The immune repertoire rised afier the immunization with prostate antigens was also analyzed and it was shown that certain T lymphocytes clones emerge in ah autoimmune animais upon immunizations. This finding suggests that these clones may be considered the driver clones of the disease. Another objetive of the present thesis proj ect was to study the putative relationship between chronic prostatitis and maJe fertility which was achieved studing the EAP model in Wistar rats. Autoimmune animais develop a strong autoimmune response against prostate antigens that can be detected sistemicahly (spleen and draining lymph nodes) and locally (semen). In addition, these animais evidenced a marked decreased semen quality. The sperm alterations were only present in semen and not in epidydimal sperm and it was shown that soluble factors (such as inflammatory mediators and cytokines) present in the autoimmune seminal plasma were responsible for them. These findings mirrored what it was previosuly found in human disease confirming the sperm cehis start to be affected when they join the prostate inflammatory secretions during ejaculation. Finahly and with the aim of assesing if the sperm alterations were able to impair maJe fertility, mating studies with fertile female rats were performed. It was demonstrated that autoimmune animals evidenced decreased fertility indexes as well as high leveis of pre and post implantation embryo loss. These findings demonstrated that an autoimmune response against prostate is able to seriuosly compromise male fertility.
Fil: Motrich, Rubén Dario. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina.
Fil: Motrich, Rubén Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigación en Bioquímica Clínica e Inmunología; Argentina.