The mechanisms of development of sperm antibodies in men are unclear. Multiple antigens appear to be involved in the pathogenesis of sperm autoimmunity, but most of the epitopes reacting with the autoantibodies are unknown. Some of the antigens identified are inrracellular proteins, and it is difficult to understand how antibodies to these could cause an abnormality of sperm function. The antibodies may be naturally occurring to sperm-coating proteins from the epididymis. It is certain that non-pepride antigens are involved. Oligosaccharide or glycolipid epitopes may have cross-reactions with bacteria or other cells. The different patterns of immunobead binding to the sperm surface: head, neck, tail, tail tip may result either from antibodies binding to different antigens in these locations, or from variations in the total amount of antibodies on the sperm.
Mechanism of Immunization
The mechanism of immunization is poorly understood. Alterations in immunomodulatory factors in the seminal plasma of men with sperm autoimmunity suggests that a loss of immune tolerance is involved in the pathogenesis. The autoantibodies could appear in the genital tract due to defects in the blood-tesris barrier or possibly because of impairment of the immunomodulatory mechanisms that allow the testis to be an immunologically privileged organ. These antibodies may also be produced by lymphocytes resident in the epithelium of the epididymis.
Effect of Autoantibodies on Sperm
Sperm antibodies of different immunoglobulin classes can be found in the serum and seminal plasma as well as on the sperm itself. IgG and IgA sperm antibodies (particularly secretory IgA) locally produced in the male genital tract may cause the greatest interference with sperm function.
Sperm antibodies may impair fertility at several levels, potentially resulting in defective spermatogenesis, sperm agglutination in the male genital tract, reduced sperm morility, impaired cervical mucus penetration, impeded transit of the female genital tract, or ultimately, interference with the process of binding to the zona pellucida, the acrosome reaction (including premature acrosome loss), and penetration of the zona. Diverse immunologic effects of the antibodies are also possible, such as complement-dependent cytotoxicity and opsonization with macrophage removal of antibody-coated sperm. The importance of such mechanisms in vivo, however, is uncertain. Direct effects in the testis are not clear as inflammatory cell infiltration and immune deposits are not common. The main pathogeneric effects of sperm antibodies appear to include the direct effects of the antibodies bound to the surface of the sperm that cause sperm agglutination, impaired morility, blockage of sperm mucus penetration and impaired sperm-oocyte interaction.
Reduced sperm penetration of cervical mucus and the shaking phenomenon (active but nonprogressive morility typical of sperm heavily coated with antibodies in cervical mucus) is particularly caused by an interaction between the Fc parts of the sperm antibodies on the sperm and components of the mucus. Both IgA and IgG antibodies may be involved, but IgA antibodies appear to be particularly important in impairing sperm-cervical mucus penetration.
Early studies showed that sperm antibodies produced variable results with impaired or enhanced human sperm-zona free hamster oocyte penetration tests. It was apparent early on, however, that high levels of antibodies impaired human fertilization in vitro. Clarke et al. conducted experiments on human fertilization in vitro indicating that human sera containing antisperm antibodies blocked fertilization and that IgA antibodies were particularly significant in interfering with fertilization. Reducing the antibody levels with glucocorticoid therapy resulted in reasonable results with standard in vitro fertilization. Although there are some reports that do not demonstrate a relationship between antisperm antibody levels and low fertilization rates with standard in vitro fertilization, most studies have confirmed these findings. Studies with human oocytes suggest that sperm antibodies interfere particularly with sperm zona pellucida binding, the zona pellucida-induced acrosome reaction, and sperm penetration of the zona pellucida. Impaired oolemma binding may also occur with high levels of sperm antibodies. There is a strong correlation between impaired in vitro fertilization fertilization rates and impaired sperm mucus penetration.
Additional adverse effects of sperm antibodies have been suggested, such as the increased production of reactive oxygen species. DNA damage and its deleterious effects on stages subsequent to fertilization have been raised, but these do not appear to be important in humans as there is no evidence of reduced embryo utilization, implantation rates, or increased pregnancy wastage with immunological infertility of male origin. Immunological infertility of female origin may be associated with some embryonic losses.