Several groups have shown that polyclonal heterologous anti-idiotype antibodies can be generated against the idiotypes on monoclonal ASA [43–45] and that the anti-idiotype could significantly inhibit the binding of the monoclonal antibody to sperm. Testing of the anti-idiotype supported the hypothesis that its’ ability to inhibit the original monoclonal antibody was due to its antigen-binding site forming a similar shape to the original antigenic epitope, the so-called internal antigen image [44].

If the male partner had ASA in his semen, how would the female immune system respond to repeated exposure to these antibodies? In light of the above information about idiotype/anti-idiotype responses, it is possible that the female would produce anti-idiotype antibodies, which could ultimately potentiate an antisperm immune response. It is also important to note that the female could potentially form anti-idiotype antibodies directed against the male partner’s antibodies specific for intracellular sperm components, in addition to those specific for sperm membrane antigens. The associated “parallel set” of anti-anti-idiotypes could also potentially react with some sperm surface epitopes. In other words, it is feasible that the idiotype hypothesis could potentially explain most of the observed range of female ASA activity.

An extremely interesting study by Naz et al. [46] demonstrated the presence of anti-idiotype antibodies in women (albeit against their own antibodies, rather than their partner’s, however it provides solid evidence that women can produce anti-idiotype antibodies against sperm antibodies). These authors concluded that both fertile and infertile women form immune responses to sperm, but that sperm antibodies are usually not detected in fertile women because their reactivity in assays is blocked by high levels of anti-idiotype antibodies. They concluded that higher levels and incidence of sperm antibodies are detected in infertile women because their sera contain relatively low concentrations of the blocking anti-idiotype antibodies. However, an alternative explanation of these findings is more consistent with current knowledge about the immune response [47]. Thus, higher levels of anti-idiotype antibodies to a particular antigen lead to active suppression of the host immune response, whereas low levels can lead to a significant stimulation of production of the idiotype (i.e., sperm antibody in this case). Thus, with respect to the study by Naz et al. [46], it is probable that sperm antibodies were not detected in the fertile women because their production had been inhibited by the anti-idiotype antibodies, rather than the anti-idiotype antibodies blocking the binding of sperm antibodies during the assay. Low concentrations (nanogram range) of anti-idiotype antibodies on the other hand can lead to enhancement of the immune response to the original antigen (ie sperm in this case). Naz et al. [46] detected anti-idiotype antibodies in only 3/23 infertile women, but the sensitivity of their assay at this concentration range may have been a factor. Further investigation of this phenomenon is vital in order to improve our understanding of female immune reactions to sperm.

With regard to the idiotype hypothesis, further research is still required in order to try to understand the relationship between anti-male idiotype antibody, which could be generated in women exposed to semen containing ASA, and anti-female anti-idiotype antibody formed when women react to their own sperm antibodies. Another consideration is whether seminal plasma contains anti-idiotype antibody in suitable amounts to have direct effects on the female immune system?

It is quite possible that the development of ASA in some women may involve one or more of the several postulated mechanisms operating in concert. For example, the stimulation by antibody-coated sperm of IFN-γ gamma synthesis in the female partner’s lymphocytes could potentially augment her immunological response to antibody idiotypes in semen (cytokines such as IL-2 and IL-4 may also be involved, as discussed above). It is also feasible that some women initially respond to microbial antigens (microbes attached to the sperm surface can also stimulate IFN-γ gamma production by the female’s lymphoid cells), resulting in the formation of antibodies which cross-react with sperm – this immune response could then be maintained over a longer period by her ongoing exposure and response to antisperm idiotypes in semen and/or generation of anti-idiotype antibodies against her own sperm antibodies. The relationship between the three hypothesized mechanisms requires investigation.