Antisperm Immunity and Infertility

Jin-Chun Lu; Yu-Feng Huang; Nian-Qing Lu


Expert Rev Clin Immunol. 2008;4(1):113-126. 

In This Article

Mechanisms of Immune Response Against Sperm & ASA-induced Infertility

The human immune system is trained during the early postnatal period. In men, at puberty when the sperm first appear in the testis and epididymis, the human immune system will have the chance to contact sperm antigens. Similarly, when women become sexually active, their immune system will inevitably contact sperm antigens. Therefore, once sperm, as an autoantigen, activates the human immune system, an autoimmune response against human sperm will occur.

The blood-testis barrier and the epididymal blood-epithelium barrier in humans are important structures in preventing sperm antigens from contacting immunocompetent cells, due to the tight junctions of Sertoli and epithelial cells.[36] This creates favorable conditions for spermatogenesis and sperm survival in the testicular fluid, and sperm maturation in the epididymal fluid. It also prevents the occurrence of autoimmunity after puberty. Therefore, alteration of the blood-testis barrier and the blood-epithelium barrier allows the production of ASAs and, hence, may lead to infertility.

Various protective mechanisms besides the blood-testis barrier and the blood-epithelium barrier have also been identified. Immunosuppressive substances have been found in semen and follicular fluid. Moreover, suppressor T lymphocytes in the human immune system, which partially mediate the normal state of immunologic unresponsiveness toward sperm autoantigens, also play an important role in preventing the autoimmune response. In addition, the cervix is a site of sperm filtration, and uterine fluid has significantly high concentrations of IgG and IgA, which lead to increased phagocytosis of intact or defective sperm, and corrupted sperm debris. Moreover, components of seminal plasma and polymorphonuclear neutrophils in semen could eliminate nonviable sperm or debris.[37]

Recently, three complement-regulatory proteins, decay-accelerating factor, membrane cofactor protein and CD59, have been found on spermatozoa and in the extrafetal tissues.[38] It is likely that these inhibitors are essential for normal reproductive function.

A soluble form of Fc γ RIII (CD16) has been isolated from seminal plasma, which may modulate immunosuppression of antisperm immune responses in both male and female reproductive tracts. Individuals who were ASA positive had lower detectable levels of Fc γ RIII compared with those who were ASA negative, indicating that the inhibition of CD16 plays an important role in preventing ASA production.[39]

During maturation of spermatogenesis, new antigens are expressed on developing spermatocytes and spermatids. When these antigens come into contact with immunocompetent cells, or spermatozoal antigens are exposed to the mucosal and systemic immune systems, ASA formation occurs. Developmental abnormalities of the formation of the blood-testis barrier, traumatic disruption, infection or unilateral focal cryptic obstructions could lead to immunogenic sperm antigens being exposed to the immune system thus initiating an immune response to produce ASAs.[40] Gastrointestinal exposure to sperm was also associated with the development of ASAs in homosexual men. In addition, in some cases, immunity to sperm cells may be the result of altered sperm antigens.

Chronic Infection. A chronic infection, such as Chlamydia trachomatis, which is capable of eliciting an immune response has been demonstrated in male and female genital tracts. Several authors reported that Hsp60 in human seminal fluid was associated with the formation of ASAs.[41] Heat-shock protein (Hsp)60 is associated with a humoral immune response to C. trachomatis or other infection agents, indicating that genital infection could be an important factor causing ASA production.

The possible relationship between ASA production and Ureaplasma urealyticum infection was also investigated. It was confirmed that U. urealyticum and human sperm membrane proteins share cross-reactive antigens (61, 50 and 25 kDa).[42] Among the cross-reactive antigens, the urease complex component UreG of U. urealyticum was determined. Furthermore, the cross-reaction between human NASP and UreG was verified. Both anti-rUreG antibodies and antiserum against synthetic peptide NASP393-408 inhibited mouse sperm-egg binding and fusion. After immunization with rUreG or synthetic peptide, 81.2 and 75% of female mice became sterile, respectively.[42] These findings proved that the cross-reactive antigens shared in sperm and microorganisms induce ASA production and infertility.

Vasectomy & Vasovasostomy. Vasovasostomy has become a popular and highly successful method for restoring fertility to those who have undergone a vasectomy. It was reported that there was a high correlation between vasostomy and ASA production. More than 50-70% of men develop ASAs after a vasectomy, and there is limited success in the regain of fertility, even after successful surgical reanastomosis in vasovasostomy attributed to the presence of ASAs.[43] The highest incidence of titers is 1 year after vasectomy, but titers can be found as early as 6 months or as late as 20 years postoperatively. These ASAs are causative factors of infertility, because disappearance of ASAs causes regain of fertility.

However, considerable disagreement remains as to whether antibodies are the primary causative agent. No significant changes were observed in the prevalence of the antibodies over the period following vasectomy, and in patients with and without postoperative sperm granulomas.[44] Sperm antigens are in abundant supply in vasectomized men as a result of the continuous resorption of spermatozoa after vasectomy. Therefore, it is possible that undetectable antibody titers reflect high levels of ASAs circulating as immune complexes.

Other Factors. Heavy metals can also adversely influence reproduction since in sensitive individuals they are able to alter the immune responses including autoantibody production, this can then cause infertility.[45] For example, after mercury stimulation, less IFN-γ and more ASAs were produced by the lymphocytes of patients.[46] This suggested that the release of metal ions from dental materials can be one of the stimulating factors that may adversely affect fertility.

Testicular cancer and testes torsion patients also have a markedly high incidence of ASAs,[47] which may be related to radiation therapy and severe damage of seminiferous tubules. However, it was observed that no rabbits had detectable levels of antisperm IgG after testes torsion compared with controls.

In addition, a high ASA rate (43.1%) was observed among prostitutes.[48] It may be related to repeated inoculations with multiple sperm antigens and/or microorganisms.

Immunologic infertility is a consequence of the combined actions of multiple ASAs.[1] ASAs can be present at different sites, can react against different antigens, and can impair fertility in various ways. ASAs can negatively affect sperm motility, cervical mucus penetration, the AR, ZP recognition and the fusion of gametes, by immobilizing and/or agglutinating sperm, blocking sperm-egg interaction, preventing implantation, and/or arresting embryo development.[1,49] The ASAs only have functional significance when they are fixed to their antigens. ASA directed against the sperm head were of primary importance, whereas those against the tail were involved in poor motility. Moreover, ASA-coated sperm may be more vulnerable to phagocytosis in the female reproductive tract.[33]

ASA decreased motility. Modifications of sperm motility were the main cause of infertility in some patients, resulting in blockage of transport to, and union with, the oocyte. However, how do ASAs interfere with sperm motility? ASAs can bind to antigens of sperm membranes, but subcellular structures can not be reached by ASAs in living cells. Therefore, it is speculated that the function of transmembrane proteins may be altered by the ASAs concerned. Another possible explanation is via complement-mediated membrane damage.

ASAs could inactivate human sperm motility in the presence of complement, showing that complement-dependent inactivation of sperm motility might be the biological mechanism of female infertility.[38] IgG ASAs were capable of activating complement and depositing MC5b-9 on human sperm. Meanwhile, the concomitant detection of sperm-bound IgG and the initial (C3d) and terminal (C5b-9) complement components on the surface of human sperm could be confirmed using a flow cytometric assay.[50] IgG- and C3-bound motile sperm adhered to human neutrophils in vitro. According to scanning electron microscopy, most of the sperm were linked to the neutrophil by the acrosomal region of the sperm head. This adhesion potentiated the localized release of oxygen radicals at the site of neutrophil/sperm membrane contact. The deposition of activated C3 fragments, the assembly of terminal membrane attack complexes (C5b-9) and oxygen radicals could lead to C3-mediated sperm binding to neutrophils or C5b-9-mediated sperm-motility loss,[51] since incubation of motile sperm with complement-fixing immune sera resulted in a significant loss (43-87%) of motility, which was associated with characteristic C5b-9-induced alterations in sperm morphology ultimately leading to sperm lysis.[52]

Only the coincubation of neutrophils with sperm in the presence of complement-fixing ASA+ sera resulted in marked neutrophil aggregation (20.5 ± 0.26 vs 2.4 ± 1.6%; p < 0.0001), a concomitant increase in neutrophils containing ingested sperm (71 ± 5.8 vs 3.5%; p < 0.0001) and maximum expression of CD11b antigen. CD11b upregulation correlated with a significant (P < 0.05) increase in tyrosine phosphorylation of neutrophil proteins during sperm phagocytosis. Only the combination of monoclonal antibodies directed to the β2-integrin, CD11b (D12/SHCL-3), or CD18 (MHM23) subunits maximally inhibited ASA- and complement-mediated sperm adhesion to neutrophils (by 70%) or sperm phagocytosis (by 75%), as well as neutrophil aggregation (by 96%).[53] These findings strongly implicate the CD11b/CD18 glycoprotein complex (CR3) in the adhesive events involved in ASA- and complement-mediated immune destruction of motile sperm by neutrophils. It also substantiated the presence of a receptor on sperm involved in susceptibility to immobilization.[31]

ASA-affected Sperm Penetration of Cervical Mucus. The presence of ASAs in cervical secretions is not frequent but nevertheless when present it is a severe cause of infertility.[54] ASAs may influence sperm penetration of cervical mucus by the immobilization and shaking phenomenon of sperm in cervical mucus. Surface antigens of the acrosome and sperm tail principal piece appear to be recognized by circulating sperm-immobilizing and -agglutinizing antibodies.

Impairment of sperm penetration into the cervical mucus appears to be of consequence in the following mechanisms: the activation of the complement cascade by immunoglobulins attached to the sperm surface, at the end of which cell lysis and initiation of the phagocytotic process may take place. The complement induced cell lysis depends on the immunoglobulin class of the antibody. IgM is far more effective than IgG, while some IgA subclasses are unable to interact with the early complement components. During their residence in the cervical mucus, sperm are exposed to complement activity. The complement activity in cervical mucus is approximately 12% of that of serum. Thus, it may take longer for sperm immobilization to occur.

In addition, binding can also occur between the Fc region of the antibody and the cervical mucus.[55] This process could contribute to the binding of spermatozoa to the antibody and the immobilization of this complex by the cervical mucus that is seen in immunological infertility.

ASA-affected AR. There is a large data pool on antigens involved in the AR and antibodies to these antigens.[1] ASA binding to the sperm head influences the AR.[49] A number of spontaneously occurring ASAs were shown to enhance the number of acrosome-reacted sperm.[28] An antiactin monoclonal antibody significantly inhibited the ZP-induced AR, the ionophore A23187-induced AR and hyperactivation of sperm in medium.[56] Other ASAs or antigens inhibiting the spontaneous AR include TSA-1, FA-1 and calpastatin.[57]

The action of mononuclear cells in ASA production leading to infertility. Antibody-coated sperm may activate lymphocytes, thus leading to the production of ASAs. This may be an additional mechanism that leads to infertility. Mononuclear cells include lymphocytes, monocytes and macrophages, which may play a role in infertility caused by ASAs. Cytokines secreted by these mononuclear cells may also have roles, however, these are unclear at present.

T lymphocytes bearing the αβ- and γδ-antigen receptors were present in semen samples. Moreover, the presence of ASA was associated with elevated concentrations of both γδ and αβT cells.[58] The αβ and/or γδT lymphocytes and/or monocytes/macrophages in semen might be a source of Hsp60, since a large fraction of γδT lymphocytes are specifically activated by Hsp60. Moreover, γδ T cells could induce Hsp60 expression in reverse.[59] Thus, the interaction of T lymphocytes with Hsp60 may be responsible for ASA production.

However, not all men with ASAs were positive for seminal Hsp60. It has been reported that no significant difference was found in the concentration of leukocytes or subpopulations of these cells (monocytes, lymphocytes and granulocytes) between fertile, sterile without ASAs and immunological sterile groups.[60] These contradictory data indicated that the association between chronic infection of the male genital tract, γδT-cell activation, antisperm autoimmunity and Hsp60 expression requires further exploration. It is also possible that both the presence of ASAs and the increase of leukocytes in semen are manifestations of an immunological response or a common etiological factor of genital tract infections, and they are not interrelated.

In addition, a significant increase in large granular lymphocytes (LGL) was detected in semen samples from immunological sterile patients when compared with fertile ejaculates and sterile ejaculates without ASAs. The LGLs form the population responsible for antibody-dependent cellular cytotoxicity (ADCC). An expansion of these cells is reflected by an increase in ADCC effector cells. Immunoregulation by ADCC induces the disappearance of the antigens recognized by each antibody. Thus, the appearance of ASAs in an ejaculate could generate the expansion and activation of LGLs to decrease ASA production by B lymphocytes. Nevertheless, LGL activity may be a specific cellular mechanism operative in limiting the fertilizing ability of these spermatozoa.

Antisperm cell-mediated immunity (CMI) has been associated with infertility in men and women. Sperm antigens can specifically induce CMI factors that have detrimental effects on sperm motility and preimplantation embryos. Products of activated lymphocytes and macrophages (lymphokines and monokines) affect the fertilizing ability of human spermatozoa in the zona-free hamster egg-penetration test,[61] indicating that soluble factors produced by activated lymphocytes and macrophages in reproductive tissues could be significant mediators of immunologic infertility.

However, antisperm CMI responses have been observed in all individuals of the following groups: infertile men and women, fertile women, virgin women, oligozoospermic men, and men with andrological disorders. Therefore, the role of antisperm CMI in reproductive processes also remains enigmatic.

In general, mechanisms by which ASAs inhibit fertility are unclear and may be unique to each individual's antibodies. Antisperm immunization has only a relative effect on impairment of fertilization, rather than an absolute effect. In any case, the interference of ASAs at the level of gamete interaction is more than that at other levels.[33]


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.