Pathogenesis of Autoimmune Male Infertility: Juxtacrine, Paracrine, and Endocrine Dysregulation

Abstract

According to global data, there is a male reproductive potential decrease. Pathogenesis of male infertility is often associated with autoimmunity towards sperm antigens essential for fertilization. Antisperm autoantibodies (ASAs) have immobilizing and cytotoxic properties, impairing spermatogenesis, causing sperm agglutination, altering spermatozoa motility and acrosomal reaction, and thus preventing ovum fertilization. Infertility diagnosis requires a mandatory check for the ASAs. The concept of the blood-testis barrier is currently re-formulated, with an emphasis on informational paracrine and juxtacrine effects, rather than simple anatomical separation. The etiology of male infertility includes both autoimmune and non-autoimmune diseases but equally develops through autoimmune links of pathogenesis. Varicocele commonly leads to infertility due to testicular ischemic damage, venous stasis, local hyperthermia, and hypoandrogenism. However, varicocelectomy can alter the blood-testis barrier, facilitating ASAs production as well. There are contradictory data on the role of ASAs in the pathogenesis of varicocele-related infertility. Infection and inflammation both promote ASAs production due to "danger concept" mechanisms and because of antigen mimicry. Systemic pro-autoimmune influences like hyperprolactinemia, hypoandrogenism, and hypothyroidism also facilitate ASAs production. The diagnostic value of various ASAs has not yet been clearly attributed, and their cut-levels have not been determined in sera nor in ejaculate. The assessment of the autoimmunity role in the pathogenesis of male infertility is ambiguous, so the purpose of this review is to show the effects of ASAs on the pathogenesis of male infertility.

Keywords: antisperm autoantibodies; autoimmune thyroiditis; ejaculate; male infertility; orchitis; sperm antigens; spermatozoa; varicocele; varicocelectomy.

Figure 1

The structure of the blood–testicular barrier (BTB) (fragment from Cheng C.Y., Mruk D.D., 2012). The BTB is formed by tight junctions, basal ectoplasmic specialization, desmosome and gap junctions, and the ultrastructural features of the BTB as typified by the actin filament bundles sandwiched between the cisternae of the endoplasmic reticulum and the plasma membranes of two opposing Sertoli cells [65].

Figure 2

The scheme of the immunobead test (IBT) (fragment from Sikka, S.C., Hellstrom, W.J.G., 2019). The immunobeads are microscopic polyacrylamide spheres that carry covalently bound rabbit antibodies directed against human immunoglobulins. Sperm and beads are mixed, and the suspension is observed by microscopy for agglutination of sperm and beads. By using beads coated with Ig-class-specific antibodies, one can identify the different antibody classes involved (IgG, IgA, IgM) [152].