Immunophysiology and pathology of inflammation in the testis and epididymis

Abstract

The ability of spermatogenic cells to evade the host immune system and the ability of systemic inflammation to inhibit male reproductive function represent two of the most intriguing conundrums of male reproduction. Clearly, an understanding of the underlying immunology of the male reproductive tract is crucial to resolving these superficially incompatible observations. One important consideration must be the very different immunological environments of the testis, where sperm develop, and the epididymis, where sperm mature and are stored. Compared with the elaborate blood-testis barrier, the tight junctions of the epididymis are much less effective. Unlike the seminiferous epithelium, immune cells are commonly observed within the epithelium, and can even be found within the lumen, of the epididymis. Crucially, there is little evidence for extended allograft survival (immune privilege) in the epididymis, as it exists in the testis, and the epididymis is much more susceptible to loss of immune tolerance. Moreover, the incidence of epididymitis is considerably greater than that of orchitis in humans, and susceptibility to sperm antibody formation after damage to the epididymis or vas deferens increases with increasing distance of the damage from the testis. Although we still know relatively little about testicular immunity, we know less about the interactions between the epididymis and the immune system. Given that the epididymis appears to be more susceptible to inflammation and immune reactions than the testis, and thereby represents the weaker link in protecting developing sperm from the immune system, it is probably time this imbalance in knowledge was addressed.

Figure Figure

. Comparison of proposed immunoregulatory mechanisms in the testis and epididymis. Adjacent epithelial Sertoli cells of the testis produce basally located extensive tight junctional (TJ) specializations that completely restrict the movement of immune cells, immunoglobulin, and other molecules into the epithelium and lumen of the seminiferous tubules. Consequently, the majority of developing spermatogenic cells and intraluminal sperm are completely isolated from the immune system within the seminiferous tubules. Regions where this restriction is less effective, notably the tubuli recti and rete testis, are zones of increased susceptibility to inflammatory and autoimmune responses. Antigens within the testis, including spermatogenic cell antigens, are picked up by antigen‐presenting cells in the interstitium (dendritic cells and macrophages) and are presented to circulating T cells in a tolerizing environment that involves the resident macrophages (M), natural killer (NK), and NK T cell subsets and immunoregulatory cytokines, such as TGFB, activin A, and IL10. This leads to production of immunoregulatory T cells, such as CD4⁺CD25⁺ T_reg cells, thereby maintaining ongoing tolerance to antigens within the testicular environment. In addition, Sertoli cells, and possibly other testicular cells, express a number of immunoregulatory molecules that inhibit T‐cell activity, survival, or both in the interstitial space: nonclassical major histocompatibility complex class molecules (HLA‐G and HLA‐E), the negative costimulatory ligand CD274 antigen, indoleamine 2,3 dioxygenase (IDO), FASL, the granzyme B inhibitor serine peptidase inhibitor A3N (SERPINA3N), anti‐inflammatory prostaglandins (PG) and leukotrienes (LT), and lyso‐glycerophosphatidylcholine species (lyso‐GPCs). In the epididymis, the interepithelial junctions are less specialized and apically located, so that immune cells (dendritic cells, macrophages, and CD8⁺ lymphocytes) and other immune products are able to enter the epithelium, where they may have contact with the luminal contents under certain conditions. Entry of antibody (IgA and IgG) into the epididymis can occur either by transepithelial transport or via the ascending tract from the accessory glands. Antigen‐presenting cells and basal cell macrophages in the epididymal epithelium could play a role in regulating T‐cell responses. Epithelial cells of the epididymis express IDO and TGFB and might possess immunoregulatory functions similar to those of the Sertoli cells, although this remains speculative.