Monika Fijak1 , Sudhanshu Bhushan1 and Andreas Meinhardt1
(1)
Department of Anatomy and Cell Biology, Justus-Liebig-University of Giessen, Giessen, D-35385, Germany
Monika Fijak (Corresponding author)
Email: monika.fijak@anatomie.med.uni-giessen.de
Sudhanshu Bhushan
Email: sudhanshu.bhushan@anatomie.med.uni-giessen.de
Andreas Meinhardt
Email: andreas.meinhardt@anatomie.med.uni-giessen.de
Abstract
The onset of spermatogenesis at puberty represents unique challenges to the immune system as neoantigens of meiotic and haploid germ cells appear long after formation of systemic self-tolerance. The protection of germ cells from autoimmune attack, the “immune privilege” of the testis, was originally attributed both to the existence of the blood-testis barrier and to a failure of the testicular immune system to respond to antigens. Recent research has now shown that the testis is by no means ignorant, but can mount well-balanced immune deviant responses that can protect the gonad from damaging inflammatory responses to pathogens. Moreover, an excessive immune response can lead to inflammatory-based male factor infertility. The mechanisms controlling immune privilege seem to involve factors that also control spermatogenesis and steroidogenesis. They appear to include androgens, a delicate balance of immunomodulatory molecules such as cytokines and chemokines and a polarizing capacity of the testicular interstitial fluids towards a tolerogenic M2 phenotype.
5.1 Introduction
Male germ cells enter meiosis beginning their complex transition into highly specialized spermatozoa at the time of puberty after the establishment of immune competence. During the process, a myriad of surface and intracellular proteins is expressed, yet these new autoantigens are tolerated by the testis. The immunogenicity of the proteins is not diminished, as shown by their ability to induce strong autoimmune reactions when injected elsewhere in the body [1, 2], rather it is the testis itself that confers protection. Initial suggestions that the testis was an immune privileged site were substantiated experimentally when histoincompatible allo- and xenografts placed into the interstitial space of the rat testis survived and prospered for indefinite periods of time [3]. Similarly, ectopically transplanted allogeneic Sertoli cells not only survive, but when co-transplanted with allogenic pancreatic islets, resist rejection without additional systemic immunosuppression in animals [4]. More recently, the transplantation of spermatogonia in germ cell depleted testis could restore spermatogenesis even across species borders in some instances [5]. There is general agreement that immune privilege is an evolutionary adaptation to protect vulnerable tissues with limited capacity for regeneration, thereby avoiding loss of function [6, 7]. For the testis, this means safeguarding reproductive capability. Notwithstanding its immune privileged status, the testis is clearly capable of mounting inflammatory responses, as proven by its effective response to viral and bacterial infection. In pathological circumstances, the misbalance between the tolerogenic and the efferent limb of the testicular immune response can lead to the formation of autosperm antibodies and in rare instances, autoimmune or granulomatous epididymo-orchitis in humans. All facets of immune infertility together are now estimated to be a considerable cause of childlessness in couples seeking medical assistance [8–12].
The most common used models for the investigation of inflammatory infertility are (1) infection models mimicking acute epididymitis and orchitis by injecting live bacteria or lipopolysaccharide and (2) models of sterile chronic, progressive inflammation, namely, experimental autoimmune orchitis (EAO), a rodent model based on active immunization with testicular homogenate and adjuvants [13]. The clinical term “orchitis” is particularly attributed to acute, symptomatic disease due to local or systemic infection, whereas subacute or chronic, asymptomatic inflammation of the testis including noninfectious disease is difficult to diagnose and therefore likely to be ignored [14]. Infection-based epididymitis and orchitis mainly represent manifestations of sexually transmitted diseases such as gonorrhea or Chlamydia trachomatis or pathogens typically causing urinary tract infections such as Escherichia colipathovars with uropathogenic E. coli as the most prevalent [15, 16]. The most common cause of viral orchitis is mumps. On balance, these data clearly indicate that the mechanism underlying immune privilege in the testis and its disruption by pathological alterations are matters of clinical importance and hence continued scientific interest. The following chapters highlight some of the mechanism that are associated with the establishment, maintenance, and disruption of immune privilege.
5.2 Mechanism of Maintenance and Disturbance of Testicular Immune Privilege
5.2.1 Role of Blood Testis Barrier and Sertoli Cells
The formation of the blood testis barrier (BTB) by Sertoli cells has long been assumed to be the most critical, if not sole factor, determining testicular immune privilege. The BTB is formed by tight junctions connecting adjacent SC and gap junction proteins, namely, junctional adhesion molecules (JAMs), claudins 1 and 11 with claudins 3-5 and claudins 7-8 also identified in the testis besides occludin [17]. The BTB barrier divides the seminiferous epithelium into two distinct compartments: the basal compartment containing the spermatogonia and preleptotene spermatocytes, while more advanced spermatocytes, secondary spermatocytes, haploid spermatids, and spermatozoa are found in the adluminal compartment. The main task of the BTB is protecting or sequestering auto-immunogenic germ cells from the systemic immune response.
In addition to BTB formation, SC maintain the immune privilege of the testis by skewing immune responses by producing immunosuppressive molecules such as PDL1, Tyro3, Axl; MER and IDO [18–22]. The immunoregulatory repertoire of SC also contains constitutively expressed immunosuppressive cytokines like transforming growth factor (TGFß) and activins [23, 24]. Mechanistically, elevated levels of tumor-necrosis factor (TNF)-α and transforming growth factor (TGF)-β, found in systemic and local testicular inflammation [25–28], have been shown to perturb the assembly of the tight junctions in cultured Sertoli cells probably by downregulating occludin expression [29, 30]. Despite the junction’s ability to isolate meiotic and postmeiotic germ cells from circulating antibodies and leukocytes, it is now accepted that the blood-testis barrier alone does not account for all the manifestations of the testicular immune privilege. It was supported by the findings that germ cell autoantigens that germ cell autoantigens are present in the basal compartment in spermatogonia and early spermatocytes, which are not protected by the blood-testis barrier [31, 32]. Moreover, the blood-testis barrier is incomplete in the rete testis, a location where immense numbers of spermatozoa with newly adapted surface molecules traverse towards the epididymis, making it a particularly susceptible region for the development of autoimmune orchitis. Furthermore, Head and Billingham [33] showed extended survival (i.e., no immune response/attack) of allografts that were placed under the organ capsule in the testicular interstitium. Therefore, some other mechanism, beside physical separation, must exist to maintain testicular immune privilege, which requests more robust protection of the tolerogenic environment of the testis.
5.2.2 Macrophages
Besides playing a crucial role in innate immune response, macrophages are also essential for maintenance and regulation of organ homeostasis. In steady state condition, testicular macrophages (TM) are exclusively found in the interstitial space; in human they can be located also in the tubular wall, but never within the seminiferous epithelium. In fetal testis development, TM have nonclassical functions in organogenesis by regulating the vascularization of the organ and spermatogenic chord formation [34]. In addition, TM seem to show a direct effect on spermatogenesis by influencing spermatogonial stem cell differentiation [35]. TM maintain the immune privilege of testis by secreting substantially lower amounts of pro-inflammatory cytokines (TNF-α, IL-12) in response to inflammatory stimuli, whereas concomitantly high amounts of the archetypical anti-inflammatory cytokine IL-10 are produced [36]. Of note, TM constitutively express low levels of the toll like receptor gene family and suppress the pro-inflammatory NF-kB signaling pathway by blocking the degradation of IkB alpha (inhibitor of p65). While blocking NF-kB signaling effectively, a more moderate innate immune response is triggered alternatively by activation of AP-1 and CREB signaling pathways [36]. Taken together, TM play an important role in normal function and development of the testis. There is little doubt that macrophages take a central role in the establishment and maintenance of the testicular immune privilege. This supposition was first substantiated by in vitro studies, in which TM displayed a reduced capacity to synthesize IL-1β and TNFα compared to macrophages from other tissues and exhibited overall immunosuppressive characteristics [37–40]. In the rat testis, at least two subsets of macrophages can be discerned. This heterogeneity has functional implications as in the testis the ED1+ “inflammatory” subsets, but only few ED2+ resident macrophages, express MCP-1 and iNOS in untreated and LPS challenged rats [41, 42]. The ED2+ resident population of testicular macrophages does not participate in promoting inflammatory processes; it is thought to have an immunoregulatory role in maintaining immune privilege and trophic functions, particularly on Leydig cells. Clear evidence points out that the ED1+ ED2− monocytes/macrophages are involved in the testicular inflammatory response, and it is the influx of ED1+ monocytes during acute and chronic inflammation, which drastically alter the composition of the macrophage population and shift the cytokine balance in favor of an inflammatory response with the potential to overcome the immune privilege [41–43] (Fig. 5.1).
Fig. 5.1
Hypothetical model of factors maintaining the testicular immune privilege. The blood-testis barrier (BTB) connects neighboring Sertoli cells (SC) and segregates the majority of neo-antigen expressing meiotic and postmeiotic germ cells (GC) from the testicular immune system. In the interstitial space, the ED2+-resident type of macrophages (Mφ) with its immunoregulatory and trophic functions constitutes the largest subpopulation of leukocytes, whereas the ED1+ “inflammatory” macrophage cohort is much smaller in number. Most likely the phenotype of testicular dendritic cells (DC) in normal testis inhibits an activation and expansion of autoreactive T lymphocyte clones. The concentration of testosterone in the testicular interstitial fluid synthesized by the Leydig cells (LC) is about 8–10 times higher than in serum. Recent data point to an increasingly important immunosuppressive role of androgens by inhibiting leukocyte function and by reducing of pro-inflammatory cytokine expression. BVblood vessels, PTC peritubular cells, MC mast cells
5.2.3 Dendritic Cells (DC)
DC belong along with macrophages to the most important antigen presenting cells (APC) and play a major role in the initiation and orchestration of primary immune responses. DC not only activate lymphocytes, but also tolerize T cells to antigens, thereby minimizing autoaggressive immune responses [44].
In normal mouse, rat, primate, and human, testis DC are found in very limited numbers [45–49]. In contrast, in the inflamed testis, the numbers of DC are significantly upregulated as shown in a rat model of experimentally induced autoimmune orchitis (EAO), where elevated levels of DC were found in the interstitial space of the testis and in testicular granulomas and lymph nodes draining the testis [46, 47, 50]. Similarly, in human azoospermic testis with chronic inflammation, higher numbers of IL-23 producing CD11c+ DC could be detected [49].
Immature DC have the highest capacity to internalize antigens, but low T cell stimulatory activity, whereas mature DC downregulate their endocytic activity and are excellent T lymphocyte stimulators [51]. Interestingly, the levels of co-stimulatory molecules (CD80, CD86) and MHC class II molecules on the DC surface from normal and inflamed rat testis are similar [46]. However, the expression of chemokine receptor CCR7 responsible for the migratory behavior to the lymph nodes was upregulated in DC from inflamed testis. Furthermore, the expression of IL-12p35 and IL-10 mRNA was detectable only in DC from EAO testis and draining lymph nodes pointing to their mature immunogenic state [46, 50]. At the functional level, DC isolated from EAO testis and draining lymph nodes significantly enhanced the proliferation of effector T cells compared with control DC, suggesting a more tolerogenic phenotype for DC in normal testis function, thereby maintaining immune privilege (Fig. 5.1) [46, 50]. Based on existing data, it seems that during development of testicular inflammation DC acquire a functional mature phenotype, take up testicular antigens, migrate to the lymph nodes, and stimulate antigen-specific T cell responses, thus initiating autoimmune responses in the testis leading to immunological infertility.
5.2.4 T Lymphocytes
In normal testis of human and experimental animals, the population of lymphocytes comprises 10–20 % of total leukocytes. Testicular T cells consist mainly of CD4+, CD8+, and CD4+ CD25+ Foxp3+ regulatory (Treg) T cells [48, 52–54]. Immunosuppressive factors produced locally in the testis such as IL-10, TGF-β, activin A or lyso-glycerophosphocholine are believed to promote diminished responses of testicular T cells leading to prolonged tolerance [48, 55–57]. A hallmark of disturbed immunological balance during testicular inflammation is significantly increased numbers of CD4+ and CD8+ T cells as well as Treg cells [58–60]. There is increasing evidence that testicular CD4+ CD25+ Foxp3+ Treg are important players in the maintenance of testicular immune privilege. Interestingly, data from our own in vivo and in vitro studies showed a stimulatory effect of testosterone on the expansion of Treg cells in the testis [59, 61]. Moreover, factors produced by cultured Sertoli cells like TGF-β trigger de novo differentiation of fully functional Treg cells [62].
5.3 Endocrine Regulation of Testicular Function and Immune Privilege
In addition to the well-established anabolic and spermatogenic effects, a role for androgens in downregulating pro-inflammatory responses has now been shown in both experimental and in clinical studies. Incubation of several immune and nonimmune cell types with testosterone resulted in the suppression of adhesion molecules and cytokines such as IL-1, IL-6, and TNFα and increased production of anti-inflammatory cytokines such as IL-10 [63–69]. Testosterone is also involved in T cell apoptosis [70]. A direct connection between sex steroid levels and testicular immune privilege was shown by Head and Billingham [71], when in transplantation studies, rats pretreated with estrogen to suppress Leydig cell testosterone production, promptly rejected intratesticular allografts in contrast to tolerance towards the grafts in untreated cohorts. In interventional studies, testosterone supplementation of hypogonadal patients with Crohn’s disease led to reduced protein C levels and inhibition of chronic inflammation [72, 73]. These findings were supported by evidence delivered from our earlier studies, showing that substitution of reduced testosterone levels during rat EAO inhibited the disease development and caused reduction of TNF-α, IL-6 and MCP-1 levels in testis. Furthermore, the number of TM and CD4+ T cells was significantly decreased with concomitant increase of Treg cells as compared to untreated EAO animals [59]. Further in vitro studies confirmed an inhibitory effect of testosterone on inflammatory responses in Sertoli and peritubular cells [61]. These studies indicate that the high local testosterone concentrations characteristic for the testis seem to play an important role in the maintenance of testicular immune privilege.
What can be surmised from the available data is that androgens appear to exert their immunosuppressive function on testicular leukocytes by stimulating the differentiation of Treg cells and by regulating the balance of pro- and anti-inflammatory cytokine expression in Sertoli, Leydig, and peritubular cells.
5.4 Conclusions
There is now widespread agreement that the immune system, spermatogenesis, and steroidogenesis, and the intrinsic testicular functions are intricately linked by a network of complex interactions. The importance of the delicate balance needed between the suppression of the immune response to protect the germ cells from autoattack on the one hand and the ability to an active immune response to prevent damage from infection, trauma, and cancer on the other is reflected by the fact that in the human male about 12–13 % of all diagnosed infertility is related to an immunological reason. It needs to be considered that the incidence can well be higher as the contribution to idiopathic infertility (31 % of all cases) still remains elusive [9–12]. The mechanisms responsible for testicular immune privilege are still far from being understood, but it is apparent that the identified factors involved are multiple. According to recent progress, androgens and possibly other steroid hormones are likely to play a major role [61, 74]. Overall, long regarded as a peculiar side issue of testis function, immune privilege is now established as part of the general scheme of male gamete formation and successful reproduction. Further research in the area will not only help to improve diagnosis and treatment of immunological based male infertility, but will also open new avenues in contraceptive development and transplantation medicine.
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