The process of sperm formation can be divided into three separate components: (1) spermatogenesis, the formation of spermatids that have undergone first and second meiotic divisions but have remained round in shape; (2) spermiogenesis, the process for that spermatids to undergo a morphologic change in shape from round cells to potentially motile, tadpole-shaped cells; and (3) spermiation, the release of elongated spermatids into the seminiferous tubules’ lumen from their relationship with Sertoli cells. The entire process of sperm production occurs over approximately 4 and 10 weeks in mice and men, respectively (Oakberg 1956; Heller and Clermont 1963). Spermatogenesis, spermiogenesis, and spermiation begin at puberty, at a time long after which the immune system recognizes the body’s own antigens as “self.” In particular, haploid cells (=spermatids and spermatozoa) are quite new typed for the body and express various new differentiation antigens that are not found in diploid cells such as spermatogonia and spermatocytes. Therefore, there is a risk that all men develop autoimmunity to their own spermatids and spermatozoa under some pathological condition.

The origin of infertility of many cases is now believed to be primarily in the male partner. Indeed, a considerable number of cases are characterized by idiopathic male infertility, a disturbance of spermatogenesis that is without obvious causes at the time of diagnosis. Recently, testicular autoimmunity is considered to be a significant cause of idiopathic male infertility (Naito et al. 2012). Many cases of the spermatogenic disturbance associated with male infertility may be the end stage of earlier episode of autoimmune orchitis. Experimentally, it is very easy to induce autoimmune orchitis by various protocols in mice, rats, and guinea pigs (Tung 1998; Itoh et al. 2005; Lustig and Tung 2006; Naito and Itoh 2008). This means that, among various autoantigens in the whole body, testicular ones may be highly autoimmunogenic.

All living organisms are subject to the principle of transience, i.e., they go through birth, growth (activity), and, after a peak is reached, regression and eventual death (extinction) (Fig. 1.1). This pattern applies not only to living organisms but also to everything in this world, including inanimate objects such as tools, cars, and buildings.

Miki (1983) noticed “phase alternation from growth to reproduction,” which is common to plants and animals. He offered profound insight into the constant change that is characteristic of everything in the universe, the spiral of eternal circumnavigation, the rhythm of the universe, and cosmic rhythm (Fig. 1.2). Scammon (1930) also described “developmental phase in each organ system,” demonstrating that each organ system has its own growth time course in an individual organism (Fig. 1.3). Based on Scammon’s growth curves, the author created the developmental waves depicted in Fig. 1.4, illustrating only the lymphoid and reproductive organs. This figure shows that the lymphoid organs are the earliest to degenerate, and the reproductive organs are the slowest to mature.

The reproductive system is responsible for maintaining species and connecting lives. The immune system, or the self-defense system, is responsible for preserving the individual. When considered from the perspective of the recognition system, which recognizes the distinction between self and nonself, immunity is also involved in maintaining species. For example, if tissues and organs from other animals could be easily transplanted with no immunological rejection, the very concept of species would be questionable. Therefore, both immune and reproductive systems provide support for the maintenance of species (Fig. 1.5).

It is known that life was born approximately 3500 million years ago. In the process of evolving from unicellular to multicellular organisms, living organisms also evolved from asexual to sexual reproduction (Fig. 1.6). If males are considered as DNA presenters and females as DNA receivers, sexual reproduction may be present at the unicellular level (Ramaley 1968; Sherwood et al. 2014). In addition, during the course of evolution, multicellular organisms acquired a system that allows classification of cells into two types: somatic and germ cells (gametes). Germ cells have further evolved from isomorphic gametes to heterogametes, and the mode of existence of the sexes has evolved from hermaphroditic to gonochoristic.

The Earth came into existence approximately 4500 million years ago, and unicellular organisms are believed to have emerged approximately 3500 million years ago. Multicellular organisms are believed to have emerged approximately 1000 billion years ago, and the appearance of spermatozoa and ova among multicellular organisms is believed to have occurred approximately 600 million years ago (Fig. 1.7). Spermatozoa and ova arose from porifera (sea sponges). By the coelenterate stage, animals were equipped with testes and ovaries. When platyhelminthes emerged, the reproductive system started to develop to the point that reproductive organs could be identified; however, no lymphoid organ-like structure had yet developed at this evolution stage. The development of immune system is another change during the evolution from unicellular to multicellular organisms. This system development was based on receptors that allowed for adherence (acceptance) between individual similar cells and rejection of foreign cell adherence. This possibly began when various humoral substances responsible for innate immunity were first produced, and then macrophages capable of phagocytozing foreign substances came into existence. Later, approximately 400 million years ago, the lymphocytes responsible for acquired immunity started to emerge (Fig. 1.7). However, only vertebrates have possessed highly evolved lymphoid organs such as thymus, spleen, tonsils, Peyer’s patches, appendix, and lymph nodes. Lymph nodes therefore did not exist until the appearance of higher organisms such as mammals and some birds (Itoh 2009).

Collectively, spermatozoa and ova, which developed earlier in the process of evolution, appeared approximately 600 million years ago, and their existence was found to be widespread in plants, invertebrates, and vertebrates. Lymphocytes, on the other hand, which developed approximately 400 million years ago and therefore later than germ cells in the process of evolution, have been absent in invertebrates. Invertebrates thus have developed only innate immunity. Therefore, the emergence of lymphoid organs has been restricted to only in higher vertebrates and was approximately 0.2 million years later than that of spermatozoa and ova (Fig. 1.8). Meanwhile, a reverse phenomenon occurs during the development of individual mammals: the more newly evolved lymphoid organs containing lymphocytes now undergo maturation earlier than the appearance of differentiated germ cells, which arose earlier in the evolution process (Fig. 1.8). The physiological relationship between the regression of lymphoid organs and the maturation of gonads in an individual mammal is characterized by the fact that when the mammal is experimentally castrated during its sexual maturation period, the atrophied thymus and spleen become hypertrophic again (Dean et al. 1984; Utsuyama and Hirokawa 1989; Utsuyama et al. 1995).

The reproductive system has evolved to allow individuals to interact with each other (i.e., fusion with the nonself), whereas immune system has evolved to make distinctions between self and nonself, thereby allowing the elimination of nonself. Therefore, while these two systems cooperate in maintaining species, they are also polar opposites (Fig. 1.9). This contradiction is especially pertinent in higher organisms because “after the immune system consisting of the exclusion of non-self has been established, mature germ cells containing new differentiation antigens (=self-antigens but recognized as non-self-like ones) appear and have a chance of their fusion (i.e., fertilization).” As a result, acquired immunity (which evolved later) may attack mature germ cells and fertilized eggs (which evoluted earlier). In fact, phenomena related to this issue include defects in the maturation of germ cells, failed fertilization, failed implantation, and miscarriages by autoimmune mechanisms (Itoh 2009).

Female reproductive organs are strongly influenced by changes in the endocrine environment such as menstruation, pregnancy, and menopause, whereas for male reproductive organs, the environment remains relatively constant after the drastic changes that take place during puberty. In the female reproductive organs, monthly ovulation and subsequent ovum transport occur, and also the entry of spermatozoa as allogeneic cells is permitted, and then the embryo and fetus as semi-allogeneic cells are nurtured. Therefore, spermatozoa, embryos, and fetuses are sometimes likely to be immunologically rejected in females. In contrast to female reproductive organs, male reproductive ones daily produce, transport, and excrete germ cells in a monotonous rhythm. Thus, the environment in the male reproductive organs seems more immunologically stable than that in the female reproductive organs. However, in the phase difference between lymphocytic differentiation and appearance of haploid cells, spermatids and spermatozoa are most likely to be targeted for immunological elimination not only in the female but also in the male (Fig. 1.10). It is noted that daily produced haploid spermatids are quite many in number compared to a monthly produced haploid ovum. Thus, males may daily present much autoimunogenic autoantigens to the immune system. Moreover, an ovum is produced just after ovulation by dividing a diploid oocyte and survives only for 1 day, indicating that an ovum can pass through immune surveillance easily in females. In contrast, spermatids and spermatozoa that survive apparently longer than an ovum may easily stimulate immunity in both males and females. Figure 1.11 shows that the life cycles of germ cells are completely different between males and females. In humans, primordial germ cells of both males and females are ready in the form of immature cells inside the gonads by the eighth week of intrauterine life. However, the number of primordial follicles in the ovaries reaches a peak (approximately 7 million) at 5 months of intrauterine life and decreases to approximately 2 million at the time of birth, then to several tens of thousands by puberty, after which it continues to decrease rapidly. These primordial follicles disappear completely by the age of approximately 50 years, at the time of menopause. On the other hand, only a small number of spermatogonia, which are the progenitors of spermatozoa, develop within the testis from the time of intrauterine life until puberty. Once puberty is reached and lymphoid organs regress, active spermatogenesis begins. Approximately 100 million spermatozoa are then produced on a daily basis. This process continues until old age.

Figure 1.12 is a combination of Figs. 1.4 and 1.11. In this figure, spermatids and spermatozoa are depicted as cells that are the last in the human body to mature. Spermatids are newcomers (=cells bearing new self-antigens and immunologically recognized as nonself-like ones) that emerge far later than the period of neonatal immune tolerance from fetal to infant period. According to previous studies, spermatids and spermatozoa on the adluminal side of the blood-testis barrier (BTB), which are composed of inter-Sertoli cell junctions in the seminiferous tubules, are believed to be protected from detrimental immune attacks (Fig. 1.13). However, based on the findings of several research groups, the BTB does not completely isolate spermatids and spermatozoa from immune system in mammals; instead, these cells are subtly maintained in a state of balance recognized by the individual’s own immune system and are not rejected under normal circumstances (Taguchi and Nishizuka 1981; Itoh et al. 1991a, b, c, 1992, 1994; Yule and Tung 1993). If this balance is broken by any chance, the spermatogenic disturbance of autoimmune origin would be triggered immediately. In any case, haploid germ cells (having 23 chromosomes), which are at the apex of male germ cell differentiation, are completely different from diploid germ cells (having 46 chromosomes); therefore, they possess newly formed autoantigens that are recognized as nonself and are likely to be subjected to immunological rejection. This is an unacceptable risk in primitive animals.