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Biology Articles » Evolutionary Biology » Auto-immunity as Evolutionary by Product of Adoptive Immunity and Source ofAnti-tumor Immunity Failure » Auto-immunity in Vertebrates

Auto-immunity in Vertebrates
- Auto-immunity as Evolutionary by Product of Adoptive Immunity and Source ofAnti-tumor Immunity Failure

There is a large body of data that many auto-immune diseases are a characteristic of vertebrates and that they are associated with MHC molecules. In fact, there is no firm evidence that would suggest the existence of auto-immune phenomena in invertebrates (2,3). The presumably MHC molecules of aberrant target cells, TCR and APCs need to interact abnormally before auto-immune disease can fully develop. In this abnormal interaction, additional aberrancies in other regulatory systems may play a role in a further exacerbation of the "self"-directed immune response, such as defects in the hormone and cytokine synthesis and secretion. The various aberrancies are partly genetically determined by a variety of separate genes, particularly MHC and related genes like TAP/LMP, but they may also be environmentally induced by viruses, chemicals, drugs or injuries (4).

In evolutionary new condition of strong (adoptive) immunity, the survival advantage imposed by an extremely reactive immune system is jeopardized if that system turns against the host and causes "self" destruction. Thus, evolutionary pressures selecting for a hyperactive immune system must be combined with similar pressures optimizing "self"-tolerance. Accordingly, the mechanisms which evolved in response to the auto-immunity-imposed evolutionary pressure or, more precisely, co-evolved with the phenomenon of auto-immunity, are related to various forms of immune tolerance, strong and multileveled control immunomodulatory and suppressive mediated by sex hormones, IL-10, TGF-β, Th2 cells, apoptosis and/or anergy of "self"-reactive clones, blood-barrier sequestration of "self" molecules, cell, tissues and organs (5,6).

Surprisingly, auto-immunity is not a feature of a young immune system, when the immune network functions at its prime. Instead, the risk of developing auto-immune disease increases with age. In general, auto-immunity manifests in hosts who have passed the apex of their reproductive years and in whom evolutionary pressures towards prompt immune responsiveness are declining. The ageing of the immune system should be associated with the loss of function, and the likelihood of developing autoimmunity should progressively decrease. The traditional paradigm interprets auto-immunity as an aberrant response of the adaptive immune system to "self" molecule(s), consistent with the view that auto-immunity is a result of overreacting. It has been proposed that T lymphocytes specific for such "self" molecule(s) induce a memory response, which is relatively resistant to natural immuno-suppressive mechanisms. Tissue destruction has been understood as the after-effects of persistent immunocompetent cells. This model ignores that the risk for auto-immunity is inversely related to the functionality of the adaptive immune system throughout a lifetime. The new evolutionary concept of auto-immunity proposes that the accelerated immunity and failure of control mechanisms after reproductive time might be the primary risk factor for auto-immunity.

From the evolutionary point of view, the immune system based on adoptive immunity has been made into a more complex and advanced defence system, developed under a strong selection pressure of microbes during the vertebrate evolution. Such model of vigorous immunity in vertebrates produced a new form of selection pressure, known nowadays as auto-immunity. Because the positive selection pressure of the adoptive immunity was probably stronger than the negative pressure of auto-immunity, the selection pressure of auto-immunity gave rise to the emergence of the control immunomodulatory and immunosuppressive mechanisms and to the "deferring" of the emergence of auto-immune diseases until post-reproductive age. Recent data have provided evidence of a feed-back loop between reproductive hormones, mainly estrogens, and the expression, distribution and activity of cytokines. For instance, in vitro studies using mice cell cultures showed that while androgens decreased the production of IFN-γ, IL-4 and IL-5, estrogens enhanced IFN-γ production by murine lymphoid cells. Moreover, estrogens treatment of macrophages from male mice increased IL-1 secretion. In CD4+ cell clones from auto-immune patients, both IL-10 and IFN-γ production were increased in the presence of estradiol (5,6,7).

In general, females have a more responsive immune system than males. Females have a greater humoral response, as evidenced by higher serum Ig concentrations than males (8) and a greater antibody response to various antigens after immunization (9). In addition, females reject skin allograft faster and have a reduced incidence of tumors, indicating that they also have a greater cellular immune response (10,11). This difference in immune response is thought to be responsible for the greater susceptibility of females to the auto-immune diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. This gender difference has also been observed in animal models of auto-immune disease in NZBxNZW mice (5).

A protective effect of testosterone is thought to underlie why males are less susceptible to autoimmune disease than females. This is based on studies that include removing testosterone from male mice via castration as well as by treatment of female mice with testosterone. For example, the castration of male non-obese diabetic mice resulted in an increased prevalence of diabetes (12), and the castration of male mice increased the incidence of auto-immunity (7). Conversely, female non-obese diabetic mice implanted with testosterone pellets had a lower incidence of diabetes and less incidence of auto-immune disease, respectively, compared with those implanted with placebo pellets (6). The same studies have indicated that gender differences in susceptibility may be due to gender differences in cytokine production upon autoantigen- specific stimulation. In males, compared with females, greater Th2 and less Th1 cytokine production has been observed. The balance between cytokines produced by Th1 and Th2 lymphocytes is considered central to the development of auto-immune disease. Th1 lymphocytes produce IFN-γ, IL-2, and TNF-α. Th2 lymphocytes secrete IL-4, IL-5, IL-6, IL-10, and IL-13. These two cell types are mutually inhibitory, and their development occurs under very specific conditions. If a naive T lymphocyte is initially stimulated with antigen in the presence of IL-12, the immune response is skewed toward Th1. However, if a naive T lymphocyte is initially stimulated with antigen in the presence of IL-4, the immune response is skewed toward Th2 (5,6). The same and other studies have collectively shown that immune cells under male sex hormones produce more IL-4 and IL-10, and less IFN-γ and IL-12, supporting the conclusion that the male immune system is shifted toward Th2 immunity (6,7). The mechanisms underlying why there is a sex hormones difference in cytokine production remain unknown. Many possibilities exist such as differences in the levels of male sex hormones, differences in female sex hormones, and differences in genes located on sex chromosomes.

Similar to previous studies, Stephanie et al. (13) found that levels of the Th2 cytokines IL-4 and IL-10 were higher and the IL-12 level was lower in splenocytes from males compared with females. Also, splenocytes from female mice implanted with testosterone pellets, like splenocytes from male mice, secreted more IL-10 and less IL-12. However, the treatment with testosterone did not cause increased IL-4 production. This clearly indicates that testosterone does not recapitulate all the cytokine differences seen in male versus female mice, and that the increase in IL-4 must be due to gender differences in other sex hormones and/or genes found on sex chromosomes (13). The finding of increased IL-10 production is equally as important as the finding of decreased IL-12 production upon testosterone treatment. Numerous studies have shown that IL-10 is essential in down regulation of cellular immune reaction. Specifically, the treatment of auto-immune patients with IL-10 has been shown to ameliorate disease (14,15), whereas the administration of anti-IL-10 antibodies has exacerbated disease (15). Although the treatment of autoimmune patients with IL-4 also ameliorated disease (16), studies of IL-4- and IL-10-deficient mice and IL- 4 as well as IL-10 transgenic mice have shown that IL-10 may play a more critical role in the protection from auto-immunity. Indeed, IL-10-/- mice developed more severe auto-immune disease compared with wild-type mice, and overexpression of IL-10 rendered mice resistant to auto-immunity (17). Because IL-10 has been shown to play a protective role and IL-12 a disease-promoting role in auto-immunity, and because testosterone increases IL-10 and decreases IL-12, testosterone would appear to play an important role in susceptibility to auto-immunity and immune reaction control. Although many cells within spleen express the testosterone receptor (TR), testosterone probably can act directly upon CD4+ T lymphocytes to increase IL-10 expression during stimulation with anti-CD3. The PCR analysis showed that CD4+ lymphocytes express the TR, supporting the possibility of direct action of testosterone on these cells. However, the TR is also expressed by CD8+ lymphocytes and macrophages. Thus, an indirect action of testosterone mediated through these cells was also possible. In vitro stimulation of CD4+ T lymphocytes in the presence of testosterone and in the absence of other cells resulted in increased IL-10 production (13).

Estrogens modulate its effect by binding to estrogens receptors (EsR) present in the immune target cells. The EsR is a nuclear transcription factor that regulates gene expression. Some of the genes regulated by estrogens are progesterone receptor, bcl-2 apoptosis inhibitor, FasL and other growth-related genes responsible for estrogen's effects on cell death and proliferation. Different authors have shown EsR in human peripheral blood mononuclear cells, thymocytes, spleen cells and APCs. The recent discovery of a second estrogens receptor, EsRb, presents new possibilities for control of immune targets by different selective estrogens receptor modulators (5,6,7,13).

A shift toward Th2 cytokine production has been demonstrated during pregnancy and high dose estrogens therapy and is thought to be the primary mechanism by which estrogens suppress the cellular immune response. However, a low dose estrogens treatment is equally suppressive in the absence of a significant shift in cytokine production. Estrogens treatment in cytokine-deficient and wild type mice up-regulate Th2 cytokine production. Also, estrogens effectively suppress the development of experimental auto-immunity in both, IL-4/IL-10 knockout mice and in auto-antigen-immunized wild type mice (5,6,7,13).


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