It is beyond the scope of this chapter to discuss the role of estrogens in all autoimmune diseases. Therefore, we focus primarily on estrogen effects on lupus, since the effects of this hormone have been noted in humans and in murine models of lupus. SLE patients have autoantibodies against many self-antigens including double-stranded DNA (dsDNA), red blood cells, platelets, leukocytes, and clotting factors, which leads to the formation of immune complexes. The deposi tion of these immune complexes triggers inflammation, culminating in widespread tissue damage (Abdou et al., 1981). Gender is a strong risk factor for SLE since this disease primarily affects women in the reproductive years and the female-to-male susceptibility ratio can be as high as 13:1 (Rider and Abdou, 2001). SLE has been associated with situations where levels of gonadal hormones are changing such as during pregnancy, postpartum period, menopause, and during estrogen administration. The first onset of the disease is unlikely to occur before puberty or after menopause. Pregnancy has been associated with flares of lupus (Wilder, 1998). SLE disease activity fluctuates with the menstrual cycle (Bruce and Laskin, 1997) and lessens after menopause (Mok et al., 1999). The flares of lupus have been reported to increase during in vitro fertilization when levels of female hormones, particularly estrogen, are clinically manipulated (Guballa et al., 2000). Further, although not unequivocal, exogenous estrogen administration such as oral contraceptives and the use of HRT (Petri, 2001) have been reported to affect the disease course. Female lupus patients tend to have increased 16a-hydroxyesterone and estriol, as well as increased oxidation at C-17 position compared to controls (Lahita, 1999). The precise contribution of altered sex hormone metabolism to lupus, although provocative, is not clear.
Estrogen has been associated with B cell activation and T cell dysregulation. For example, direct exposure of peripheral blood mononuclear cells (PBMCs) from lupus patients to 17P-estradiol induced the secretion of anti-dsDNA antibodies and enhanced the secretion of immunoglobulins (Kanda et al., 1999). In similar cultures of PBMCs from healthy donors, estrogen enhanced immunoglobulin levels but did not induce anti-dsDNA autoantibodies, thereby suggesting that estrogen has differential effects in SLE and normal individuals. This estrogen-induced increase in autoantibodies to dsDNA and secretion of immunoglobulins may be related to IL-10, since estrogen was found to increase IL-10 secretion by monocytes, and anti-IL-10 partially blocked the increase in B cell secretion of autoantibodies and immunoglobulins (Kanda et al., 1999). Interestingly, aberrant T cell activation was evident in lupus T cells when cultured in the presence of estrogen. T cells from female lupus patients had a dose-dependent increase in calcineurin steady-state mRNA levels and an increase in phosphatase activity. In contrast to the estrogen effects on T cells from female SLE patients, estrogen had no effect on cal-cineurin in T cells from normal females, normal males, or lupus males (Rider and Abdou, 2001). This suggests that estrogen has differential effects depending upon the source of target T cells. These effects of estrogen are mediated through the estrogen receptor (ER), since culturing of female SLE T cells in the presence of an ER antagonist blocks the estrogen-induced increase in calcineurin and phosphatase activity. Additionally, differences in the response of lupus T cells to estrogen have been noted. Estrogen increased CD40L mRNA and the amount of CD40L expression on T cells from SLE patients, but not on T cells from normal individuals. It is conceivable that the estrogen-dependent increases in CD40L expression could hyperstimulate SLE T cells and may contribute to the pathogenesis of SLE (Rider et al., 2001).
Much evidence supporting the role of sex hormones in lupus has come from studies in B/W mice, where mere alterations in the levels of sex hormones can have profound effects on the disease. For example, relatively resistant male
B/W mice (that have a delayed onset of the disease) can be made susceptible by the administration of estrogens or depletion of male hormones (by orchiectomy or administration of anti-androgens) (Ansar Ahmed et al., 1999). Conversely, susceptible female B/W mice can be made relatively resistant to the disease by the administration of androgens or the estrogen antagonist, tamoxifen (Ansar Ahmed et al., 1999). In yet another model of lupus, MRL/lpr mice, which develop an aggressive disease together with lymphadenopathy, estrogen was shown to be a potent accelerator of lupus (Carlsten et al., 1990). Estrogen treatment of MRL/lpr mice resulted in the appearance of forbidden autoreactive clones in the liver (Okuyama et al., 1992). These cells include apTCRIntermediate, Vp3+, or Vp8+ T cells that are often deleted in the thymus.
Studies in our laboratory have shown that 17p-estradiol treatment of non-autoimmune mice (e.g., C57BL/6) induce autoantibodies against dsDNA and phospholipids, which are common in lupus (Ansar Ahmed et al., 1999; Ansar Ahmed, 2000). This is an important conceptual finding that implies that estrogen can override B cell tolerance to induce autoimmunity even in normal mice. Similarly, others have also shown that 17p-estradiol can break B cell tolerance in non-autoimmune BALB/c mice transgenic for the heavy-chain of pathogenic anti-DNA antibodies. 17p-estradiol can induce high-affinity autoantibodies against DNA as well as immune complex glomerulonephritis (Grimaldi et al., 2001). Hybridomas generated from estrogen-treated mice express high-affinity, unmutated anti-DNA antibodies. This indicates that naive B cells that are normally deleted or anergized are rescued from tolerance induction (Bynoe et al., 2000). Further, like 17p-estradiol, the synthetic estrogen DES has also been shown to induce autoantibodies in both normal and lupus-prone mice (Forsberg, 2000; Yurino et al., 2004).
Recently, a new class of estrogens called environmental estrogens (or endocrine-disrupting chemicals) has been identified in the environment (Sonnenschein and Soto, 1998). These compounds are generally considered to be weak estrogens, yet they can disrupt the endocrine system through many mechanisms including hormone mimicry, blocking or altering hormonal binding to receptors, binding to ERs (or conceivably other receptors) to alter gene regulation, and/or altering the metabolism of natural estrogen. A current concern is whether environmental estrogens can affect autoimmune diseases. Experimental evidence suggests that this may be likely. For example, studies using the well-documented environmental estrogen, Bisphenol-A (BPA), which is present in resins, plastics, dental sealants, adhesives, flame retardants, and optical lens materials suggest that it can promote autoimmunity. Administration of BPA to lupus-prone B/W mice resulted in increased autoantibody secretion by B-1 cells (CD5+, IgMhi, B220Int, IL-5R+) (Yurino et al., 2004). Direct in vitro exposure of B-1 cells to BPA induced IgM autoantibodies to a level that was comparable to that noticed in cultures exposed to DES or estradiol. These effects were more pronounced in B-1 cells from aged mice (8-12 months of age) compared to young mice (1 month of age). This supports the argument that environmental estrogens may affect autoimmune diseases.
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