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Systemic lupus erythematosus (SLE) is a disease like most of the connective tissue diseases, where the prevalence is greatest in young women of childbearing age. [8] This is one of the most obvious clinical observations in both the human form of the disease and that of certain animal models. Because of this, gender and age are most likely linked to both cause andpathogenesis. Despite these facts, an explanation of this sexual predilection is elusive, although there are many theories. Factors like sex hormones [60] and genetics [85] are suspected reasons for the large number of young women with the disease. The sex steroid hypothesis is particularly attractive. Sex steroids are important to the health of most vertebrates because they play an important role in the maturation of organ systems that affect animals throughout life. [6] Although the most obvious effects of sex steroids occur at puberty as the development of secondary sexual characteristics, major developmental changes occur long before that, even before parturition. Various genetic theories centered about the X chromosome are popular explanations for the female predominance of autoimmune disease in human beings [74] and animals. [77] [81]
Basic research on the sexual dimorphism of the immune system is likely to validate either argument. There are good clues from the clinic and laboratory that are revealing. One clue is the close link between organ-specific cytokine production during the normal menses, pregnancy, and immune function. Changes occur at the cellular level in animals and cell culture in response to sex steroids. Clinical changes occur in men and women who experience an excess or depletion of sex hormones. Sex hormones are important modulators of activity for many systems of the body like the brain, gonadal tissue, and skin. The immune system is also an organ system in which sex steroids play a major role in both normal maturation and disease.
Estrogen is shown to augment CD8 levels [101] and CD4-mediated cytolysis [80] in human beings. Estrogen also enhances production of interferon-gamma and interleukin (IL)-10 by T-helper (Th)1 and Th2 cells. Early studies show that T-cell helper activity priming B cells to differentiate was also affected by estrogens, whereas androgens generally had the opposite effect. [98] Cytokine regulation of the immune system is well accepted, and the production by the ovary of immunopotent cytokines that regulate local and systemic synthesis of steroids probably plays a major role in this rheumatic disease. [78] [96] In women, sex steroids have a direct effect on normal reproductive functions like oocyte implantation, influence the life of the conceptus, and alter resident immune cell populations. [28] Additional aspects of sexual dimorphism of the immune system in normal individuals include a woman's greater propensity for warding off infection and an increased ability to accept transplanted grafts. There are also subtle differences of immune function between the sexes like different levels of T-cell subtypes and varying immunoglobulin levels. [36]
Although it is clear that a sexual dimorphism exists within the immune system, the true roles of hormones like estrogen and testosterone need clarification. From data given below, it is clear that autoimmune syndromes in certain strains of mice are of greater severity in female mice than in male mice. Recent studies suggest a dimorphism concerning the hypothalamic-pituitary-adrenal axis, a dimorphism that might have an effect on other diseases besides lupus. For example, endotoxin-induced corticosterone release does not change throughout the different stages of the normal menstrual cycle of mice, whereas gonadectomy of animals results in an enhanced adrenal and immune response to endotoxin. This exaggerated response can be reversed by testosterone treatment regardless of the sex of the mice. Testosterone is important to the modulation of endotoxin-induced corticosterone secretion, and there is a sex steroid hormone basis for a neuroendocrine-immunologic sexual dimorphism. [33]
Sex hormones could affect the immune system by modifying T-cell receptor signaling and regulating the expression of T-surface cell signals or autoantigens, the transcription or translation of cytokine genes, or lymphocyte homing. Research shows that the regulation of cytokine genes is dependent on sex hormone levels in experimental systems. [78] [107] The other mechanisms, although attractive, have not been proven.
Recent evidence indicates that calcineurin mRNA levels in T cells from a group of eight SLE patients rose in response to estradiol. This rise of mRNA was not found in normal controls or patients with other diseases like rheumatoid arthritis (RA) or vasculitis. These data suggest that estrogen-dependent calcineurin could be a molecular marker for lupus patients. The change in this molecular marker could alter cytokine gene regulation and T- and B-cell interactions. [88]
The sexual dimorphism mentioned previously underlies the sexual differences observed in patients with SLE. The environment established by the cytokines made locally and systemically is in all likelihood the basis for the gender gap in the disease lupus erythematosus. [116] Cytokines released by immune cells, particularly the T-helper populations, vary and are regulated by estrogen levels. The Th1 lymphocytes secrete proinflammatory cytokines that promote the cell-mediated immune responses, and Th2 cells secrete anti-inflammatory cytokines that trigger antibody production. The proinflammatory cytokines are those found in the diseases RA and multiple sclerosis, whereas the anti-inflammatory cytokines are common to pregnancy and SLE. Progesterone, and to a great degree, high levels of estrogen promote a Th2 response that antagonizes the Th1 response, and the reverse is the case with RA, both of which are promoted with prolactin and low physiologic levels of estrogen. In a recent report, such changes were used to explain the improvement of patients with RA and multiple sclerosis who became pregnant, although the reverse was the case for SLE patients (Fig. 1) .
Figure 1. Metabolism of estradiol.
There is also a notion that genes related to autoimmunity might be regulated by hormones themselves. Although this is a possibility, there is no direct evidence for this. Preliminary work by investigators in lupus mice indicates that apoptosis might be regulated by sex hormones, at least in part. The regulation of apoptosis by sex steroids is well known in the thymus of human beings [83] and in the gonads of animals. [38] [40] [118] The specific gene expression affected by these steroids needs elucidation, because it is conceivable that certain genes such as FAS (promoter of apoptosis) and BCL-2 (an inhibitor of apoptosis) might be regulated by sex hormones. Recent work has demonstrated the presence of estrogen receptor transcripts in both T and B cells, [103] but there is no abnormality observed between these transcripts from patients and normal controls.
It is appropriate to mention the manner by which gender affects lupus in the experimental mouse. There are several strains of mice that are used as models of autoimmune disease (Table 1) . [9] The disease in some murine models predominates in female mice; examples are the New Zealand White/Black (NZW/NZB) Fl hybrid and the MRL lpr strains, in which female mice die at a younger age than male mice. [44] [45] The NZB/NZW strains were the first mouse strains in which the effects of gonadal hormones were noted to play a regulatory role in SLE. The descendants of those strains were important because their inbreeding resulted in accelerated disease, and the F1 strain developed disease manifestations like autoimmune hemolytic anemia [44] [45] and diffuse proliferative glomerulonephritis, concomitantly circulating DNA containing immune complexes and a variety of autoantibodies like those to native DNA and ssDNA. [73] [105] [109] Estrogens also adversely affect the course of disease in female hybrids of the NZB/NZW cross. Sexual maturity increases the morbidity of this strain, but prepubertal castration of the NZB female mouse does not increase longevity. Early castration and estrogen therapy accelerate the disease in female mice, although castration and testosterone therapy prolong life. In male mice of this strain, castration causes early death and estrogen produces mortality similar to that of female mice. [95] [102] Overall, testosterone therapy of female mice prolongs life and decreases overall morbidity. [18] [90] [91] [92]
In one specific strain of mice, the disease favors male mice, the BXSB (derived from the C57BL/6 and satin beige mouse). It is unusual in that the male mice die of early SLE-like disease. [81] Unlike the female-predisposed strains of mice, the disease manifestations in the BXSB mouse are not hormonally mediated, because neither administration of sex steroids nor gonadal extirpation improves or changes disease manifestations. The accelerated autoimmune disease in these mice is linked to the Y chromosome, and prepubertal castration fails to change the course of the disease. The transfer of bone marrow cells from diseased to nondiseased male mice leads to the development of the autoimmune disease, suggesting that the major problem is cellular. [26] [27]
Evidence cited previously indicates that gender plays a major role in the modulation of autoimmune diseases of certain mouse strains; in one case, it is hormonally predisposed, although in the other, there is a clear relation to the Y chromosome. There are certainly many other aspects to consider in the morbidity of murine SLE. Undoubtedly, factors like genetics and a possible transmissible agent could play a major role. Unlike the case in mice, it is apparent that sex steroids act on the disease in a sporadic manner in human beings. Disease manifestations wax and wane in a fashion commensurate with fluctuating steroid levels, and these vary with cycles such as the menses in women. Fundamental questions such as the susceptibility to SLE and the window (if any) during which sex steroids exert their most profound influence are the subjects of current investigation.
Androgens have many effects on immune function. They are immunosuppressive because of in vitro observations in normal lymphocytes and because of their effects on the disease manifestations of inbred autoimmune mice. [2] Testosterone has also been shown to suppress anti-DNA antibody production in peripheral blood mononuclear cells from patients with SLE. [55] This was shown to occur through the downregulation of IL-6 and the inhibition of B-cell activity. Graft rejection in rodents is delayed by injection of testosterone, and resistance to viral infections is reduced and resistance to certain infections is enhanced when androgens are given at certain doses. [1] [25] A consistent effect of androgens in animals is their ability to immunosuppress chickens by retarding the function and development of the bursa of Fabricius. [41] [42] [43] Androgens also have an effect on the pluripotential stem cells of the bone marrow, namely, the accelerated proliferation and differentiation of such stem cells into compartments of cells that number among them lymphoid elements. The important effects of androgens on immune maturation are reflected by the discovery of receptors for estrogen and dihydrotestosterone, a 5alpha reduced metabolite of testosterone in the thymus. [35] [36] [37] Despite the fact that androgen receptors are not found on lymphocytes, they also inhibit B- and T-cell maturation, reduce B-cell synthesis of immunoglobulins, and suppress the phytohemagglutinin-induced blast transformation of lymphocytes. The androgens are implicated as modifiers of the regulatory genes that influence the function of structural genes. [75] For example, guinea pig mammary epithelial Ia antigens are increased in number through the effects of estrogens and prolactin and are decreased by testosterone. [56] The wide range of effects that this steroid displays might be caused by variable androgen sensitivity of certain cell groups or the in vivo conversion of androgens to estrogens through well-recognized pathways.
Female mice make more antibodies to foreign antigens than do male mice, and this difference is reported for a variety of antigens. [106] Depending on dose, estrogens have been immunosuppressors and immunostimulants. The steroid 17beta-estradiol prolongs first and second sets of skin grafts in mice after X-irradiation and inhibits corneal graft acceptance in preimmunized rabbits. [108] In general, the skin allograft rejection process is generally accelerated in female subjects compared with male subjects. [115] Estrogens regulate immunity by way of the thymus in rodents, [13] and in higher doses, they decrease the overall thymic population of small lymphocytes. Estrogen given before bone marrow transplantation results in increased graft failure. Estradiol and diethylstilbestrol (in concentrations of 10-50 mug/mL) are known to reduce the phytohemagglutinin and concanavalin A response of lymphocytes in vitro. [117] The mixed lymphocyte reaction is enhanced by estradiol. Enhanced lymphocyte activity is observed at 200 ng/mL, and the effects are inhibited at 2000 ng/mL (e.g., thymidine incorporation). Fluctuating lymphocyte responses are observed during normal menses, [10] pregnancy, and the use of oral contraceptives (Table 2) . [98] Castrated male mice and certain female mice display hyperplastic spleens and thymuses after challenge with thymic-dependent antigens, indicating a steroid effect on thymic cell activity. [82] [93] Castration of male rats leads to accelerated allograft rejection. Syngeneic grafts of ovaries in male rats and grafts of testes in female rats have no significant effect on allograft rejection. [34] Sustained levels of estrogens in mice led to a marked reduction in natural killer cell activity. In other studies, high-dose estrogens depress cell-mediated immunity, natural killer cell function, and cancer cell immune surveillance. Estrogens also deplete thymic hormones and are known to produce a relative lymphopenia. It has been established that estrogens are detrimental to animals with SLE. In fact, tamoxifen and antiestradiol antibody have beneficial effects in experimental SLE. This benefit occurs via cytokine regulation. [23] [100] Men with prostatic cancer who are given diethylstilbestrol have markedly depressed cell-mediated immunity. Using normal lymphocytes, estradiol treatment of pokeweed-mitogen-treated B cells shows an increase in plaque-forming cells (in vitro). [86] [103] Estrogen receptors are found on CD8+ T lymphocytes in some studies, [21] [22] although data derived from more sensitive estrogen receptor cDNA probes have not confirmed these findings. There are studies to show that CD4+ T-helper cells increase after estrogen therapy. [86] In some studies, estrogens are thought to act by inhibiting CD8+ suppressor T cells. Consequently, helper cells would be enhanced, with resulting polyclonal B-cell immunoglobulin production. An exciting new direction is the inhibition of apoptosis in vitro using peripheral blood mononuclear cells from women with normal menses. Estradiol decreases tumor necrosis factor-alpha in SLE cells but not those from normal people. [28]
Other sex steroids like progesterone have been considered as effective therapeutic agents in diseases like SLE. Progesterone is an immunosuppressive agent, [51] [102] [110] and levels of this substance rise during pregnancy, when the placenta assumes an active role in its synthesis and secretion. Lymphocyte responses to phytohemagglutinin and concanavalin A are reduced in vitro in the presence of this steroid at concentrations of 10 to 15 mug/mL. Other analogues like 20alpha-hydroxyprogesterone have similar effects. [79] Progesterone has been known to increase the relative amounts of CD8+ suppressor cells and to decrease them in mice. In addition, progesterone has been invoked to explain many of the suppressive effects found in the sera of pregnant female subjects.
In human SLE, there is little consistency of disease manifestation from patient to patient even within the same family. A patient or sibling from one family may present with autoimmune hemolytic anemia, whereas another may present with encephalopathy. Siblings from the same family who are of different genders might be equally affected.
Although gender plays a major role in the expression of SLE, it is not likely to be the cause but rather a modifier of expression. Most patients who present with SLE after puberty are female. The present evidence suggests that estrogens or those steroids that are exceptionally feminizing exacerbate SLE. [64] Among such compounds are the synthetic estrogens such as birth control agents. [20] [87] The times in a woman's life that are important to SLE activity are the menstrual period [10] [89] and pregnancy before and after parturition. The activity of SLE may worsen during these periods and depends on the levels of gonadal steroids. Because of the large numbers of women with lupus, the X chromosome could play a role. [77]
A major concern in relation to women with SLE is the fact that they are 50 times more likely to have a myocardial infarction than men (35-44 years old age group). The risk was increased further in those who had a prior cardiovascular event, were at an older age at diagnosis, had a longer disease duration, used more steroids, and had postmenopausal status and high cholesterol levels. [76]
Patients with Klinefelter's syndrome (XXY chromosomes) are described who have clinical SLE and disordered estrogen metabolism. [66] Study of such persons provoked the initial experiments designed to look at the patterns of estrogen and androgen metabolism in SLE. These studies revealed that patients with SLE have an altered sex steroid metabolism. Because the sex steroids regulate immune function in diseased and normal people, the differences in their overall activity must be based on the way in which the immune systems of male and female patients with lupus respond. The only gonadotropin that has been thoroughly explored in regard to the SLE of mice and human beings is prolactin. Although other gonadotrophins are interesting, they are not thought to have a role in SLE.
Women are likely to have greater aberrations of the immune system than men. Male and female patients with SLE have normal levels of estrogen; however, the overall metabolism of such compounds is altered to favor more feminizing compounds. [64] Specifically, the pattern of hydroxylation of estrone (Fig. 2) favors the 16-hydroxylated compounds over the cathechol estrogens. [61] Patients of both sexes have increased levels of 16alpha-hydroxyestrone, whereas only women with SLE and men with Klinfelter's syndrome (XXY chromosomes) had elevated levels of estriol. [62] The compound 16alpha-hydroxyestrone and its elevation in SLE patients could have some special significance, because later studies demonstrated that this hormone had unique qualities. [16] This steroid metabolite covalently bound to proteins like cell receptors spontaneously by way of Heyn's rearrangement. No other steroid save cortisone was known to bind in this fashion.
Figure 2. Immune responses. MS =
multiple sclerosis; SLE = systemic lupus erythematosus; RA = rheumatoid
arthritis.
One estrogen, 16alpha-hydroxyestrone, is feminizing, highly uterotropic, and modestly bound to cytosol receptors and testosterone-estradiol-binding globulin in contradistinction to compounds like 17beta-estradiol. [30] A radioimmunoassay failed to show uniformly elevated levels of 16alpha-hydroxyestrone in active SLE patients, however. [47] This suggested either that an undetectable conjugated form of this steroid was active or that there were many other metabolites that were important from this pathway. Enzymatic systems in certain animals might favor the formation of such compounds, although nothing is known about this metabolism in lupus mice.
Clinical studies on the steroid 16alpha-hydroxyestrone showed that it had interesting properties in vivo that might explain its possible role in disease; these include covalent binding of this steroid to erythrocytes and lymphocytes by way of Heyn's rearrangement in vivo and the possibility that such covalent binding might occur at the level of the estrogen receptor or the T-cell receptor and result in alteration of immune function. [14] [15] Studies of family members of SLE patients indicated that elevated hydroxylation of estradiol was commonly observed in nonaffected first-degree relatives and patients. [68]
Enhanced binding of 16alpha-hydroxyestrone to various cell proteins was found in patients ingesting oral contraceptives, irrespective of SLE. Of particular interest, specific antiestrogen protein adduct immunoglobulins were isolated from normal and SLE patients ingesting oral contraceptives. This finding suggested a common pathway to adduct formation in all women who ingest large amounts of estradiol or have an endogenous source of high estrogen level. [16] Men with SLE who had hormone protein adduct-specific IgG in their sera were also reported.
There have been several studies of androgen levels in plasma and of androgen metabolism in men and women with SLE. [64] Some investigators have said that the reasons for SLE in men are the result of too little androgen and too much estrogen. [48] [49] These study results are exceptions, however, because most studies indicate that men with SLE have normal levels of androgens and that estrogen:androgen ratios might be minimally elevated (if at all) in some men. Furthermore, data from the studies of men with SLE do not help to explain the large numbers of women who predominate with the disease.
Studies of androgen metabolism in women with SLE indicate that a difference in the overall metabolism of androgens can be found in that sex. The oxidation of testosterone at C17 in women with SLE is increased in comparison with that of men with SLE, who have both normal oxidation of testosterone and normal plasma levels of androgenic steroid. [70] Several studies of women with active SLE who never took corticosteroids demonstrated decreased plasma levels of androgen. [52] [53] [71] This observation was also found in Klinefelter's syndrome patients. These findings of low plasma androgens in women with SLE form the basis for androgen replacement therapy in this disease. Clinical studies involving the use of dehydroepiandrosterone (DHEA) as a therapy for lupus are a result of this observation.
There is great interest in the effects of prolactin on immune function in mice and human beings. [52] There are diverse effects of hyperprolactinemia in male and female mice. In the male NZW/NZB mouse, autoimmune disease is accelerated and mortality is worsened by prolactin. [112] [114]
High prolactin concentrations are particularly associated with worsened renal disease in inbred lupus mice. The use of prolactin inhibitors like bromocriptine has beneficial effects in these mice, namely, renal disease is abated, and there is delayed mortality. In human patients, elevated prolactin levels can be found in some men and women with SLE, but this is not a universal observation. A survey of premenopausal women whose sera were submitted for autoantibody testing showed that 20% of them had higher than normal prolactin levels and high anti-DNA levels. Additionally, many women referred to an endocrine clinic for hyperprolactinemia who did not have lupus had elevated antinuclear antibodies (33% of women and 53% of men). Autoimmune phenomena not related to lupus are associated with high levels of prolactin. [113]
The age at onset of the disease is more evenly distributed in men, because one fourth are diagnosed after the age of 50 years. [97] The hormonal metabolic data suggest that an increase in feminizing 16-hydroxylated estrogenic metabolites is found in men with SLE, although no clinical findings of hyperestrogenism are found. [61] [63] [65] [68] [69] Studies of a murine strain like the BXSB associate the onset of SLE-like diseases with the presence of the Y chromosome and are not hormonally dependent. A group of human male relatives has been described who resemble the mouse strain BXSB in that male-predominant families exist in which SLE occurs in men in preference to women. [67]
In some series, men with SLE are reported to be clinically different. [5] [11] [46] Several studies of men with SLE show no clinical difference between gender, however, and others have suggested that men have a more severe form of the disease. [99] Increased pleuropericardial disease and peripheral neuropathy are said by some to be more common in men. In another study, men were found to have more discoid lupus erythematosus and papular nodular mucinosis. [55] In a Spanish series of 261 SLE patients, 11.5% were male, and they had less arthritis, more serositis, and a greater propensity for discoid rashes.
Studies of Russian male lupus patients are perhaps the most insightful. [4] [31] The investigators describe elevated luteinizing hormone and follicle-stimulating hormone in men with SLE; a lower trochanteric index (1.89 vs 2.00 for normal men), which is indicative of a lack of androgen effect on bone growth; severe aortic insufficiency and sacroileitis (12% of all men); and, overall, a greater incidence of severe vascular diseases like Raynaud's phenomenon and digital vasculitis. [3] The Russian investigators found more severe disease in men, with 63% dying from end-stage renal disease. The only significant increases of clinical findings in Russian men with SLE are those of nephritis, Raynaud's phenomenon, and malar rash.
Finally, the Russian study also includes male SLE patients with profound impotence. The causes of such impotence in young men with SLE remain unknown. Elderly men who present with SLE are also found to have low androgen levels and are hypogonadal. [7] Such men might respond to androgen therapy.
Some patients with Klinefelter's syndrome also have a variety of rheumatic diseases like SLE and scleroderma. [12] [29] [32] [39] [57] [58] Such men commonly have gynecomastia, infertility, a female fat pattern, and the usual sequela of hypogonadism. These Klinefelter's syndrome patients have met the American College of Rheumatology criteria for SLE serologically and clinically. The incidence of SLE or any other autoimmune disease is not increased in patients with Klinefelter's syndrome. The patient with SLE and Klinefelter's syndrome has the estrogen and androgen metabolism of a woman with SLE. [66] When SLE does occur in young Klinefelter's syndrome patients, it can be treated with synthetic androgens. Androgens such as methyl-testosterone in a tablet form or as an androgen patch can alleviate the symptoms of the disease in Klinefelter's syndrome patients but do not alter the serologic character of the patients. The male patient with Klinefelter's syndrome and SLE oxidizes testosterone like female patients with SLE. This increased oxidation is not found in men with SLE, who have a normal karyotype. The hypergonadotropic state of patients with Klinefelter's syndrome has not been investigated at this time and may have some role in the etiopathogenesis of the disease.
A major controversy among investigators is whether androgen therapy should become part of the lupus treatment protocol and whether the use of exogenous estrogen can be used in the pre- and postmenopausal SLE patient. The estrogen issue is under study by several groups worldwide. A large multicenter study to examine both pre- and postmenopausal estrogen use is underway in the United States. This study is called the Safety of Estrogens in Lupus Erythematosus-National Assessment. Early data [17] suggest that there are significant health benefits from the use of hormone replacement therapy (HRT) in the postmenopausal group of patients with SLE. Osteoporosis is one such disease in patients with SLE who are postmenopausal, particularly as such patients use corticosteroids throughout life. Retrospective studies, although lacking validated measures of clinical improvement or worsening, suggest that HRT may be well tolerated. The degree of clinical activity must be established before placing patients on HRT. Guidelines for lupus activity such as those used by pregnant patients may be recommended. Premenopausal use of estrogens in SLE is still to be avoided, because the current data suggest that such hormone supplements induce a flare of disease. Everyone agrees that one subgroup, namely, those with positive antiphospholipid antibodies with or without evidence of thromboembolism, should avoid both HRT and the casual use of estrogens for contraception. [84] There is new anecdotal evidence that patients who experience hyperestrogenemia because of attempts to enhance fertility can suffer exacerbation of disease. [19]
One androgen for the treatment of lupus is currently undergoing clinical trial, namely, DHEA. The idea of using androgens to treat lupus began with the early work in murine models, where use of testosterone implants decreased morbidity and mortality in mice. Later work showing the enhanced oxidation of testosterone and subsequent low levels of plasma androgens in patients not on corticosteroids made androgen replacement logical.
The use of DHEA in small numbers of female patients resulted in cytokine and cellular effects. [24] [59] [111] The patient assessments performed by the physicians and the self-reporting of patients suggested clinical improvement. Mice given this hormone had a decrease of Th2 cytokines IL-4, IL-6, and IL-10. In addition, there was enhanced cytotoxicity in these animals. One of the more interesting observations was a natural increase of IL-2 in human patients with SLE. IL-2 given to lupus mice reverses disease activity. In fact, defective IL-2 activity has been tied to a deficiency of DHEA in SLE patients. [104] A large clinical trial of DHEA in women with lupus is complete. Preliminary data would suggest that the drug has good effects on SLE activity based on patient and physician assessments. Trials in men with SLE are in progress. The safety and efficacy of DHEA in men with SLE are not clear. One must prove that men who take this steroid are not made worse, a phenomenon that was observed with other male hormones given to men with SLE. [72]
Lupus is one disease in which sex hormones and gender are quite important. Studies of autoimmune diseases like lupus have made the hormone connection more important and increased our overall understanding of the sexual dimorphism of the immune system. It is clear that some fundamental biologic mechanism is at work here and that only knowledge of the molecular mechanisms behind the action of the hormones can help us to understand the gender preference in this illness. [54] Hormones may be potent regulators of cytokine levels and, consequently, disease activity.