Introduction

Systemic lupus erythematosus (SLE) is a polygenic autoimmune disease. The disease is characterized by a breakdown of B cell tolerance, which results in the development of tissue-specific and non-tissue-specific autoantibodies that mediate a variety of pathologic outcomes. The common targets of many of the autoantibodies are ubiquitous nuclear antigens: single- or double-stranded DNA, chromatin, nuclear proteins such as Ro/SS-A or U1RNP. The most common clinical manifestations include glomerulonephritis, arthritis, vasculitis, cerebritis, pericarditis, cytopenias, and serositis [1]. It is now apparent that the predisposition to producing autoantibodies is genetically determined, and that many genes and genetic loci can contribute to this predisposition. The production of autoantibodies can precede clinical disease by several years [2]. Recently, it has become clear that target organ vulnerability to autoimmune attack is also genetically determined [3]. Thus, some individuals will experience more tissue destruction than others, despite harboring the same autoreactivity.

Susceptibility to SLE is influenced by nongenetic factors also, and there is compelling evidence that sex hormones can exacerbate disease, in at least some individuals.

SLE is nine times more common in women than men [4]. It has a characteristic age of onset after menarche and before menopause. Outside the period of female reproductive activity, the onset of disease is uncommon and without sex preference [5, 6]. These observations suggest that endogenous sex hormones may play a role in the development of the disease, with estrogen acting to trigger disease and androgen to reduce disease susceptibility. Consistent with this hypothesis, some women with SLE have low levels of plasma androgen [7] and abnormal patterns of estradiol metabolism, leading to increased estrogenic activity [8].

Because endogenous estrogen may promote SLE disease, clinical studies have been conducted to question the safety of exogenous estrogen therapies, hormone replacement therapy (HRT), and oral contraception (OCP). Early studies described a link between estrogen and disease flares [9-14], but later studies failed to show a correlation [15-20]. Two large retrospective surveys suggested that the use of exogenous estrogen increases the risk of developing SLE: HRT with a relative risk of 2.1 [21] and OCP with a relative risk of 1.9 [22]. The recent Safety of Estrogens in Lupus Erythematosus: National Assessment trial demonstrated that HRT increases the number of mild and moderate flares, while OCP does not. Why there should be discordance between HRT and OCP is not resolved [23]. One possible explanation is the heterogeneity of the genetic background of SLE patients, which might influence the response to estrogen. This would flatten the statistics of large cohorts and might explain the inconsistent results obtained for small cohorts. The discrepant studies on the effects of estrogen have highlighted the need for additional research to determine the molecular pathways affected by estrogens and potential genetic links between estrogen susceptibility and the onset and exacerbation of disease.

Murine models that spontaneously develop a syndrome resembling human SLE have been exploited to question the potential effects of estrogen. Data obtained with the lupus-prone NZB/W F1 mice clearly demonstrate that estrogen can modulate disease. Female mice treated with 170-estradiol manifest an earlier onset of lupus and an earlier mortality [24]. Similar results have been established for lupus-prone MRL/lpr mice [25-27]. Conversely, when female mice are ovariectomized and treated with testosterone [24,28] or simply treated with an antiestrogenic drug such as tamoxifen [29] orICI-182,780 [27] or fed with an antiestrogenic diet [30], they exhibit a prolonged lifespan.

SLE severity has also been linked to elevated prolactin levels. Approximately 15%-20% of patients have elevated prolactin levels [31]. Few have pituitary adenomas; therefore, the etiology of the prolactin elevation is unclear [32]. In NZB/W F1 mice, increasing prolactin levels results in earlier onset of disease and earlier mortality [33,34].

We have begun to dissect the role of estrogen and prolactin in the fate of autoreactive B cells using a nonspontaneous mouse model of autoantibody production, the R4A transgenic mouse. This mouse is transgenic for the y2b heavy chain of the R4A anti-DNA antibody. In BALB/c mice, approximately 5%-10% of the B cells express the transgene; the remaining B cells express a full endogenous heavy chain repertoire. All B cells express an endogenous light chain [35-37]. The association of some light chains with the R4A heavy chain generates an antibody with no binding to DNA. Other light chains confer low-affinity DNA binding and still others confer high-affinity DNA binding. The B cells making antibodies with no or low affinity for DNA mature to immunocompetence, but those B cells making high-affinity anti-DNA antibodies are subject to tolerance induction.

Female BALB/c R4A mice are not spontaneously autoimmune. After administration of exogenous estrogen, they develop elevated titers of high-affinity anti-dsDNA antibodies composed of the R4A heavy chain and a number of different light chains, and display kidney deposition of these antibodies [38]. Exogenous estrogen is a sufficient factor for the development of an SLE serology in this model. A doubling of serum prolactin in BALB/c R4A transgenic mice also leads to autoantibody production, demonstrating that prolactin as well as estrogen can alter B cell repertoire selection, and B cell activation [39]. This model, therefore, provides the opportunity to observe how estrogen and prolactin alter B cell selection and maturation and allow autoreactive R4A B cells to survive and mature to antibody secreting cells.

In this chapter, we will review the mechanisms by which estrogen and prolactin appear to contribute to autoantibody production. Based on the R4A model, we will describe the mechanisms responsible for the estrogen-or prolactin-dependant breakdown of B cell tolerance. We will discuss the clinical relevance of these observations for SLE patients. It is highly probable that both hormones may also affect target organ sensitivity to autoantibody attack. This question will not be addressed in this review, but remains an important topic for future study.

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