Hormones

Sex hormones

Nine out of ten patients afflicted with SLE are women, indicating that the female gender is an important factor in disease development. A skewed X chromosome-inactivation pattern, sex hormone defects, and reproductive history are factors that contribute to the breakdown of tolerance leading to autoimmunity. Several X chromosome defects have been reported in patients with SLE. These include gene translocation causing triplication of genes, X duplication with an increased incidence of SLE in males with Klinefelter’s (XXY) syndrome, and demethylation of genes such as CD40L on the X chromosome resulting in overexpression of CD40L. The importance of the X chromosome was shown in a pristane-induced model of lupus wherein the XX sex chromosome complement conferred increased susceptibility to disease over the XY ^– mice. The gender bias in SLE reflects not only the role of sex chromosomes but also that of sex hormones.

The role of sex hormones in SLE pathogenesis is supported by the fact that the disease manifests predominantly in the reproductive phase of life. Before puberty, the female to male prevalence is 3:1, which increases to 9:1 after the onset of puberty. In addition, there is evidence of an increased estrogenic environment in both men and women with SLE. Animal studies using both the New Zealand Black/New Zealand White (NZB/NZW) and the MRL/lpr mouse models of lupus have shown that lupus-prone female mice succumb to disease sooner than male mice. Early studies demonstrated improvement or worsening of disease with gonad removal of ovaries or testicles, respectively, suggesting a critical role of hormones in pathogenesis. Female mice survived longer after ovariectomy than castrated male mice. Administration of estrogen worsened disease while androgen supplements improved disease in both female or male castrated mice. Accordingly, treatment with the estrogen receptor antagonist tamoxifen-reduced anti-DNA antibodies, immune complex deposition in the kidney, and improved survival. Although serum estrogen levels are not significantly altered in patients with SLE, androgen levels are found to be significantly lower. There appears to be an increase in estrogen metabolism in SLE. Increased levels of the feminizing 16-hydroxyestrone and estriol metabolites occur in the serum of patients resulting from an increased oxidation of the androgen precursor dehydroepiandrosterone (DHEA). On the other hand, androgen levels specifically DHEA are low in lupus patients. Besides estrogen, the female hormone prolactin is associated with worse renal disease in lupus-prone mice while the prolactin inhibitor Bromocriptine improved disease and prolonged survival in these mice.

Estrogen-estrogen receptor signaling

Estrogens are a group of steroid hormones that includes estrone, estradiol, and estriol. Most of the effects of estrogens are mediated by intracellular receptors—estrogen receptor (ER) α and ERβ. ERα and β belong to the steroid hormone receptor superfamily and are expressed in most immune cells including T cells, B cells, monocytes and dendritic cells ( Fig. 13.1 ). Estradiol diffuses through the cell membrane and binds to the ER which leads to the homo- or hetero-dimerization of the ER which then bind with high affinity to consensus estrogen response elements (ERE) sites within target genes thus functioning as transcription factors to regulate gene expression. Besides the direct binding to target genes, ER-mediated regulation of gene transcription can occur indirectly via other proteins, and can be ligand-dependent or independent. The ER can act as a transcriptional co-activator and bind to other transcription factors such as specific protein 1 (Sp1), activator protein (AP)-1, or nuclear factor kappa-light-chain enhancer of activated B cells (NFκB). In addition to the conventional intracellular ER, membrane bound G protein coupled receptors (GPR30) and cytoplasmic receptors have been identified which upon estrogen ligation can induce rapid intracellular calcium fluxing and intracellular signaling in various cell types. Interestingly, the ER can function in gene regulation in a ligand-independent manner—for example, extracellular stimuli such as insulin, IGF1, EGF, and TGFβ can lead to ER phosphorylation by MAP kinases and result in gene transactivation.