Updated advances of linking psychosocial factors and sex hormones with systemic lupus erythematosus susceptibility and development

Estrogens

The potential role of estrogen in autoimmune diseases has been extensively investigated, particularly for SLE. The mode of action of estrogen and its metabolites differs with regards to the specific effects on the modulation of immunity (Cutolo, Sulli & Straub, 2012). It is well established that low doses of estrogen enhance T helper (Th)1 cell responses, whereas high estrogen levels raise Th2 responses (Beagley & Gockel, 2003; Salem, 2004). By contrast to estradiol (E2), estriol (E3) strongly provokes antibody production in response to bacteria (Ding & Zhu, 2008). In genetically predisposed individuals, estrogens increase the risk of disease and have a pathogenic role in SLE. The pathogenic mechanisms may involve the production of type 1 interferon (IFN), survival of auto-reactive B cells and production of pathogenic immunoglobulin (IgG) auto-antibodies, and/or differentiation of CD4⁺ Th cells (Sakiani, Olsen & Kovacs, 2013; Tabor & Gould, 2017). Estrogen signals act on the nuclear receptors estrogen receptor (ER)-α and ER-β in many types of immune cells (Cunningham & Gilkeson, 2011; Hill et al., 2011; Kovats, 2012; Moulton, 2018; Yakimchuk, Jondal & Okret, 2013). Enhanced expression of type 1 IFN-inducible genes has been detected in SLE, and this so-called “IFN signature” has been shown to play a critical role in the pathogenesis of SLE and is associated with active disease (Baccala et al., 2007; Baechler et al., 2003; Li et al., 2010; Ronnblom & Eloranta, 2013). Thus, active immunization with IFN-kinoid can downregulate this IFN signature in SLE (Lauwerys et al., 2013). In a mouse model, estrogens were suggested to increase the production level of IFN-α through up-regulation of genes regulating the production of type 1 IFN such as Ifi202 (Choubey, 2012; Choubey et al., 2011; Panchanathan et al., 2009), Unc93b1 (Panchanathan, Liu & Choubey, 2013), or Irf5 (Choubey et al., 2011; Shen et al., 2010). Simultaneously, type 1 IFNs also increase estrogen signaling in immune cells by provoking the expression of ER-α, thereby contributing to SLE development and progression (Choubey et al., 2011; Panchanathan et al., 2010).

Moreover, numerous studies have suggested that estrogens have various effects on B cell development, survival, and differentiation, and in regulating the production of pathogenic auto-antibodies (Hill et al., 2011). Estrogen promotes the survival of self-reactive B cells by preventing their elimination or inactivation at developmental checkpoints. This is possibly related to the up-regulated expression of Bcl-2, CD22, SRC homology region 2 domain-containing phosphatase-1 (SHP-1), vascular cell adhesion molecule 1 (VCAM-1), protein tyrosine phosphatase, non-receptor type 6 (PTPN6), and B-cell activating factor (BAFF) (Bassi et al., 2015; Bynoe, Grimaldi & Diamond, 2000; Grimaldi et al., 2002; Hill et al., 2011; Panchanathan & Choubey, 2013). However, selective estrogen receptor modulators raloxifene suppressed estrogen-mediated effects on the survival, differentiation, and activation of autoreactive B cells in NZB/WF1 mice, which might serve to ameliorate lupus activity (Zhang et al., 2010).

An Ig class switch occurs in B cells from IgM to IgG, which requires activation-induced cytidine deaminase (AICDA), and estrogens have been shown to increase the expression of AICDA and homeobox protein Hox-C4 (HOXC4) in B cells, leading to the development of pathogenic IgG auto-antibodies (Mai et al., 2010; Pauklin et al., 2009; Sakiani, Olsen & Kovacs, 2013). Estrogens can also enhance the production of anti-double-stranded DNA (dsDNA) antibody and IgG or IgM by peripheral blood mononuclear cells and serum, which enhances the disease severity causing flare-ups (Khan & Ansar Ahmed, 2016). Moreover, estrogen has multiple effects on the development, differentiation, and functions of CD4⁺ T cells (Walters et al., 2009). In SLE, estrogen induces activation of the T lymphocytes via ER-α and ER-β, and increases the expression of T cell activation markers such as CD154 and calcineurin (Lin et al., 2011; Rider et al., 2006). Estrogen was also shown to exacerbate lupus disease severity via an ERα-independent mechanism along with other immune effects contributing to lupus pathogenesis, including modulation of Toll-like receptor (TLR) pathways, dendritic cell development, or E2-TWEAK signaling (Scott et al., 2017). These mechanisms might also contribute to the pathogenic mechanism of SLE, primarily affecting women.

Progesterone

The relationship between progestogens and SLE is complex. Progesterone has been suggested to play an important protective role against SLE disease activity (Hughes, 2012; Hughes & Choubey, 2014; Tan, Peeva & Zandman-Goddard, 2015; Tsur et al., 2015). Progesterone can also counteract the effects of estrogens summarized above, such as the estrogen-induced increase in type 1 IFN production, survival of auto-reactive B cells and pathogenic IgG auto-antibodies production, and differentiation of CD4⁺ Th cells. Progesterone has immune-modulatory effects that generally have anti-inflammatory outcomes (Tait, Butts & Sternberg, 2008). In SLE, the promotion of IFN-α/β production is primarily controlled by IFN regulatory factors (IRFs) such as IRF-3, IRF-5, and IRF-7 (Baccala et al., 2007; Fu et al., 2011; Niewold et al., 2012; Ronnblom, Eloranta & Alm, 2006; Ronnblom & Pascual, 2008; Sigurdsson et al., 2005; Stone et al., 2012; Wang et al., 2013). Progestogens impair IRF-7 activation in plasmacytoid dendritic cells (Hughes et al., 2008), which regulate the TLR-mediated decreased production of IFN-α, a major source of type 1 IFN, through depot medroxyprogesterone acetate (DMPA), thereby ameliorating the IFN signature and consequently SLE disease activity (Tan, Peeva & Zandman-Goddard, 2015). Moreover, progesterone has the opposite effect of estrogen with regards to the Ig class switch of B cells, resulting in a decrease of the IgM to IgG class switch recombination via suppressing the transcription of AICDA (Park, 2012; Pauklin & Petersen-Mahrt, 2009; Pauklin et al., 2009; Sakiani, Olsen & Kovacs, 2013). Specifically, progesterone reduces the production of IFN-γ, which induces a class switch to IgG2a in B cells, leading to pathogenic IgG auto-antibodies production (Hughes, Clark & Wong, 2013). In the last decade, there has been much research focused on the promotion effect of progesterone for Th2 differentiation; in particular, high levels of progesterone will induce a Th2-type immunologic response and suppress a Th1-type response via inhibiting IL-12 signaling in SLE (Hughes, Clark & Wong, 2013; Miyaura & Iwata, 2002). Meanwhile, there is a decrease in mortality, glomerulonephritis and Th1-related autoantibody production after DMPA treatment in NZB/NZW mice, which suggest that progesterone may have therapeutic benefit for SLE patients (Hughes et al., 2009; Recalde et al., 2018).

Androgens

Androgens may play an important protective role in the pathogenic mechanisms contributing to the development of SLE. Similar to progesterone, androgens target key immune pathways that can protect against SLE by counteracting the effects of estrogens. In particular, androgens down-regulate the levels of Ifi202, which in turn decreases the production of type 1 IFN (Choubey, 2012; Choubey et al., 2011; Panchanathan et al., 2009). Compared with estrogens, androgens may enhance the checkpoints for the auto-reactivity of B cells to induce B cell apoptosis via decreasing the level of Bcl-2 in B cells (Altuwaijri et al., 2009), and can also increase the level of transforming growth factor beta 1 (TGF-β1) in marrow stromal cells (Olsen, Gu & Kovacs, 2001), thereby suppressing the development of autoimmunity (Gubbels Bupp & Jorgensen, 2018; Sakiani, Olsen & Kovacs, 2013; Zhu et al., 2016). Androgens have also been shown to decrease the level of pathogenic IgG auto-antibodies production through inhibition of Ig class switching (Sakiani, Olsen & Kovacs, 2013). Androgens decrease the Th1 differentiation of CD4⁺ T cells via inhibiting IL-12 signaling, which in turn mitigates CD4⁺ responses in autoimmune disease (Kissick et al., 2014). Androgens also appear to modulate the accumulation of Gr1⁺CD11b⁺ cells in male mice and could inhibit the function of T follicular helper cells, formation of the germinal center, and the differentiation of plasma cells (Bird et al., 2017). CD11b⁺ cells were shown to overexpress DHT-regulated genes and colony-stimulating factor 3 receptor (Gubbels Bupp, Jorgensen & Kotzin, 2008), which was identified to influence the development of lupus and RA (Elera-Fitzcarrald et al., 2017; Gubbels Bupp, Jorgensen & Kotzin, 2008).

Prolactin

Only very limited data are currently available on the contributions of PRL to the development of autoimmune diseases. Indeed, the relationship between PRL and SLE and the underlying mechanisms remain controversial; however, the general perception is that PRL does play a pathogenic role in SLE, particularly with respect to hyper-prolactinemia (Costanza et al., 2015; Karimifar et al., 2013; Shelly, Boaz & Orbach, 2012). Under a specific genetic background, like estrogen, PRL has also been shown to promote the survival of self-reactive B cells by impairing B cell receptor-mediated clonal deletion and decreasing B cell apoptosis, thus breaking down B cell self-tolerance, leading to the development of autoimmunity (Elera-Fitzcarrald et al., 2017; Gonzalez, Saha & Peeva, 2013; Orbach & Shoenfeld, 2007; Saha et al., 2009, 2011). In B6.Sle3 mice, PRL increases the expression of co-stimulatory molecules (CD40, CD86 (B7-2), and MHC II molecules) on B cells, leading to enhanced antibody responses (Gonzalez, Saha & Peeva, 2013; Matera, Mori & Galetto, 2001). With respect to the differentiation of CD4⁺ Th cells, PRL up-regulates the levels of INF-γ, IL-12, IL-2, and CD40L (Clevenger, Altmann & Prystowsky, 1991; Clevenger et al., 1990; Gonzalez, Saha & Peeva, 2013; Jara et al., 2017; Matalka, 2003; Mukherjee, Mastro & Hymer, 1990; Orbach et al., 2012), leading to CD4⁺ T cell activation that can drive the development of autoimmunity in SLE. Recent studies have also implicated PRL in STAT5 activation, and in the induction of Ig synthesis and anti-dsDNA antibodies in SLE. However, it is reported that bromocriptine, a drug that inhibits PRL secretion, abrogates some of the immune effects of PRL in mice (Saha et al., 2011). Actually, the association between PRL levels and disease activity in SLE is still controversial (Elera-Fitzcarrald et al., 2017). Thus, further research on these relationships is warranted.

Here, we updated the roles and the effects of sex hormones including estrogens, progesterone, androgens, PRL on SLE, and some feasible measures could suppress some of effects of sex hormones in SLE mice. Most importantly, the mechanisms linking these factors with SLE susceptibility and development were explored (Table 1), which can guide the establishment of practical measures to benefit SLE patients and offer new ideas for therapeutic strategies.