Females display an increased incidence of autoimmune diseases, with a sexual dimorphism in the immune response. The autoimmune diseases involve both genetic and environmental factors and the autoimmune process is characterized by the breakdown of tolerance in subjects with genetic susceptibility, with subsequent target (organ-specific and not) injury, that, in turn, elicits repairing mechanisms. Increasing evidence in the literature suggests an important role of the microenvironment on the immune system activity and of sex steroids in this context. Sex steroids may act at the multiple steps of the autoimmune process with different (and contrasting) effects, depending on the type of the steroid (natural or synthetic), the concentration and co-presence of the ligands and the binding to their specific receptors. Regarding the effectors of the immune system, different actions of sex steroids depend on the type of immunocytes involved (with final stimulatory or inhibitory actions). To complete the scenario, sex steroids may influence the whole process through multiple, contrasting and time-dependent pathways, for instance, modulating the autoimmune destroying process and/or stimulating the reparation. The clinical resulting effect is a balance of these complex and contrasting modifications. In this chapter we will summarize the fundamental and clinical aspects of the neuroendocrine-immune interactions in three main autoimmune diseases, systemic lupus erythematosus (SLE), multiple sclerosis (MS) and rheumatoid arthritis (RA) (see Reference 1 for more details).
The tolerance against self-antigens is a highly regulated process, involving both B and T-cells  Thymic negative selection (central deletion) eliminates the danger of pathogenic autoimmune T-cell, whereas peripheral mechanisms inactive T-cells which escape thymic deletion , (Table 1).
The professional antigen presenting cells (APCs) control the tight balance between tolerance and immunity. Dendritic cells (DCs) represent a family of professional APCs that are derived from hematopoietic precursors and have the capacity to induce antigen-specific T-cell responses.
The mechanisms causing loss of tolerance in autoimmune diseases remain elusive. Autoimmunity develops when genetically predisposed individuals encounter environmental agents that trigger the disease. Sex steroids influence this process at different levels.
A sexual dimorphism in the immune response has been described. The immune system (antibody and cell-mediated response) is more active in females, protecting from infectious diseases and conferring a greater longevity . Sex steroids influence immune cell development in primary lymphoid tissues and have immunomodulatory effects on both peripheral T-cell and B-cell subsets in adult life. Recent evidence suggests that tolerogenic DCs can be programmed by a variety of factors, including innate immune receptor signaling, cell–cell interactions, and micro-environmental cues (e.g., steroid hormones, cytokines, and other soluble mediators).
Tolerogenic DC populations regulate immune responses through numerous potential mechanisms, including altered co-stimulatory molecule expression, inhibition of proinflammatory mediators (e.g., IL-12, TNF-α, NO, NF-κβ), enhanced production of immunoregulatory factors (e.g., IL-10, TGF-β, IDO, arginase), or increased expansion and/or differentiation of Tregs . Sex steroids are divided in androgens (testosterone T,5-α-dihydrotestosterone DHT, dehydroepiandrosterone sulphate DHEAS, dehydroepiandrosterone DHEA, androstenedione A), oestrogens (17β-estradiol E2, estrone E1, estriol E3) and progesterone (P).
Sex steroid receptor in the immune system
Classical steroid actions are mediated through receptors that belong to the nuclear hormone receptor superfamily . Transcription-independent actions can be mediated by membrane associated receptors (mR). Estrogens interact with two receptors, ER-α (ESR1) and ER-β (ESR-2), from NR3A1 and NR3A2 genes located on chromosome (Ch) 6 and 14, respectively. Estrogen receptors are expressed in thymocytes, thymic epithelial cells and mature peripheral B- and T-lymphocytes . Splenic B-cells express classical ER-α, but not ER-β . ER-α66 and ER-α46 splice variant are expressed in human monocytes and macrophages . mER in mice have been demonstrated in macrophages and T-cells .
Progesterone has 3 isoforms of receptors (PRs) (PR-A, PR-B, and PR-C, from the NR3C3 gene located at Ch 11. The presence of PRs has been detected in about 21% of lymphocytes , immature DCs , activated peripheral blood lymphocytes of females, peripheral NK cells and tissue macrophages ; mPR were detected in T-lymphocytes .
The androgens act through the androgen receptor (AR), from the NR3C4 gene located on Ch X. ARs are present in bone marrow (BM) stromal cells , thymocytes  and immature DCs . Splenic T cells and macrophages express mAR .
In summary, the presence of the steroid receptors in immune cells supports the hormonal action in the development and modulation of the immune system. During physiological pregnancy, P and E2 reach high concentrations (up to 100 times higher) compared to normal levels: there is a thymic involution, a Th1 to Th2 shift and an increased expression of FoxP3; thymus size normalizes in the 1st month postpartum . Systemic lupus erythematosus (SLE), a Th2-mediated disease is exacerbated by pregnancy; whereas RA and MS, Th1-mediated diseases, improve during pregnancy [20, 21].
Systemic lupus erythematosus
The prevalence of SLE is higher in females (F:M=9-10:1), during the reproductive phase. SLE is less common before the menarche (with a ratio F:M=3-4:1) and after the menopause .
Genetic variation of the IRF5 (a protein related to IFN-α production) and Stat4 (an IFN-α-inducible intracellular signalling molecule) has been reported to be associated with risk of SLE, suggesting that IFN-α and Th1/Th17 pathways interact with genetic and hormonal actions . Risk of SLE is also related to the gene UBE2L3 (a co-activator of PRs and other sex steroid receptors) .
Central and peripheral B-cell tolerance mechanisms involved in the control of survival, differentiation and activation of autoreactive B- and T-cells are altered in SLE [25, 26]. In SLE, autoAb-containing ICs activate pDCs through these same pathways to induce IFN-α, which is believed to act on multiple immune cell types to break tolerance and amplify autoimmunity.
Oestrogen and their catechol metabolites play an important role in SLE . Interactions among TNF, IFN-γ, E2, and IFN-α may regulate the expression of IFN-inducible (IFI) genes . E2 upregulated six pathways that control T-cell function including IFN-α signalling . In an interesting study, T cells cultured in medium containing 2-fluoroE2 showed a significant increase in the amount of CD40 ligand (CD40L) on the cell surface. The binding of CD40L (on Th cells) to CD40 protein (on APCs) is a well known co-stimulatory signal that induces a variety of downstream pathways supporting autoimmune B cells. The estrogen receptor antagonist ICI 182,780 blocked the estrogen dependent increases in SLE T cell CD40L mRNA and cell surface protein, suggesting that E2 worked through the ER .
Minimal changes were observed in the lupus nephritis using ER-α deficient (ER-α knock out, AERKO) mice exposed to E2, whereas E2 treatment in wild-type mice induced a lupus phenotype with accelerated death, increased kidney damage, Th2-type cytokines and autoAb production . DHT administration lowered anti-DNA Ab levels and improved the prognosis; P treatment modestly worsened survival in mice . The treatment with medrossiprogesterone acetate markedly decreased death, kidney damage, suppressing pathogenic Th1-related anti-dsDNA IgG2a in the serum and kidneys . Androgen deficiency induced premature death .
Not all lupus features occur in a similar way (immune complex glomerulonephritis vs focal sialadenitis, renal vasculitis, and periarticular inflammation); E2 stimulates Ab production and immune complex phenomena but inhibits T cell mediated organ pathologies . E2 may play a modulatory role depending on its conversion to downstream mitogenic proinflammatory 16α-OH-E1 or naturally occurring anti-estrogens such as 2-OH-E1.
In SLE females, serum E1 levels and urinary levels of 16α-OH-E1 are increased (the conversion to the mitogenic 16α-OH-E1 is upregulated) , serum P is reduced  and an androgen deficiency (T and DHEA) is present [36-39]. Increased incidence of SLE has been reported in hypogonadal states in males . Women taking oral contraceptives (OC, estrogens and P) demonstrated no increased risk to develop SLE , although exogenous estrogens might exacerbate lupus activity . The OC use should be considered only for inactive SLE. Pregnane progestin contraception (with chlormadinone acetate 10 mg/day and cyproterone acetate 50 mg/day) is well tolerated .
Hormonal replacement therapy (HRT) increases the risk of developing SLE/discoid lupus in postmenopausal women . SLE tends to flare during pregnancy and puerperium, directly depending on the disease activity before conception . SLE disease activity scores increased in the 2nd trimester and decreased in the 3rd trimester .
Dehydroepiandrosterone (DHEA) (200 mg/day) reduced flares by 16% compared with placebo, enabling reduction of steroids . In Chinese women, DHEA reduced serum IL-10 . However, in a recent meta-analysis, authors concluded that DHEA had a modest impact with not consistent effect on SLE disease activity (as measured by SLE disease activity index, SLEDAI) . Testosterone therapy (150 g patches, twice weekly) did not significantly affect disease activity in SLE females .
Fulvestrant (ICI 182,780,selective ER down-regulator) therapy (250 mg intramuscular) in patients with moderately active SLE significantly improved SLEDAI . Raloxifene was well tolerated in patients with inactive SLE, maintaining femoral neck and spinal bone mineral density (BMD) in patients receiving corticosteroids .
Tibolone (progestogen derived from 19-nortestosterone) is one of the available options for HRT in SLE. Tibolone (2.5 mg/day) in post-menopausal patients with inactive or stable SLE did not affect the flares and controlled hypoestrogenism related symptoms .
Multiple sclerosis (MS) is more frequent in young females (F:M=3-2:1) . Men have a later onset of disease (when testosterone is low) , and have a poor prognosis . Gender differences in brain damage have been found (both white matter and intra-cortical lesions) .
The role of IL-12, IL-13 and IL-23 has been evaluated in EAE . Perivascular IL-17-producing T-cells are present in brain lesions of active MS patients . FoxP3+ Treg cells may limit the expansion of encephalitogenic T-cells .
The C57BL/6 mice show no sex difference in the manifestation of EAE. SJL mice presented increased incidence in female. Ovariectomy led to an earlier EAE onset and treatment with estrogens (E3>E2) delayed the onset itself. Treatment with pregnancy-level E2 (mediated by ERα) reduced subsequent neurologic disease, through suppression of Th1 and Th17 cell .
Clinical EAE was induced by orchidectomy . Oral tolerance induction of EAE in male B10.PL mice was blocked by castration . The myelin basic protein (MBP)-primed T cells from female and castrated male mice, but not from male mice, produced proinflammatory molecules, such as NO, IL-1β, and IL-6 in astroglia . Androgen-selected T-cell lines secreted less IFN-γ and more IL-10 than untreated cell lines . EAE susceptibility in females is influenced by specific proinflammatory effects of IL-13, in part through up-regulation of Th1-inducing cytokines and MHC II on CD11b+ macrophages .
In EAE, several studies have demonstrated the potent suppressive effects of estrogens . Naive cells are more sensitive to sex hormones than differentiated effector cells. E2 diminished EAE clinical manifestations in C57BL/6 IL-4, IL-10, and IFN-γ KO mice, suggesting that these Th2 cytokines are dispensable for the oestrogen protective effect in mice . Low E2 doses reduced the capacity of myelin-reactive T-cells to initiate disease, suggesting autoimmunity in females is dependent on homeostatic levels of oestrogen .
In the presence of E1, E2 and E3, human CD4+ T-cell clones from MS patients showed an enhancement of IL-10 secretion , whereas the secretion of TNF was biphasic (enhanced at low but inhibited at high concentrations). E2 treatment decreased frequency of DCs in the brain of EAE mice, reducing TNF-α, IFN-γ and IL-12 production . E2 have multiple effects on DC function, including inhibition of homing and migration, suppression of antigen presentation and shifting cytokine production towards a Th2 profile. Estrogen effects may be mediated by TGF-β . Sustained sub-pregnancy E2 levels prevented clinical and histological signs of EAE, probably due to expansion of Tregs. E2 induced dependent increase in FoxP3 expression .
E2 treatment reduced the production of IL-17 . E2 treatment did not protect against EAE or suppress IL-17 production in PD-1 gene deficient mice . E2 (pregnancy levels) decreased disease-mediating chemokine receptors in a model of EAE . The protective effect of E2 in animals with EAE was abolished in AERKO mice but not in BERKO mice . ER-alpha agonist (propyl pyrazole triol) and selective estrogen receptor modulators (SERMs) (raloxifene and WAY-138923) but not ER-beta selective agonist suppressed clinical symptoms of disease .
EAE-protective effects of E2 were abrogated in B cell-deficient (muMT−/−) mice . E2 treatment of wild type mice selectively up-regulated expression of PD-L1 on B cells and increased the percentage of IL-10-producing CD1dhighCD5+ regulatory B cells. Upregulation of PD-L1 was critical for E2-mediated protection since E2 did not inhibit EAE in PD-L1−/− mice. The results demonstrate a requirement for B cells in E2-mediated protection against EAE involving ERα and PD-1/PD-L1 negative co-stimulatory pathway. E2-primed B cells may represent an important regulatory mechanism in MS, with significant implications for women receiving current MS therapies that cause B-cell depletion .
Other studies demonstrated that ER-α was dispensable for the E2 improvement in EAE model . Treatment with either ER-α or ER-β ligand was neuroprotective, reducing demyelination, with preserved axon numbers in white matter and decreased neuronal abnormalities in gray matter. It is possible to dissociate the anti-inflammatory effect from the neuroprotective effect of estrogen treatment (neuroprotective effects of oestrogen treatment do not necessarily depend on anti-inflammatory properties) .
Oral 17α-ethinyl estradiol (EE, a semisynthetic estrogen compound) and androstenediol (5-AED, rank of binding ERβ > ERα AR), like E2, suppressed EAE induction and severity [81, 82].
Progesterone has shown variable effects in EAE. In rats, while EE inhibited EAE, the progestagen medroxyprogesterone acetate augmented disease activity . In C57BL/6 females, 20-100 mg P before EAE induction attenuated disease severity (inflammation, demyelination and axonal pathology . Regarding remyelination, P treatment after onset of EAE fosters CNS myelin regeneration, involving suppression of IL-2 and IL-17 .
In susceptible female Lewis rats ovariectomized, E2 limited both EAE behavioral impairments and inflammation. On the contrary, P-treated rats had more severe sensorimotor deficits with increased inflammatory infiltrates and apoptotic neurons. Interestingly, co-administration of E2 with P prevented the consequences of P, including neuronal apoptosis . Progesterone has been also associated with enhancement of EAE . Testosterone and DHT were shown to have protective effects in EAE (both males and females) by directly promoting the production of IL-10 at the expense of IFN-γ from myelin reactive CD4+ lymphocytes [62, 88]. In mice, female and castrated male MBP-primed T cells expressed both α4 and β1 integrin. Interestingly, the expression of β1 was absent in male MBP-primed T cells . Male sex hormones (T and DHT), but not female sex hormones (E2 and P), were able to suppress the mRNA expression of β1 in female MBP-primed T cells . Fluasterone (HE2500, a synthetic androstene derivative), and androstenetriol (HE2200, a natural androstene hormone) delayed the onset of EAE and prevented the relapses .
Approximately 40% of women with MS reported worsening of symptoms at menopause . One study reported beneficial effects in 75% of MS patients with HRT . In women with MS, the rate of relapses declined during pregnancy, especially in the 3rd trimester (from 0.7 before pregnancy to 0.2/woman/year in the 3rd trimester), and increased during the 3 months postpartum (1.2/woman/year) before returning to the pre-pregnancy rate . Serial magnetic resonance imaging (MRI) examinations did not show differences in brain lesion activity during ovarian cycle [93, 94]. Changes in the P/E2 luteal (PEL) ratio were significantly related to the corresponding changes in the number and volume of enhancing lesions: increased PEL values corresponded to increased MRI activity . The T/E2 ratio in the follicular phase showed a significant positive correlation with the mean MRI activity (measured as number and volume of enhancing lesions) of the next 3 months . Other authors did not confirm these results . Hormonal fluctuations during menstrual cycles may be associated with exacerbations of MS symptoms, with a premenstrual worsening .
Oral contraceptives do not affect the risk of developing MS. In a case-control study, the incidence of MS was 40% lower in recent users of OCs (mainly EE plus a progestagen) compared with nonusers . OC use in women with relapsing-remitting MS is associated with a milder disabling course . The observations indicate that MS patients do not need to stop OCs, unless other risks (such as thrombosis or neoplasia) become significant .
E3 treatment (pregnancy levels, 8 mg/day) in patients with relapsing remitting MS decreased the number and volume of inflammatory lesions on monthly cerebral MRI , increased IL-5 levels (by CD4+, CD8+ T-cells) and IL-10 (by CD64+ monocytes/macrophages) and decreased TNF (by CD8+ T-cells) in stimulated mononuclear cells .
The preventive effect of combined E2/progestagen (17β-E2 transdermal 75 μg once a week + oral nomegestrol acetate 10 mg/day, for 3 months after delivery) on post-partum relapses is currently being tested in a randomized, placebo-controlled European trial (POPART’MUS study) .
Gonadal function in MS patients may be variable, ranging from hyper- to hypo-function depending on the course of the disease, the presence of relapse and the concurrent therapy. Both hyperandrogenism and low testosterone concentrations have been reported in females and males [94, 104]. Hormonal abnormalities are present in 56% of patients, consisting of decreased P level, increased E2 level or both . Treatment with T gel (100 mg/day) in men with relapsing-remitting MS was associated with improvement in cognitive performance and a slowing of brain atrophy, with no significant effect on gadolinium-enhancing lesion numbers .
The prevalence of RA is higher in females than in males (F:M=4:1). Predisposition to RA has been linked to the major histocompatibility complex (MHC) class II HLA-DRB1 locus, and in particular to the HLA-DR4 genes such as DRB1*0401, DRB1*0404, and DRB1*0405 .
Reduced central tolerance to type II collagen (CII) in AIRE-KO mice manifested as increased CD4 T-cell help to B-cells for cross-reactive autoAb production and enhanced type II collagen induced arthritis (CIA) . Cells that are primed by DCs, such as B-cells, Th1 and Th17 cells are being considered as additional targets for immune-based therapy . Multiple factors induced by IL-17 seem to promote bone resorption, extracellular matrix degradation, synovium proliferation, angiogenesis, and recruitment and activation of immune cells for bone erosion and articular destruction in RA joints.
Ovariectomy of female DBA/1 mice increased arthritis induced with CII ; E2, E3 and 2-methoxyestradiol presented positive effects . An ER-alpha agonist propylpyrazoletriol (PPT) in female DBA/1 ovariectomized mice ameliorated the disease in CIA . Raloxifene and E2 treatment decreased the frequency of arthritis, prevented joint destruction and countered generalized osteoporosis in CIA in B10.Q-ncf1*/*mice . Addition of E2 or raloxifene to dexamethasone-treatment in CIA in female DBA/1-mice prevented generalized bone loss and induced a marked improvement in the arthritic disease .
Pregnancy-level P had little effect on joint swelling or serum TNF-α and PGE2, but reduced the beneficial effects of pregnancy level estrogen, acting primarily at the level of joint inflammation (on the effector phase of immune injury), rather than induction of autoimmunity .
A highly specific agonist of the ER-β (called ERB-041) had a strong beneficial effect in the Lewis rat adjuvant-induced arthritis (AIA) model . HE3286 (17α-ethynyl-5-androstene-3β, 7β, 17β-triol) is a novel metabolically stabilized, orally bio-available derivative of an active DHEA metabolite (androstene-3β, 7β, 17β-triol, AET). It was used in CIA, reducing clinical signs of disease and proinflammatory signals, including IL-6 and matrix metallopeptidase 3, with increased Tregs [117, 118].
Female sex has a negative effect on RA, but the menopausal state with lower steroid hormone levels is responsible for the differences in outcome between men and women . A reduced blood androgen concentration has been found in RA .
The age at RA diagnosis was lower in Polish patients with the ER-α rs9340799 (A allele) as well as in patients with ER-α rs2234693 (TT and TC genotypes) . An ERα polymorphism (Pvu II and Xba I restriction fragment length) affected the course of RA in Japanese patients . The polymorphism of the ER-β (rs1256049, Rsa, in exon 5) was more frequent in female Japanese RA patients . A CA repeat polymorphism in ERβ has been associated to the presence of RA . The CAG repeat polymorphism (with a lower number of repeats, shorter allele) in the AR gene was associated with the presence of articular erosions in RA patients .
OC use was not associated with changes in the disease course in patients with RA. 41% of woman with RA are taking the OC. Flares before menses were 28% in patients with RA.
Prior HRT did not increase the risk to develop RA. HRT markedly improved bone mineral density and reduced bone resorption markers in RA . In addition, HRT had marginal beneficial effects on the articular index, pain score, and morning stiffness . Treatment with HRT suppressed erythrocyte sedimentation rate (ESR) and elevated haemoglobin concentration, with a better clinical outcome assessed by response on the Disease Activity Score 28 . Therefore HRT is useful to prevent postmenopausal osteoporosis in women with RA. Young women with RA can undergo pregnancy and/or use OC.
RA joint involvement tends to improve during pregnancy . The improvement generally starts during the 1st trimester and continues during the 2nd and 3rd trimesters. A pregnancy-induced remission is experienced by 75% of patients with RA, in more than half of the cases, remission is complete, but a flare-up occurs in more than 60% after delivery . In the 3rd-trimester of normal pregnancy, ex vivo monocytic IL-12 production was about 3-fold and TNF-α production was approximately 40% lower than postpartum values, supporting RA remission during pregnancy . Significantly higher concentrations of soluble TNF receptor 2 and IL-1ra were measured in pregnant compared with non pregnant women . Compared with non pregnant patients and other pregnant women, RA patients showed elevated levels of Th2 lymphocyte markers . RA with onset after the initiation of aromatase inhibitor therapy has been reported .
Serum E2 and E1 levels are similar in female RA patients compared with controls . In male RA patients, E2 levels were higher than healthy men, and E2 levels were positively correlated with inflammation . Androgens (DHEAS, T and DHT) are markedly lower in inflammatory diseases, playing an unfavorable role [136, 137]. The low androgen/oestrogen ratio might have a pathogenic role in patients with RA . High local levels of oestrogens in inflamed synovial tissue and synovial fluid, particularly in relation to androgens, are proinflammatory in RA .
The presence of ARs and ERs has been demonstrated in synovial macrophages in RA [140, 141]. PR has been identified in inflammatory cells from synovial tissue in RA . Synovial macrophages present enzymes of steroid metabolism (including 17β-OH steroid dehydrogenase and 5α-reductase) that transform steroid precursors, leading to accumulation of T and E2 and formation of biologically active derivatives, especially DHT . A better response to treatment in RA patients with ER gene polymorphism (rs9340799 AA and rs2234693 TT) has been observed after 12 months of therapy with leflunomide . No correlation between CAG repeat polymorphism in the AR gene and response to leflunomide has been found in women with RA . There is no evidence to promote the use of estrogens in preventing or treating RA in females .
Increasing evidence in the literature indicates an immunomodulatory role of sex steroids in the pathogenesis of autoimmune diseases. The results of the clinical trials will give the basis in order to better define the use of sex steroids in combination with current therapeutic drugs in autoimmunity [147, 148]. Sex steroid receptor modulating drugs are a promising class of therapeutic agents that will provide new approaches in these pathologies.
Antonio Martocchia, Silvia Raja, Manuela Stefanelli, Anna Cocca, Paolo Falaschi – S. Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome, Via di Grottarossa 1035, 00189 Rome, Italy
Corresponding Author: Antonio Martocchia, MD, PhD, Email: email@example.com
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