Estrogen Impact on Autoimmunity Onset and Progression: the ...

INTERNATIONAL TRENDS IN IMMUNITY VOL.1 NO.2 APRIL 2013ISSN 2326-3121 (Print) ISSN 2326-313X (Online) http://www.researchpub.org/journal/iti/iti.htmltheir high levels in humans under certain nutritionalconditions could induce significant biologicaleffects. Although an extensive literature showed thatgenistein exerts a dose dependent suppression ofboth humoral and cell-mediated immune responses,other studies reported that genistein or otherphytoestrogens stimulate various aspects of immunefunction [81, 82]. In autoimmune proneMRL/Mp-lpr/lpr (MRL/lpr) mice, a soy diet (20%soybean protein and 5% soybean oil) was found toexacerbate renal damage, leading to acceleratedproteinuria, elevated serum creatinine, reducedcreatinine clearance, and increased glomerulardisease severity [83]. In contrast, a study by Hong etal. [84] showed that dietary supplementation of soyisoflavones decreased serum anti-dsDNA IgG andanticardiolipin IgG levels, decreased IFN-γsecretion from stimulated T cells, and prolonged lifespan in MRL/lpr mice. Similarly, alfalfa sproutethyl acetate extract prolonged the life span ofMRL/lpr mice [85]. A mild beneficial effect onlupus disease was also exerted by a low dose ofcoumestrol (a phytoestrogen in alfalfa) in (NZB ×NZW)F1 mice [86]. Overall, a generalizedconclusion concerning whether phytoestrogens havebeneficial or detrimental immune effects is notpossible. Future studies should take into accountthat a particular exposure could have differentimmune effects depending on the species, sex, levelof exposure, dosing regimen, and age at exposure.B. Oral contraceptives and hormone replacementtherapyDiethylstilbestrol (DES), a synthetic estrogen withstrong estrogenic activity, was prescribed in the pastto pregnant women to ameliorate problems duringpregnancy. It caused adverse effects on the femaleoffspring known as ‘‘DES daughter syndrome’’ [87].Limited studies in humans have suggested thatDES-exposed women developed a variety of ADs[88]. Animal studies have confirmed that DES hasprofound immunomodulatory effects, including theinduction of autoantibodies to cardiolipin [89]. Theseresults are consistent with findings by Yurino et al.[77] who showed that DES implant resulted inincreased IgG anti-DNA antibody production andimmune complex deposition in ovariectomized(NZB × NZW)F1 mice. Even if it is no longer usedduring pregnancy, exposure to DES may occurthrough consumption of milk and meat productsfrom animals that received DES as a food additive.17α-ethinyl estradiol (EE), a synthetic analog of E2,is a primary component in hormonal contraceptivesand it is also used in hormone replacement therapy.Clinical trials have now proven that the use ofhormonal contraceptive in SLE patients with stablediseases does not increase the risk of flare [90].Differently, mild to moderate flares, but not severeflares, are increased in women under hormonereplacement therapy [91]. EE as well as E2 have beenalso identified in the environment, most prominentlyin the aquatic environment where the main sources ofcontamination are sewage treatment plants andagricultural runoff or discharge [92]. EE tends to bepresent in the environment at much lower levels thanE2 but it is more persistent and less volatile [93].Surprisingly, there are no published reports on theeffect of EE in animal prone to develop ADs andmany key questions in relation to potentialimmunologic effects of EE are unanswered. Studiesin animal models are needed to assess whethersub-acute or chronic exposure to EE at lowconcentrations affect the immune system, whetherEE effects occur equally with regard to age (preversuspost-menopausal women), sex, and route ofexposure (subcutaneous and oral).C. Anti ERα antibodiesAlterations of T lymphocyte homeostasis and theproduction of multiple pathogenic autoantibodies,including antibodies specific to ER (anti-ERantibodies), have been repeatedly demonstrated inthe peripheral blood of patients with SLE [29, 94]. Ina recent study, our research group found thatautoantibodies specific to ERα (anti-ERα Abs) werepresent in 45% of SLE patients, and they weresignificantly associated to clinical parameters, i.e.,the SLE Disease Activity Index and arthritis [95].Anti-ERα Abs are able to induce cell activation andconsequent apoptotic cell death in resting Tlymphocytes. Conversely, they increase proliferationof anti-CD3-stimulated T cells. The pro-apoptoticeffect of anti-ERα Abs on T lymphocytes maycontribute to the release of nuclear material in thecirculation that can represent an important source ofautoantigens if not timely removed. In this regard, animpaired clearance of dying cells is a typical featureof SLE where accumulation of nuclear autoantigens29