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

More documents

Recommendations

Info

INTERNATIONAL TRENDS IN IMMUNITY VOL.1 NO.2 APRIL 2013ISSN 2326-3121 (Print) ISSN 2326-313X (Online) http://www.researchpub.org/journal/iti/iti.htmlcontribute to the gender bias in SLE modulatingselected miRNA expression [50]. miR-146a, whichis a negative regulator of the IFN-α pathway, andmiR125a, which negatively regulates theinflammatory chemokine RANTES, wereprofoundly decreased in PBMC from patients withSLE as compared to healthy donors [51, 52].Conversely, miR21 and miR148a, which contributeto DNA hypomethylation in lupus CD4+ T cells [53],were found up-regulated [54]. Notably, Dai et al. [55]observed that miR148a was up-regulated whereasmiR146a and miR125a were down-regulated by E2,at least in splenocytes from estrogen-treated mice.Together, the aforementioned studies show thatmiR-146a, miR-125a, and miR-148A aredysregulated in SLE contributing to diseasepathogenesis and estrogens regulate these miRNAexpression [50].As stated above, ERα and ERβ are encoded by theESR1 and ESR2 genes which are both polymorphic.rs2234693 and rs4986938 are two single nucleotidepolymorphisms (SNPs) whose C and A variantsincrease transcription of ESR1 and ESR2,respectively. Although no associations betweenrs2234693 genotype and SLE were found, thispolymorphism has been suggested to influence therisk for particular forms of disease [56-58]. Notably,two studies performed in Asian [57] and Caucasian[58] populations reported that the T allele ofrs2234693 (ESR1) was associated with early onset ofSLE. Conversely, in another study, Kisiel et al. [59]reported the association of the allele C of rs2234693(ESR1) with juvenile SLE, and they also found anassociation of allele A of rs4986938 (ESR2) withadult SLE. In contrast, two genome-wide associationstudies in SLE were published but neither reportedassociation with the ESR1 or ESR2 variants [60, 61].In summary, genetic variation in estrogen-relatedpathways might be important for SLE development,but this field needs further investigations taking intoaccount clinical characteristics of patients.Studies of mice models revealed that lupus alsopredominates in females. Moreover, ovariectomizedfemale (NZBxNZW)F1 mice live longer andcastrated males develop an accelerated autoimmunedisease [62]. The role of ERα in lupus-like diseasehas been suggested by different studies. A study in(NZBxNZW)F1 mice that utilized ERα-selective andERβ-selective agonists indicated that the ERα27activation plays an immunostimulatory role inmurine lupus, whereas the ERβ activation has mildimmunosuppressive effects [63]. The key role ofERα, but not ERβ, in the pathogenesis of lupus wasfurther confirmed in experiments with ERα −/−NZM2410 and ERα −/− MRL/lpr lupus prone mice.ERα-deficient mice manifested significantly lesspathologic renal disease and proteinuria and hadsignificantly prolonged survival compared towild-type mice [64]. Since anti-dsDNA antibodylevels and number and percentage of B/T cells werenot significantly impacted by ERα genotype, theauthors hypothesized that the primary benefit of ERαdeficiency in lupus nephritis was via modulation ofthe innate immune response. In a subsequent study,they found that ERαKO-derived cells have asignificantly reduced inflammatory response afterstimulation with TLR agonists [65]. In fact, in theabsence of ERα, the inflammatory response to TLR9stimulation was significantly blunted. Additionally,ERα was required for TLR-induced stimulation ofIL-23R expression, which may have paracrine andautocrine effects on T cells and dendritic cellsinvolved in the IL-23/IL-17 inflammatory pathway[65] . In contrast, ERβ deficiency had no effect onlupus activity [64]. Overall, these data implicate therole of estrogen and ERα in the progression oflupus-like disease.V. ESTROGEN RECEPTOR MODULATORSA. Environmental estrogensIn addition to the endogenous estrogens, the immunesystem can be targeted by natural (phytoestrogensand mycoestrogens) or synthetic (xenoestrogens)compounds with estrogenic activity, i.e., theestrogenic endocrine disruptors (EEDs) [66, 67].Xenoestrogens are widely found in plastics (e.g.,bisphenol-A, BPA), detergents and surfactants (e.g.,octylphenol, nonylphenol), pesticides (e.g.,methoxychlor, chlordecone, ando,p’-dichlorodiphenyltrichloroethane, DDT), andindustrial chemicals (e.g.,2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD). Thethree major classes of phytoestrogens are isoflavones,coumestans, and lignans. Genistein and daidzein arethe major bioactive isoflavones, principally availablein soybean and soy products. It is worthy to underline
INTERNATIONAL TRENDS IN IMMUNITY VOL.1 NO.2 APRIL 2013ISSN 2326-3121 (Print) ISSN 2326-313X (Online) http://www.researchpub.org/journal/iti/iti.htmlthat soy is found in up to 60% of processed food,being a food additive and a meat substitute. Foodsources of coumestans (e.g., coumestrol) includeclover sprouts, alfalfa sprouts, dry split peas, andother legumes [68]. Food sources of lignans includesesame seed, Brassica vegetables and olive oil.Zearalenone, produced by Fusarium moulds growingon damp [69], is the best characterized mycoestrogen,and it is a fungal contaminant of corn and grains.EEDs are able to exert their effects through multiplemethods of action. They have the ability to bind avariety of nuclear receptors including ERs [70].Through these interactions, EEDs are able to alter theactivity of response elements of genes, block naturalhormones from binding to their receptors, or in somecases increase the activity of endogenous hormoneby acting as a hormone agonist. Although they areless potent than estrogen, long-term exposure tothese compounds could result in accumulation in thebody fat and lead to key alterations in the immunesystem [67, 71]. Epidemiological evidence andstudies in animal models suggest a link betweenEEDs exposure and increasing prevalence of ADs. Infact, by interacting and modifying the functionand/or response of immune cells, EEDs could trigger,aggravate, or alter the development and/orprogression of ADs. Because of the predominance offemales in ADs, the role of estrogens of therapeuticsources, i.e., oral contraceptives and hormonereplacement therapy, should also be taken intoconsideration. Here, we summarize those studiesinvestigating the potential effects of EEDs onautoimmunity focusing on SLE (Table III). To notethat these studies do not have a direct counterpart inhumans, an aspect which warrants intenseinvestigation.XenoestrogensBPA is a classic example of an estrogen mimic [72,73]. It binds as an agonist to ERβ, albeit with a muchlower affinity ( > 1000-fold) than E2 [74], and hasbeen observed to have both agonist and antagonistactivity at the ERα in vitro [75]. In vitro and in vivodata suggest that BPA displays significant effects onthe immune system. For instance, BPA has beenshown to increase T cell proliferation and Th1/Th2polarization skewing T cells toward a Th2 phenotype,to increase the production of IgA and IgG2a in Bcells, and to decrease number of CD4+ CD25+regulatory T cells [72]. Studies of BPA-treated lupusmice are not definitive in their results. Short termexposure of (NZBxNZW)F1 mice to BPAsuppressed autoimmunity development through areduction of IFN-γ production, a delay in proteinuriadevelopment, and an increase in the disease-freeperiod [76]. In a subsequent study, subcutaneousadministration of BPA for 3 to 4 months promotedIgM autoantibody production by B1 cells inovariectomized (NZBxNZW)F1 mice [77]. Incontrast to BPA, organochlorine pesticides withestrogenic activity such as chlordecone,methoxychlor, and DDT were found to speed theprogression of lupus in ovariectomized female (NZB× NZW)F1 mice [78]. In particular, a dose-responsestudy conducted with chlordecone showed adose-related early appearance of elevatedanti-dsDNA IgG titres and immune complexdeposition in the kidneys [78]. It is worthwhilenoting that the lowest doses of methoxychlor andchlordecone used in the above mentioned study werebelow the oral reference dose (i.e., the maximumacceptable oral dose of a toxic substance) establishedby the United States Environmental ProtectionAgency for these compounds (for informationconcerning human exposure relevant doses, consulthttp://www.epa.gov/iris). This suggests that an effecton autoimmunity might be a sensitive toxic end point(an effect that occurs at doses lower than otheradverse effects) for these compounds, and thereforeof particular interest for risk assessment.Surprisingly, in a subsequent study examining theeffects of exposure to high doses of DDT and TCDDin female (NZB × NZW)F1 mice, DDT did not showany effect on disease development and TCDD hadmarked immunosuppressive effects on murine SLE[79]. Overall, xenoestrogens, while sharing estrogenagonistic and antagonistic activities, appear to havecompound- and tissue-specific effects. It is likely thatvariations in compound dose, administration routeand exposure duration would produce differentresults, which require further evaluation in futureworks.PhytoestrogensSoybeans and foods containing soy have significantlevels of isoflavones such as genistein and daidzein[80]. In contrast to E2, which binds ERα and ERβwith similar affinities, genistein and daidzein havegreater affinity for ERβ than ERα [81]. Despite thelimited estrogenic potency of these compounds,28
Page 1 and 2: INTERNATIONAL TRENDS IN IMMUNITY VO
Page 3: INTERNATIONAL TRENDS IN IMMUNITY VO
Page 11: INTERNATIONAL TRENDS IN IMMUNITY VO

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

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?