Investigation of sex-specific effects of apolipoprotein E on severity of EAE and MS.

Lisa Schrewe ,Anke Salmen ,Tania Kümpfel ,Denis A Akkad ,Tian Liu ,Christiane Graetz ,Isabelle Cournu-Rebeix ,Seray Demir ,Anne Böhme ,Sabine Hoffjan ,Lars Bertram ,Nina Hagemann ,Ralf Gold ,Christina M Lill ,Uwe K Zettl ,Paul Blaschke ,Bertrand Fontaine ,Peter Rieckmann ,Frauke Zipp ,Léna Guillot‐Noël ,Dirk M Hermann ,Antje Kroner ,Mathias Buttmann ,Ayman Elali ,Lisa-Ann Gerdes ,Andrew Chan

doi:10.1186/s12974-015-0429-y

Abstract

BackgroundDespite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS.MethodsMOG35-55 induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses.ResultsEAE disease course was slightly attenuated in male apoE-deficient (apoE−/−) mice compared to wildtype mice (cumulative median score: apoE−/− = 2 [IQR 0.0–4.5]; wildtype = 4 [IQR 1.0–5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE−/− mice compared to wildtype mice (cumulative median score: apoE−/− = 3 [IQR 2.0–4.5]; wildtype = 3 [IQR 0.0–4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex.ConclusionsapoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0429-y) contains supplementary material, which is available to authorized users.

Highlights

Despite pleiotropic immunomodulatory effects of apolipoprotein E in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial
Cumulative disease severity was attenuated in apolipoprotein E (apoE)−/− mice compared to wt mice
In the female group, EAE was more severe in apoE−/− mice compared to wt controls

Summary

Introduction

Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. A recent study compiling data on nearly 30,000 subjects showed that these polymorphisms do not influence MS susceptibility [7] Their role in disease progression still remains ambiguous, which at least in part pertains to the fact that the majority of studies have assessed rather small, i.e., underpowered datasets (for an overview see e.g., [8]). Divergent findings may be due to confounders or effect modifiers such as sex, age, or patient subgroups Along these lines, a comparatively small study testing 221 patients suggested that the association between APOE and MS severity was limited to women [9]; this has not been described in other studies [8]. In the current study, we comprehensively assessed the role of apolipoprotein E on disease severity of EAE as well as MS by taking into consideration potential sex-specific effects of APOE genotypes

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