Apolipoprotein E (apoE) is a 34.2 kDa glycosylated protein characterized by its wide tissue distribution and multiple functions. ApoE has been widely studied in lipid metabolism, cardiocerebrovascular diseases, and neurodegenerative diseases like Alzheimer's disease and mild cognitive impairment, and so forth. Recently, a growing body of evidence has pointed to nonlipid related properties of apoE, including suppression of T cell proliferation, regulation of macrophage function, facilitation of lipid antigen presentation by CD1 molecules to natural killer T (NKT) cells, and modulation of inflammation and oxidation. By these properties, apoE impacts physiology and pathophysiology at multiple levels. The present paper summarizes updated studies on the immunoregulatory function of apoE, with special focus on isoform-specific effects of apoE on Guillain-Barré syndrome (GBS) and its animal model experimental autoimmune neuritis (EAN).
1. Introduction
Apolipoprotein E (ApoE) is a 34.2 kDa glycosylated protein with 299 amino acid residues. The APOE gene is located on chromosome 19q13.2, consisting of four exons and three introns and spanning 3597 nucleotides [1]. There are three isoforms in human (apoE2, apoE3, and apoE4) due to different amino acid residues at positions 112 and 158, among which apoE3, with a cysteine residue at position 112 and an arginine residue at position 158, is the most common. The other two “variants,” apoE2 and apoE4, respectively, contain two arginines and two cysteines at positions 112 and 158 [2]. However, there is only one isoform of apoE in rodents, which resembles human apoE3 in terms of lipoprotein binding and metabolism, preferably associating with high density lipoprotein (HDL), the clearance of which is mediated principally by hepatic low density lipoprotein receptors (LDLRs) [3, 4].
ApoE is synthesized predominantly in the liver, but also by cells in the spleen, brain, lung, kidney, ovary, adrenal, and muscle tissues. Hepatic parenchyma cells are the main apoE producing cells in mammalian body, probably accounting for two thirds to three fourths of the plasma apoE [5]. In the nervous system, apoE mRNA is present in neurons, astrocytes, ependymal cells, nonmyelinating Schwann cells, but not in microglia, oligodendroglia, choroidal cells, or myelinating Schwann cells [6–8]. As reported by a variety of studies, apoE produced by mammalian cells exists in different forms, monomers, dimers, modified, unmodified, lipid-rich, and lipid-poor, and so forth [9–13]. It is noteworthy that there is limited permeability of the blood brain barrier (BBB) to apoE, and local synthesis and production by brain tissue contribute to the homeostasis of apoE in brain tissue and cerebrospinal fluid (CSF) [14].
ApoE has been widely studied in lipid metabolism, cardiocerebrovascular diseases [15], multiple sclerosis (MS) [16, 17], neurodegenerative diseases such as Alzheimer’s disease [18, 19], and mild cognitive impairment [20, 21]. In addition, growing evidence points to nonlipid-related properties of apoE. An immunoregulatory role of apoE has been proposed for decades. This role was originally described as suppression of lymphocyte activation [22–25]. Only in the recent years, with the development of APOE knockout mice and APOE transgenic (Tg) mice, have the studies on the specific mechanism of immunomodulation been greatly deepened. In this paper, we outlined the immunoregulatory functions of apoE, with exclusive focus on the isoform-specific effects of apoE on Guillain-Barré syndrome (GBS) and its animal model experimental autoimmune neuritis (EAN).
2. The Role of ApoE in Immune Responses
To date, there has been strong evidence supporting a role for apoE as an immunomodulatory agent in immune responses. Effects of apoE on immune system are extensive and some of them are dependent on different ligands of the protein, different concentrations, and lipid-binding state. The properties include suppression of T cell proliferation [26], stimulation of cultured neutrophils [27], regulation of macrophage functions [28–32], facilitation of lipid antigen presentation by CD1 molecules to natural killer T (NKT) cells [33, 34], and modulation of inflammation and oxidation [35, 36], and so forth. By these properties, apoE impacts physiology and pathophysiology at multiple levels.
This role of apoE was originally discovered as an immunoinhibitory activity of plasma lipoproteins in vitro by a variety of experiments [23, 37–44]. Succedent studies ascribed this activity to immunoregulatory functions of apoE. A series of studies demonstrated both apoE containing lipoproteins and multimers of synthetic apoE peptides inhibited proliferation of cultured lymphocytes by inhibiting DNA synthesis and reducing phospholipid turnover in T cells [26, 45–48]. APOE knockout mice greatly facilitate apoE research. ApoE-deficient mice showed abnormal humoral and cellular immune responses. Significantly higher levels of antigen-specific IgM and significantly decreased antigen-specific delayed-type hypersensitivity responses were shown in apoE-deficient mice after immunization with tetanus toxoid as compared with control C57BL/6 mice [49]. Moreover, spleen weights of apoE-deficient animals were greater than age- and sex-matched C57BL/6 controls, indicating an idiopathic immune dysfunction in apoE-deficient mice [49]. In vivo, apoE downregulates T helper (Th) 1 immune responses, which is postulated to be mediated by either modification of macrophage or T cell functions [50, 51]. ApoE can also affect innate and acquired immune responses in vitro by its ability to suppress stimulation of cultured neutrophils [27]. Hypercholesterolaemia resulting from APOE knockout, can facilitate Th2 immune responses in mice [52], indicating that apoE plays a double-role in immune responses.
ApoE can bind lipopolysaccharide (LPS), attenuate the inflammatory response, and thus reduce LPS induced lethality [53]. Injection of LPS stimulated higher expression of inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-12, and interferon-γ (IFN-γ), as well as IL-6, and so forth, in the brains of apoE-deficient mice compared with wild type controls [49, 50, 54]. And apoE-deficient mice have impaired immune responses to bacterial challenge with Listeria monocytogenes, and increased susceptibility to endotoxemia after intravenous LPS injection [55, 56]. Moreover, these mice are highly susceptible to tuberculosis, which has been suggested to depend upon the severity of hypercholesterolemia [57], and Klebsiella pneumoniae infection [58]. The deficiency of neutralization of Gram negative LPS seems to be one of the reasons that may explain this susceptibility. As regards isoform-specific effects that may exist, APOE ε2 Tg mice appear to be more susceptible to endotoxin or bacterial infection [59]. Ophir et al. have shown that either intraperitoneal or intraventricular injection of LPS results in significantly higher production of proinflammatory cytokines, defense response genes or chemotaxis genes in APOE ε3 Tg mice than in APOEε4 Tg ones [60].
In the immune system, apoE is primarily produced by macrophages, which act as principal effector cells in both innate and adaptive immunity [61–63]. It is observed that pretreatment with apoE reduces inflammatory signaling in astrocytes and microglia in the brain [35, 64–67], and classical activation of macrophages by proinflammatory stimuli such as IFN-γ, TNF-α, IL-1β and LPS, down-regulates apoE production [68–73]. However, transforming growth factor-β and estrogen promote apoE synthesis and release [73–76]. ApoE suppresses proinflammatory signaling in macrophages, and vice versa, indicating an intricate apoE-mediated feedback regulation of inflammation and immune responses.
The production of nitric oxide (NO) represents one of the principle features of activated macrophages, and NO is considered to be a principal effector of macrophage-mediated immune responses. In mononuclear-phagocyte system, NO is formed enzymatically from L-arginine by inducible NO synthase (iNOS), which yields L-citrulline as a coproduct [77]. Treatment of microglia and peripheral macrophages with apoE could increase NO production stimulated by IFN-γ, and LPS, and so forth [78]. This effect supports its potential role in innate immune responses [29, 79]. ApoE alone is unable to induce the production of either iNOS mRNA or protein. Its action results from alteration of arginine availability by apoE [80]. Interestingly, the effect of apoE on NO production is not found only in macrophages. NO production in platelets can be stimulated likewise by apoE [81]. Further studies demonstrated that microglia and peripheral macrophages from male APOE ε4 Tg mice could produce significantly higher levels of NO than from APOE ε3 Tg mice. This increase in nitrite production reflects an increase in the innate immune response of the APOE ε4 Tg macrophages [30, 32]. Similar results were found also in human studies [82]. The increased NO production was shown to be coupled with an increased arginine uptake in male APOE ε4 Tg mice and to depend on p38 mitogen activited protein kinase (MAPK) [83, 84]; whereas it is not the case in female mice. Macrophages from female APOE Tg mice produced higher level of NO than male ones, and there is no isoform-dependent difference as in male ones [30, 85, 86].
Activation of macrophages and microglia is important in both the innate immunity and adaptive immunity [87, 88]. ApoE can down-regulate microglial activation [89]. Duan et al. in our group found that apoE deficiency enhances activation of microglia in CNS and aggravates kainic acid (KA) induced hippocampal neurodegeneration. Increased CC chemokine receptor 3 expression on microglia in apoE-deficient mice after KA administration appeared to facilitate the microglial recruitment and accumulation in the injured areas [90]. Macrophages of apoE-deficient mice stimulated by exogenous antigen are more effective in the upregulating of main histocompatibility complex (MHC) class II molecules and costimulatory molecules like CD40 and CD80, with increased IFN-γ secretion in responding T cells [91]. Furthermore, apoE suppressed the secretion of TNF-α and IL-1β in an isoform-specific fashion (E2 > E3 > E4) [84]. A significantly higher level of TNF-α was observed in the supernatant of cultured macrophages derived from adult male APOE ε4 Tg mice compared with macrophages from APOE ε3 ones [28]. ApoE genotype significantly affects the cellular immune response in stably transfected murine macrophages. In apoE4 versus apoE3 macrophages, higher levels of proinflammatory cytokines including TNF-α appeared evident followed by LPS stimulation [92]. ApoE displayed an isoform-specific effect on inflammation in primary adult microglia, with apoE4 potent to stimulate production of prostaglandin E2 and IL-1β [93]. APOE ε4 targeted replacement (TR) mice demonstrate a proinflammatory phenotype including increased iNOS mRNA synthesis and NO production, and higher proinflammatory cytokine production (TNF-α, IL-6, IL-12p40) in glial cell culture, compared with APOE ε3 TR mice [28]. Activation of primary astrocytes from APOE TR mice with LPS led to genotype-dependent differences in cytokine secretion that were the greatest in APOE ε2 TR mice [94]. Taken together, these findings suggest immunomodulatory dysfunction in apoE 4 isoform. Similar to apoE-deficient mice, APOE ε4 Tg mice seem to bear an insufficiency to deal with an inflammatory insult.
Although the antigen presenting function of antigen presenting cells (APCs) in adaptive immunity appears to increase in apoE-deficient mice, there still lacks direct evidence that apoE functions directly on antigen presentation process. The difference might either be due to the increased susceptibility to proinflammatory stimulation, resulting in the high expression of MHC class II molecules and costimulatory molecules on innate immune cells like macrophages, or be due to tendency to Th1 cytokine production in apoE-deficient mice. However, a role of apoE in facilitating lipid antigen presentation by CD1 molecules to NKT cells has been presented and confirmed, which appears of great importance in autoimmune diseases [95, 96]. Naïve NKT cells express high level surface marker NK1.1 and an invariant T cell receptor (TCR) [34, 97–100]. Upon TCR ligation, they respond rapidly to secrete high levels of IFN-γ and IL-4, which has been postulated to be of great importance in the shaping of adaptive immune responses and the shifting between Th1 and Th2 immune responses [101–103] (Figure 1). CD 1 molecules (CD1a-d in humans and CD1d in mice), similar in structure to MHC molecules, resemble MHC II molecules in function in that they present lipid antigens to NKT cells, in which process, apoE is implicated. ApoE, the major serum factor that binds lipids, could efficiently bind lipid antigens and dramatically facilitate their presentation by CD1b, CD1c and CD1d molecules via the binding to LDLR [33, 104]. More recently, human B cells have been demonstrated to utilize apoE-mediated pathways of lipid antigen presentation more efficiently than dendritic cells [105]. In terms of CD1-mediated self-lipid presentation, apoE might be involved in autoimmune diseases due to facilitation of self-lipid antigen presentation by CD1 molecules to NKT cells. ApoE might provide a pathway for the delivery of self-antigens and subsequently contribute to inflammatory diseases like MS [31, 106–109]. Kattan et al. suggested that apoE treatment also promoted a Th1 cytokine response in a rat model of sepsis. Whether this is partly due to facilitation of CD1 restricted lipid antigen presented by apoE remains to be clarified [110], and whether this effect of apoE is isotype-dependent is not yet known.
ApoE facilitates activation of CD1 restricted NKT cells. Inactivated NKT cells express surface marker of NK1.1 and an invariant TCR. ApoE facilitates lipid antigen presentation by CD1 positive APCs mainly through binding to LDLR. And then CD1 molecules present lipid antigen to NKT cells. Upon TCR ligation, naive NKT cells respond rapidly to secrete high levels of IFN-γ and IL-4.
In vitro, apoE can inhibit proliferation of antigen and mitogen stimulated CD4+ and CD8+ T cells, which although not precisely known, has been suggested to be mediated by modification of IL-2 receptor or modification of intracellular signaling pathways perhaps involving calcium and phosphatidylinositol [111–113], while there seems no isoform-dependent suppression on T cell proliferation stimulated by phytohemagglutinin, or anti-CD3, as revealed by an in vitro human study [49]. Of note is that apoE is naturally presented by murine MHC II molecules. In a pathophysiological state this might be of immunological significance [114, 115]. And a naturally processed self-peptide from apolipoprotein E, Ep1.B, is capable of inducing dendritic cell differentiation. Nuclear factor κB (NFκB), a transcription factor essential for DC differentiation, is fundamental in mediating the effects. [116]. A peptide containing the receptor binding region (residues 133–149), other than apoE holoprotein, is enough to suppress inflammation [117]. This peptide is almost the same as the one proposed by Pham et al. to be responsible for antioxidant properties [118]. In addition, apoE deficiency results in elevated autoimmune activity in mice, which can be detected as early as 7 weeks of age, and might explain the susceptibility of deficient mice to either EAN or EAE [119]. Moreover, apoE deficiency in mice leads to impaired clearance of apoptotic cells and a systemic proinflammatory condition, independent of its role in lipoprotein metabolism [120], providing another possible mechanism by which apoE may influence immune responses and autoimmune diseases.
The exact molecular mechanisms by which apoE isoforms alter the immune responses still remain undefined. However they have been postulated to influence different signaling pathways. ApoE isoforms might be in part responsible for the differential modulation of the redox sensitive transcription pathways such as NFκB and MAPK [36, 86, 94]. Alternatively, apoE can act by binding to cell surface receptors. LDLR-related protein (LRP) is postulated to be implicated to mediate the immunomodulatory effects of apoE, albeit there is no difference in the binding affinity of apoE isotypes with LRP [121, 122].
3. The Role of ApoE in GBS and EAN
GBS is presently defined as an organ specific immune mediated disorder resulting from a synergistic interaction between cellular and humoral immune responses to incompletely characterized antigens in the peripheral nervous system (PNS) [123, 124]. As yet, there has been no evidence that APOE genotype may influence susceptibility to GBS or its clinical course [125]. It might be either due to the small sample size of the experiment or due to the difference of APOE allele distribution and GBS clinical features among populations.
In several studies attempting to find specific biomarker of GBS in the serum and CSF, apoE was shown to decrease in CSF in GBS patients. Our group used comparative proteomic methods to show a decreased level of apoE in CSF, which was later confirmed by other researchers [126, 127]. This was further confirmed by enzyme-linked immunosorbent assay in our group (unpublished data). As there is limited permeability of the BBB to lipoproteins [14, 128, 129], this change might be due to a decrease of local apoE synthesis and secretion by brain tissue, as part of systemic decrease of apoE synthesis in acute phage reaction [4].
The blood nerve barrier (BNB) breakdown and autoreactive T cell penetrating BNB are crucial in the initiation of GBS [130, 131]. Data from animal experiments suggested that BNB dysfunction resulting from apoE deficiency might lead to more susceptibility to GBS, and exacerbate clinical GBS [132, 133]. Although there still lacks evidence that apoE isoforms contribute differently in maintaining BNB or BBB integrity, considering the preference of apoE isoforms binding to different lipoprotein and apoE receptors, it might be presumed that apoE isoforms might influence the recovery of GBS due to cholesterol transport difference in regeneration and remyelination [134, 135].
EAN, first described in rabbits in 1955 by Waksman and Adams [136], is a CD4+ T cell mediated autoimmune disease of PNS, characterized by perivascular infiltration of T cells and macrophages, and demyelination in the peripheral nerves in pathological feature, which can be induced in susceptible animal strains including mouse, rat, sheep, chicken, and monkey by active immunization with peripheral nerve myelin [136] or its component P0 or P2 proteins or their neuritogenic peptides [137, 138] together with complete Freud’s adjuvant. EAN shares many of clinical, immunological, electrophysiological, and morphological characteristics with GBS, thus serves as a useful model for exploring the pathogenesis and immunotherapy of GBS. ApoE can modulate immune responses in EAN through modification of functions of macrophages, T cells, and BNB, shifting Th1/Th2 balance, as well as other effects (Figure 2). Autoreactive T cells penetrating the broken-down BNB to accumulate in peripheral nervous tissue gives rise to the effector phase of the immune response in EAN [139]. A number of observations support the role of apoE in maintaining the integrity of the BNB or BBB. And apoE-deficient mice were shown to suffer impaired BNB and BBB, which might be one of the reasons why apoE-deficient mice underwent more severe EAN [132, 133]. ApoE may inhibit the migration of blood derived inflammatory cells across the BNB or the transduction of chemotactic signals for migration. This is a critical step in the migratory process of inflammatory cells across tight endothelial junctions [140, 141].
Schematic illustration of the potential role of apoE in the pathogenesis of EAN. ApoE can modulate immune responses in EAN through modification of functions of macrophages, T cells, and BNB, and through shifting Th1/Th2 balance. (−) suppressive function; (+) supportive function.
Previously, we explored the role of apoE in P0 peptide 180–199 induced EAN. Our data, in accordance with data from other studies, showed that apoE deficiency increased antigen presentation capacity of macrophages, which can explain the elevated susceptibility to EAN in apoE-deficient mice [91, 133]. We further revealed an increased susceptibility to EAN after upregulation of the autoreactive T cell response to peripheral nerve components in APOE knockout mice. The results provided strong evidence that apoE might act as an inhibitor for EAN by inhibiting the Th1 response and P0-specific antibody production. Shifting the Th1/Th2 to the Th1 direction is one mechanism underlying increased susceptibility to EAN in apoE-deficient mice. Th cells can differentiate to Th1 and Th2 subpopulations with cross-regulating cytokine profiles that may play a decisive role in the initiation and termination of an autoimmune process [142]. Dysregulation of the Th1/Th2 balance can result in autoimmune diseases [143]. In EAN, Th1 cytokines predominate and mediate inflammatory damage, whereas Th2 cytokines are associated with recovery from the disease [144–147]. ApoE-deficient mice were shown to produce higher levels of IFN-γ, IL-12, and TNF-α and lower levels of IL-10 than C57BL/6 mice in EAN.
Macrophages are the principal antigen presenting cells and effector cells in the pathogenesis of EAN. In demyelinated peripheral nerves, the MHC class II positive cells are mainly macrophages [148]. The pivotal role of macrophages in immune-mediated nerve damage is direct phagocytic attack on myelin, and the release of proinflammatory cytokines including TNF-α, IL-1; and IL-6 and other noxious molecules [149, 150]. A variety of studies demonstrated an isoform-specific effect of apoE on macrophage functions, including NO production and cytokine secretion [28, 30, 79]. Considering the critical importance of NO and cytokines in the pathogenesis of EAN, this effect might contribute to isoform-dependent susceptibility or clinical severity of EAN [151, 152]. Schwann cells can function as facultative antigen presenting cells in certain conditions (see review by Meyer zu Hörste et al.) [153]. Duan et al. in our group, further revealed that the antigen presenting capacity of Schwann cells in apoE-deficient mice was enhanced, which might occur via down-regulation of intracellular IL-6 production. SCs may actively participate in local immune resonses as a source of IL-6 in the PNS [154]. ApoE-deficient mice were observed to reduce the expression of intracellular IL-6 accompanied with higher levels of MHC II and CD 40 expression on SCs. Moreover, an enhanced antigen-presenting function of SCs was found in apoE-deficient mice to P0 peptide 180-199 specific T cells [155].
Ongoing studies in our group have shown a preliminary result of an isotype-specific effect of apoE in EAN, with the most severe clinical course occurring on APOE ε4 Tg mice, while with the least severe EAN on APOE ε3 Tg mice (unpublished data). Apart from all above, strong evidence supports a crucial role of apoE in peripheral nerve regeneration and remyelination [156]. ApoE has been proposed to scavenge lipid debris from the degenerating myelin and provide it to sprouting axons via LDLR-mediated endocytosis [157, 158]. Despite this, regenerating nerves in both apoE-deficient and control mice were morphologically indistinguishable one month after sciatic nerve crush [159], indicating a surrogate effect of other apolipoproteins in PNS regeneration.
4. Conclusions and Prospective
The immunomodulatory functions of apoE have been extensively studied in the past decades. Increasing studies have focused on the ambiguous or even controversial isotype-dependent effects. It appears difficult partly due to the difficulty of interpretation of results from animal experiments to a general conclusion. For example, the difference of serum and tissue apoE concentration in APOE ε2, ε3, and ε4 Tg mice might be a confounding factor when comparing the isotype-dependent effects of apoE on immune system and immune responses [28, 160–163]. Domain interaction, which distinguishes apoE4 from apoE2 and apoE3 in biological function, has been suggested to contribute to the detrimental effects of apoE4 [163, 164]. Because of domain interaction, apoE4 bind preferentially to very low density lipoproteins, which are more rapidly removed from plasma than other lipoproteins such as HDL, to which apoE3 and apoE2 binds preferentially [164–166]. Also of note is that apoE levels in the CNS vary during the estrous cycle and estrogen could increase ApoE levels [76, 167–169]. Moreover, the lipid-free apoE was shown only to bind LRP [93, 170, 171]. Therefore in interpreting the effects of apoE on immune responses, its lipidation state, its concentration, and its location of action must be taken into consideration. It still remains to be defined whether a crucial, isoform-dependent activity of apoE role exists in GBS, or MS, considering the different distribution of APOE allele in the whole population. Anyhow, preliminary findings about the role of apoE in immune system and immune responses have shed light on the research of autoimmune diseases such as GBS and MS. The elucidation of the exact mechanisms by which apoE functions on immunity is appealing in that it may provide new insight to preventive or therapeutic strategies of autoimmune diseases and even other diseases [172].
Acknowledgments
The work was supported by grants from China Scholarship Council, Swedish Medicine Association, Swedish National Board of Health and Welfare, as well as funds from Karolinska Institute.
RallS. C.Jr.WeisgraberK. H.MahleyR. W.Human apolipoprotein E. The complete amino acid sequence198225741714178WeisgraberK. H.Apolipoprotein E: structure-function relationships1994452493022-s2.0-0028303072RaffaiR. L.DongL. M.FareseR. V.Jr.WeisgraberK. H.Introduction of human apolipoprotein E4 “domain interaction” into mouse apolipoprotein E2001981158711591LiL.ThompsonP. A.KitchensR. L.Infection induces a positive acute phase apolipoprotein E response from a negative acute phase gene: role of hepatic LDL receptors20084981782179310.1194/jlr.M800172-JLR2002-s2.0-48349148598MahleyR. W.Apolipoprotein E: cholesterol transport protein with expanding role in cell biology198824048526226302-s2.0-0024299370BoylesJ. K.PitasR. E.WilsonE.MahleyR. W.TaylorJ. M.Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system1985764150115132-s2.0-0022350033BeffertU.DanikM.KrzywkowskiP.RamassamyC.BerradaF.PoirierJ.The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease199827211914210.1016/S0165-0173(98)00008-32-s2.0-0031800003RefoloL. M.FillitH. M.Apolipoprotein E4 as a target for developing new therapeutics for Alzheimer's disease200423315115510.1385/JMN:23:3:1512-s2.0-4143055668ZannisV. I.KurnitD. M.BreslowJ. L.Hepatic apo-A-I and Apo-E and intestinal Apo-A-I are synthesized in precursor isoprotein forms by organ cultures of human fetal tissues198225715365442-s2.0-0020030393ZannisV. I.OrdovasJ. M.CladarasC.ColeF. S.ForbesG.SchaeferE. J.mRNA and apolipoprotein E synthesis abnormalities in peripheral blood monocyte macrophages in familial apolipoprotein E deficiency19852602412891128942-s2.0-0022364774ZannisV. I.van der SpekJ.SilvermanD.Intracellular modifications of human apolipoprotein E19862611341513421Mahmood HussainM.ZanniE. E.KellyM.ZannisV. I.Synthesis, modification, and flotation properties of rat hepatocyte apolipoproteins19891011901012-s2.0-45149143506AleshkovS.AbrahamC. R.ZannisV. I.Interaction of nascent apoe2, apoe3, and apoe4 isoforms expressed in mammalian cells with amyloid peptide β (1–40). Relevance to Alzheimer's disease19973634105711058010.1021/bi96263622-s2.0-0030867936MahleyR. W.WeisgraberK. H.HuangY.Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS200950S183S188KnopmanD. S.RobertsR. O.GedaY. E.Association of prior stroke with cognitive function and cognitive impairment: a population-based study200966561461910.1001/archneurol.2009.302-s2.0-66249139187JulianL. J.VellaL.FrankelD.MindenS. L.OksenbergJ. R.MohrD. C.ApoE alleles, depression and positive affect in multiple sclerosis200915331131510.1177/13524585080994782-s2.0-61849092511MazurekA. A.ShiJ.APOE epsilon4 allele is associated with cognitive impairment in patients with multiple sclerosis2008711203KimJ.BasakJ. M.HoltzmanD. M.The role of apolipoprotein E in Alzheimer's disease200963328730310.1016/j.neuron.2009.06.0262-s2.0-68249134074GuoZ.FratiglioniL.ViitanenM.Apolipoprotein E genotypes and the incidence of Alzheimer's disease among persons aged 75 years and older: variation by use of antihypertensive medication?2001153225231EwersM.ZhongZ.BürgerK.Increased CSF-BACE 1 activity is associated with ApoE-ε4 genotype in subjects with mild cognitive impairment and Alzheimer's disease200813151252125810.1093/brain/awn0342-s2.0-44949221768HeunR.GühneU.LuckT.Apolipoprotein E allele 4 is not a sufficient or a necessary predictor of the development of mild cognitive impairment20102511518ClayM.AnantharamaiahG.MistryM.BalasubramaniamA.HarmonyJ.Localization of a domain in apolipoprotein E with both cytostatic and cytotoxic activity19953435111421115110.1021/bi00035a0202-s2.0-0029095314MacyM.OkanoY.CardinA.AvilaE.HarmonyJ.Suppression of lymphocyte activation by plasma lipoproteins198343supplement 52496s2502sMistryM.ClayM.KellyM.SteinerM.HarmonyJ.Apolipoprotein E restricts interleukin-dependent T lymphocyte proliferation at the G1(A)/G1(B) boundary19951601142310.1016/0008-8749(95)80004-32-s2.0-0028939267PepeM.CurtissL.Apolipoprotein E is a biologically active constituent of the normal immunoregulatory lipoprotein, LDL-In198613610371637232-s2.0-0022608931AvilaE. M.HoldsworthG.SasakiN.JacksonR. L.HarmonyJ. A.Apoprotein E suppresses phytohemagglutinin-activated phospholipid turnover in peripheral blood mononuclear cells198225710590059092-s2.0-0020313079TerkeltaubR. A.DyerG. A.MartinJ.CurtissL. K.Apolipoprotein (Apo) E inhibits the capacity of monosodium urate crystals to stimulate neutrophils characterization of intraarticular Apo E and demonstration of Apo E binding to urate crystals in vivo199187120262-s2.0-0026033247VitekM. P.BrownC. M.ColtonC. A.APOE genotype-specific differences in the innate immune response20093091350136010.1016/j.neurobiolaging.2007.11.0142-s2.0-67649104088BargerS. W.HarmonA. D.Microglial activation by alzhelmer amyloid precursor protein and modulation by apolipoprotein E1997388664587888110.1038/422572-s2.0-0030610645BrownC.WrightE.ColtonC.SullivanP.LaskowitzD.VitekM.Apolipoprotein E isoform mediated regulation of nitric oxide release200232111071107510.1016/S0891-5849(02)00803-12-s2.0-0036591851ColtonC.BrownC.CzapigaM.VitekM.Apolipoprotein-E allele-specific regulation of nitric oxide production20029622122252-s2.0-0036268903ColtonC. A.BrownC.CookD.APOE and the regulation of microglial nitric oxide production: a link between genetic risk and oxidative stress200223577778510.1016/S0197-4580(02)00016-72-s2.0-0036752024van den ElzenP.GargS.LeonL.Apolipoprotein-mediated pathways of lipid antigen presentation2005437906BorgN. A.WunK. S.Kjer-NielsenL.CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor20074487149444910.1038/nature059072-s2.0-34447131000LynchJ. R.MorganD.ManceJ.MatthewW.LaskowitzD.Apolipoprotein E modulates glial activation and the endogenous central nervous system inflammatory response20011141-210711310.1016/S0165-5728(00)00459-82-s2.0-0035283401OphirG.AmariglioN.Jacob-HirschJ.ElkonR.RechaviG.MichaelsonD. M.Apolipoprotein E4 enhances brain inflammation by modulation of the NF-κB signaling cascade200520370971810.1016/j.nbd.2005.05.0022-s2.0-27744552618SchumacherK.Maerker AlzerG.WehmerU.A lymphocyte inhibiting factor isolated from normal human liver197425154766556562-s2.0-0016314761MorseJ. H.WitteL. D.GoodmanD. S.Inhibition of lymphocyte proliferation stimulated by lectins and allogeneic cells by normal plasma lipoproteins19771466179118032-s2.0-0017705523ChisariF. V.Immunoregulatory properties of human plasma in very low density lipoproteins19771196212921362-s2.0-0017752128HuiD. Y.HarmonyJ. A.Phosphatidylinositol turnover in mitogen-activated lymphocytes. Suppression by low-density lipoproteins1980192191982-s2.0-0019214788HuiD. Y.HarmonyJ. A.Inhibition by low density lipoproteins of mitogen-stimulated cyclic nucleotide production by lymphocytes19802554141314192-s2.0-0018886324CurtissL. K.EdgingtonT. S.The biologic activity of the immunoregulatory lipoprotein, LDL-in, is independent of its free fatty acid content19811264138213862-s2.0-0019496790CuthbertJ. A.LipskyP. E.Immunoregulation by low density lipoproteins in man. Inhibition of mitogen-induced T lymphocyte proliferation by interference with transferrin metabolism198473499210032-s2.0-0021249765AkesonA. L.ScuphamD. W.HarmonyJ. A.The phosphatidylinositol response and proliferation of oxidative enzyme-activated human T lymphocytes: suppression by plasma lipoproteins19842511119512052-s2.0-0021719569HuiD.HarmonyJ.InnerarityT.MahleyR.Immunoregulatory plasma lipoproteins. Role of apoprotein E and apoprotein B19802552411775117812-s2.0-0019275306PepeM. G.CurtissL. K.Apolipoprotein E is a biologically active constituent of the normal immunoregulatory lipoprotein, LDL-In198613610371637232-s2.0-0022608931DyerC. A.SmithR. S.CurtissL. K.Only multimers of a synthetic peptide of human apolipoprotein E are biologically active19912662315009150152-s2.0-0025837970MistryM. J.ClayM. A.KellyM. E.SteinerM. A.HarmonyJ. A.Apolipoprotein E restricts interleukin-dependent T lymphocyte proliferation at the G1A/G1B boundary19951601423LaskowitzD. T.LeeD. M.SchmechelD.StaatsH. F.Altered immune responses in apolipoprotein E-deficient mice20004146136202-s2.0-0034001020LauratE.PoirierB.TupinE.In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice200110421972022-s2.0-0035838424AliK.MiddletonM.PuréE.RaderD. J.Apolipoprotein E suppresses the type I inflammatory response in vivo200597992292710.1161/01.RES.0000187467.67684.432-s2.0-27644482670RobertsonA. K.ZhouX.StrandvikB.HanssonG. K.Severe hypercholesterolaemia leads to strong Th2 responses to an exogenous antigen200459328529310.1111/j.0300-9475.2004.01403.x2-s2.0-1842505176Van OostenM.RensenP. C.Van AmersfoortE. S.Apolipoprotein E protects against bacterial lipopolysaccharide-induced lethality: a new therapeutic approach to treat gram-negative sepsis200127688208824DavenportP.TippingP. G.The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice20031633111711252-s2.0-0042926424de BontN.NeteaM. G.DemackerN. N.Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection199940680685RoselaarS. E.DaughertyA.Apolipoprotein E-deficient mice have impaired innate immune responses to Listeria monocytogenes in vivo1998399174017432-s2.0-0031687891MartensG. W.ArikanM. C.LeeJ.RenF.VallerskogT.KornfeldH.Hypercholesterolemia impairs immunity to tuberculosis20087683464347210.1128/IAI.00037-082-s2.0-48849098369de BontN.NeteaM. G.DemackerP. N.KullbergB. J.van der MeerJ. W.StalenhoefA. F.Apolipoprotein E-deficient mice have an impaired immune response to Klebsiella pneumoniae200030818822Jofre-MonsenyL.MinihaneA. M.RimbachG.Impact of apoE genotype on oxidative stress, inflammation and disease risk200852113114510.1002/mnfr.2007003222-s2.0-38949163967OphirG.AmariglioN.Jacob-HirschJ.ElkonR.RechaviG.MichaelsonD. M.Apolipoprotein E4 enhances brain inflammation by modulation of the NF-κB signaling cascade200520370971810.1016/j.nbd.2005.05.0022-s2.0-27744552618BasuS. K.BrownM. S.HoY. K.HavelR. J.GoldsteinJ. L.Mouse macrophages synthesize and secrete a protein resembling apolipoprotein E198178754575492-s2.0-0011895713BasuS. K.GoldsteinJ. L.BrownM. S.Independent pathways for secretion of cholesterol and apolipoprotein E by macrophages198321945868718732-s2.0-0020665553TakemuraR.WerbZ.Modulation of apoprotein E secretion in response to receptor-mediated endocytosis in resident and inflammatory macrophages198415911671782-s2.0-0021356569BaskinF.SmithG. M.FosmireJ. A.RosenbergR. N.Altered apolipoprotein E secretion in cytokine treated human astrocyte cultures19971481151810.1016/S0022-510X(96)05335-X2-s2.0-0031149081LaskowitzD. T.GoelS.BennettE. R.MatthewW. D.Apolipoprotein E suppresses glial cell secretion of TNF α1997761-2707410.1016/S0165-5728(97)00021-02-s2.0-0030904236LaskowitzD. T.ThekdiA. D.ThekdiS. D.Downregulation of microglial activation by apolipoprotein E and apoE-mimetic peptides20011671748510.1006/exnr.2001.75412-s2.0-0035152093AleongR.BlainJ. F.PoirierJ.Pro-inflammatory cytokines modulate glial apolipoprotein E secretion200851333710.2174/1567205087838846662-s2.0-42149152105BrandK.MackmanN.CurtissL. K.Interferon-γ inhibits macrophage apolipoprotein E production by posttranslational mechanisms1993915203120392-s2.0-0027233082OropezaR.WekerleH.WerbZ.Expression of apolipoprotein E by mouse brain astrocytes and its modulation by interferon-γ1987410145512-s2.0-0023263013SauraJ.PetegniefV.WuX.LiangY.PaulS.Microglial apolipoprotein E and astroglial apolipoprotein J expression in vitro: opposite effects of lipopolysaccharide20038561455146710.1046/j.1471-4159.2003.01788.x2-s2.0-0038810288StarckM.BertrandP.PepinS.SchieleF.SiestG.GalteauM. M.Effects of pro-inflammatory cytokines on apolipoprotein E secretion by a human astrocytoma cell line (CCF-STTG1)20001819162-s2.0-0033976301WerbZ.ChinJ.Apoprotein E is synthesized and secreted by resident and thioglycollate-elicited macrophages but not by pyran copolymer- or bacillus Calmette-Guerin-activated macrophages19831584127212932-s2.0-0020629312ZuckermanS.EvansG.O'NealL.Cytokine regulation of macrophage apo E secretion: opposing effects of GM-CSF and TGFb1992962-320321410.1016/0021-9150(92)90066-P2-s2.0-0026649351Levin-AllerhandJ.McEwenB. S.LominskaC.LubahnD.KorachK.SmithJ.Brain region-specific up-regulation of mouse apolipoprotein E by pharmacological estrogen treatments200179479680310.1046/j.1471-4159.2001.00627.x2-s2.0-0035184372SrivastavaR.SrivastavaN.AvernaM.Estrogen up-regulates apolipoprotein E (ApoE) gene expression by increasing ApoE mRNA in the translating pool via the estrogen receptor α- mediated pathway199727252333603336610.1074/jbc.272.52.333602-s2.0-0031454921StoneD.RozovskyI.MorganT.AndersonC.HajianH.FinchC.Astrocytes and microglia respond to estrogen with increased apoE mRNA in vivo and in vitro1997143231331810.1006/exnr.1996.63602-s2.0-0031079601StuehrD. J.ChoH. J.KwonN. S.WeiseM. F.NathanC. F.Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: An FAD- and FMN-containing flavoprotein19918817777377772-s2.0-0025787205VitekM.SnellJ.ChernyshevO.ColtonC.Modulation of nitric oxide production in human macrophages by apolipoprotein-E and amyloid-beta peptide1997240239139410.1006/bbrc.1997.74082-s2.0-0031576547EgenspergerR.KöselS.Von EitzenU.GraeberM. B.Microglial activation in Alzheimer disease: association with APOE genotype1998834394472-s2.0-0031831690ColtonC. A.CzapigaM.Snell-CallananJ.ChernyshevO. N.VitekM. P.Apolipoprotein E acts to increase nitric oxide production in macrophages by stimulating arginine transport20011535213414410.1016/S0925-4439(00)00092-22-s2.0-0035857491RiddellD.Apolipoprotein E inhibits platelet aggregration through the l-arginine: nitric oxide pathway19972728995ColtonC. A.NeedhamL. K.BrownC.APOE genotype-specific differences in human and mouse macrophage nitric oxide production20041471-2626710.1016/j.jneuroim.2003.10.0152-s2.0-1642534291CzapigaM.ColtonC. A.Microglial function in human APOE3 and APOE4 transgenic mice: altered arginine transport20031341-2445110.1016/S0165-5728(02)00394-62-s2.0-0037219011MaezawaI.NivisonM.MontineK. S.MaedaN.MontineT. J.Neurotoxicity from innate immune response is greatest with targeted replacement of E4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK200620679779910.1096/fj.05-5423fje2-s2.0-33646242262BrownC.XuQ.OkhuboN.VitekM.ColtonC. A.Androgen-mediated immune function is altered by the apolipoprotein E gene200714873383339010.1210/en.2006-12002-s2.0-34347245595BrownC. M.ChoiE.XuQ.VitekM.ColtonC. A.The APOE4 genotype alters the response of microglia and macrophages to 17β-estradiol200829121783179410.1016/j.neurobiolaging.2007.04.0182-s2.0-53649097589GordonS.Alternative activation of macrophages200331233510.1038/nri9782-s2.0-0037265240LehnardtS.MassillonL.FollettP.Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway2003100148514851910.1073/pnas.14326091002-s2.0-0037477629LaskowitzD. T.MatthewW. D.BennettE. R.Endogenous apolipoprotein E suppresses LPS-stimulated microglial nitric oxide production1998946156182-s2.0-0032498810DuanR. S.ChenZ.DouY. C.Apolipoprotein E deficiency increased microglial activation/CCR3 expression and hippocampal damage in kainic acid exposed mice2006202237338010.1016/j.expneurol.2006.06.0132-s2.0-33750609665TengerC.ZhouX.Apolipoprotein E modulates immune activation by acting on the antigen-presenting cell2003109339239710.1046/j.1365-2567.2003.01665.x2-s2.0-0038803973Jofre-MonsenyL.LobodaA.WagnerA. E.Effects of apoE genotype on macrophage inflammation and heme oxygenase-1 expression2007357131932410.1016/j.bbrc.2007.03.1502-s2.0-34147152150ChenS.AverettN. T.ManelliA.LaduM. J.MayW.ArdM. D.Isoform-specific effects of apolipoprotein E on secretion of inflammatory mediators in adult rat microglia20057125352-s2.0-15244340085MaezawaI.MaedaN.MontineT. J.MontineK. S.Apolipoprotein E-specific innate immune response in astrocytes from targeted replacement mice20063, article 1010.1186/1742-2094-3-102-s2.0-33746053293ChaussabelD.SemnaniR. T.McDowellM. A.SacksD.SherA.NutmanT. B.Unique gene expression profiles of human macrophages and dendritic cells to phylogenetically distinct parasites2003102267268110.1182/blood-2002-10-32322-s2.0-0038342438Le NaourF.HohenkirkL.GrolleauA.Profiling changes in gene expression during differentiation and maturation of monocyte-derived dendritic cells using both oligonucleotide microarrays and proteomics200127621179201793110.1074/jbc.M1001562002-s2.0-0035947669BendelacA.RiveraM. N.ParkS. H.RoarkJ. H.Mouse CD1-specific NK1 T cells: development, specificity, and function19971553556210.1146/annurev.immunol.15.1.5352-s2.0-0030890603CardellS.TangriS.ChanS.KronenbergM.BenoistC.MathisD.CD1-restricted CD4+ T cells in major histocompatibility complex class II- deficient mice19951824993100410.1084/jem.182.4.9932-s2.0-0029112507BeharS. M.PodrebaracT. A.RoyC. J.WangC. R.BrennerM. B.Diverse TCRs recognize murine CD11999162, article 161BrossayL.TangriS.BixM.CardellS.LocksleyR.KronenbergM.Mouse CD1-autoreactive T cells have diverse patterns of reactivity to CD1+ targets19981608368136882-s2.0-0032522851ChenH.PaulW. E.Cultured NK1.1+CD4+ T cells produce large amounts of IL-4 and IFN-γ upon activation by anti-CD3 or CD119971592240YoshimotoT.BendelacA.WatsonC.Hu-LiJ.PaulW. E.Role of NK1.1+ T cells in a TH2 response and in immunoglobulin E production19952705243184518472-s2.0-0029562066SinghA. K.WilsonM. T.HongS.Natural killer T cell activation protects mice against experimental autoimmune encephalomyelitis2001194121801181110.1084/jem.194.12.18012-s2.0-0035905471BriglM.BrennerM. B.CD1: antigen presentation and T cell function20042281789010.1146/annurev.immunol.22.012703.1046082-s2.0-2542448243AllanL. L.HoeflK.ZhengD. J.Apolipoprotein mediated lipid antigen presentation in B cells provides a pathway for innate help by NKT cells20091141224112416TupinE.NicolettiA.ElhageR.CD1d-dependent activation of NKT cells aggravates atherosclerosis2004199341742210.1084/jem.200309972-s2.0-1342321659MahleyR. W.RallS. C.Jr.Apolipoprotein E: far more than a lipid transport protein20001507537FazekasF.Strasser-FuchsS.KolleggerH.Apolipoprotein E epsilon 4 is associated with rapid progression of multiple sclerosis200157853857ShamshievA.DondaA.CarenaI.Self glycolipids as T-cell autoantigens1999295166716752-s2.0-0032902960KattanO. M.KasraviF. B.ElfordE. L.SchellM. T.HarrisH. W.Apolipoprotein E-mediated immune regulation in sepsis20081812139914082-s2.0-49049090627KellyM. E.ClayM. A.MistryM. J.HsiehL. H.HarmonyJ. A.Apolipoprotein E inhibition of proliferation of mitogen-activated T lymphocytes: production of interleukin 2 with reduced biological activity1994159212413910.1006/cimm.1994.13022-s2.0-0028135706BockschL.StephensT.LucasA.SinghB.Apolipoprotein E: possible therapeutic target for atherosclerosis200112931062-s2.0-0038471115GetzG. S.ReardonC. A.Apoprotein E as a lipid transport and signaling protein in the blood, liver, and artery wall200950S156S161HuntD. F.MichelH.DickinsonT. A.Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-A(d)19922565065181718202-s2.0-0026664454RiderB. J.FragaE.YuQ.SinghB.Immune responses to self peptides naturally presented by murine class II major histocompatibility complex molecules1996337-862563310.1016/0161-5890(96)00022-32-s2.0-0030152129StephensT. A.NikoopourE.RiderB. J.Dendritic cell differentiation induced by a self-peptide derived from apolipoprotein E200818110685968712-s2.0-58149189056LynchJ. R.TangW.WangH.APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response200327849485294853310.1074/jbc.M3069232002-s2.0-1542467336PhamT.KodvawalaA.HuiD. Y.The receptor binding domain of apolipoprotein E is responsible for its antioxidant activity200544207577758210.1021/bi04726962-s2.0-18844375108ZhouY.CheshireA.HowellL. A.RyanD. H.HarrisR. B.Neuroautoantibody immunoreactivity in relation to aging and stress in apolipoprotein E-deficient mice199949317317910.1016/S0361-9230(99)00052-02-s2.0-0033019725GraingerD. J.RecklessJ.McKilliginE.Apolipoprotein E modulates clearance of apoptotic bodies in vitro and in vivo, resulting in a systemic proinflammatory state in apolipoprotein E-deficient mice200417310636663752-s2.0-8444242086MisraU. K.AdlakhaC. L.GawdiG.McMillianM. K.PizzoS. V.LaskowitzD. T.Apolipoprotein E and mimetic peptide initiate a calcium-dependent signaling response in macrophages20017046776832-s2.0-0034787587RuizJ.KouiavskaiaD.MiglioriniM.The apoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor20054681721173110.1194/jlr.M500114-JLR2002-s2.0-23244454385HahnA. F.Guillain-Barré syndrome1998352912863564110.1016/S0140-6736(97)12308-X2-s2.0-0032558184SheikhK. A.HoT. W.NachamkinI.Molecular mimicry in Guillain-Barré syndrome1998845307321PritchardJ.HughesR. A. C.ReesJ. H.WillisonH. J.NicollJ. A. R.Apolipoprotein E genotypes and clinical outcome in Guillain-Barré syndrome200374797197310.1136/jnnp.74.7.9712-s2.0-0038141315JinT.HuL. S.ChangM.WuJ.WinbladB.ZhuJ.Proteomic identification of potential protein markers in cerebrospinal fluid of GBS patients200714556356810.1111/j.1468-1331.2007.01761.x2-s2.0-34247139196YangY. R.LiuS. L.QinZ. Y.Comparative proteomics analysis of cerebrospinal fluid of patients with Guillain-Barré syndrome200828573774410.1007/s10571-007-9257-72-s2.0-46149089887LintonM. F.GishR.HublS. T.Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation19918812702812-s2.0-0025878638DanikM.ChampagneD.Petit-TurcotteC.BeffertU.PoirierJ.Brain lipoprotein metabolism and its relation to neurodegenerative disease19991343574072-s2.0-0033303337HarveyG. K.GoldR.ToykaK. V.HartungH. P.Non-neural-specific T lymphocytes can orchestrate inflammatory peripheral neuropathy19951185126312722-s2.0-0028840943PollardJ. D.WestlandK. W.HarveyG. K.Activated T cells of nonneural specificity open the blood-nerve barrier to circulating antibody199537446747510.1002/ana.4103704092-s2.0-0028923747FullertonS. M.ShirmanG. A.StrittmatterW. J.MatthewW. D.Impairment of the blood-nerve and blood-brain barriers in apolipoprotein E knockout mice20011691132210.1006/exnr.2001.76312-s2.0-0035022053YuS.DuanR. S.ChenZ.Increased susceptibility to experimental autoimmune neuritis after upregulation of the autoreactive T cell response to peripheral myelin antigen in apolipoprotein E-deficient mice200463120128GoodrumJ. F.Cholesterol from degenerating nerve myelin becomes associated with lipoproteins containing apolipoprotein E19915662082208610.1111/j.1471-4159.1991.tb03469.x2-s2.0-0025946238HarrisH. W.Apolipoprotein E: from Alzheimer's to sepsis200533112696269710.1097/01.CCM.0000186895.78159.142-s2.0-27944507278WaksmanB. H.AdamsR. D.Allergic neuritis: an experimental disease of rabbits induced by the injection of peripheral nervous tissue and adjuvants1955102213236RostamiA.GregorianS. K.BrownM. J.PleasureD. E.Induction of severe experimental autoimmune neuritis with a synthetic peptide corresponding to the 53–78 amino acid sequence of the myelin P2 protein1990302-31451512-s2.0-0025052428ZouL. P.LjunggrenH. G.LeviM.P0 protein peptide 180–199 together with pertussis toxin induces experimental autoimmune neuritis in resistant C57BL/6 mice20006257177212-s2.0-0033675434HartungH. P.WillisonH.JungS.PetteM.ToykaK. V.GiegerichG.Autoimmune responses in peripheral nerve19961819712310.1007/BF007926122-s2.0-0029942968PanW.KastinA. J.Changing the chemokine gradient: CINC1 crosses the blood-brain barrier20011156470ZouL. P.PelidouS. H.AbbasN.Dynamics of production of MIP-1α, MCP-1 and MIP-2 and potential role of neutralization of these chemokines in the regulation of immune responses during experimental autoimmune neuritis in Lewis rats199998216817510.1016/S0165-5728(99)00100-92-s2.0-0033020153OlssonT.Critical influences of the cytokine orchestration on the outcome of myelin antigen-specific T-cell autoimmunity in experimental autoimmune encephalomyelitis and multiple sclerosis19951442452682-s2.0-0028990468RomagnaniS.The Th1/Th2 paradigm19971862632662-s2.0-0031172781ZhuJ.MixE.LinkH.Cytokine production and the pathogenesis of experimental autoimmune neuritis and Gulllain-Barré syndrome1998841405210.1016/S0165-5728(97)00238-52-s2.0-0032054104FujiokaT.JimiT.HilliardB. A.VenturaE. S.RostamiA.The expression of cytokine mRNA in the cauda equina of Lewis rats with experimental allergic neuritis199884222322910.1016/S0165-5728(97)00252-X2-s2.0-0032522188ZhuJ.BaiX. F.MixE.LinkH.Cytokine dichotomy in peripheral nervous system influences the outcome of experimental allergic neuritis: dynamics of mRNA expression for IL-1β, IL-6, IL-10, IL-12, TNF-α, TNF-β, and cytolysin1997841859410.1006/clin.1997.43562-s2.0-0030738576ZhuJ.BaiX. F.MixE.LinkH.Experimental allergic neuritis: cytolysin mRNA expression is upregulated in lymph node cells during convalescence1997781-210811610.1016/S0165-5728(97)00087-82-s2.0-0030779057SchmidtB.StollG.HartungH. P.HeiningerK.SchaferB.ToykaK. V.Macrophages but not Schwann cells express Ia antigen in experimental autoimmune neuritis1990281707710.1002/ana.4102801132-s2.0-0025316669JungS.HuitingaI.SchmidtB.The role of macrophages in dichlormethylene diphosphonate-containing liposomes suppresses experimental autoimmune neuritis1993119219520210.1016/0022-510X(93)90134-K2-s2.0-0027446659KieferR.KieseierB. C.StollG.HartungH. P.The role of macrophages in immune-mediated damage to the peripheral nervous system200164210912710.1016/S0301-0082(00)00060-52-s2.0-0035123658GoldR.ArchelosJ. J.HartungH. P.Mechanisms of immune regulation in the peripheral nervous system1999923433602-s2.0-0032896682ContiG.RostamiA.ScarpiniE.Inducible nitric oxide synthase (iNOS) in immune-mediated demyelination and Wallerian degeneration of the rat peripheral nervous system2004187235035810.1016/j.expneurol.2004.01.0262-s2.0-2342658904Meyer zu HörsteG.HuW.HartungH. P.LehmannH. C.KieseierB. C.The immunocompetence of Schwann cells200837313KoskiC. L.Mechanisms of Schwann cell damage in inflammatory neuropathy1997176supplement 2S169S172DuanR. S.JinT.YangX.MixE.AdemA.ZhuJ.Apolipoprotein E deficiency enhances the antigen-presenting capacity of Schwann cells200755777277610.1002/glia.204982-s2.0-34247526332BoylesJ. K.ZoellnerC. D.AndersonL. J.A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve1989833101510312-s2.0-0024574009GoodrumJ. F.WeaverJ. E.GoinesN. D.BouldinT. W.Fatty acids from degenerating myelin lipids are conserved and reutilized for myelin synthesis during regeneration in peripheral nerve1995654175217592-s2.0-0029097983PoirierJ.BaccichetA.DeaD.GauthierS.Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats1993551819010.1016/0306-4522(93)90456-P2-s2.0-0027298061PopkoB.GoodrumJ. F.BouldinT. W.ZhangS. H.MaedaN.Nerve regeneration occurs in the absence of apolipoprotein E in mice1993603115511582-s2.0-0027411295RamassamyC.KrzywkowskiP.AverillD.Impact of apoE deficiency on oxidative insults and antioxidant levels in the brain2001861-2768310.1016/S0169-328X(00)00268-02-s2.0-0035977715RiddellD. R.ZhouH.AtchisonK.Impact of Apolipoprotein E (ApoE) polymorphism on brain ApoE levels20082845114451145310.1523/JNEUROSCI.1972-08.20082-s2.0-58149251844DongL. M.WeisgraberK. H.Human apolipoprotein E4 domain interaction. Arginine 61 and glutamic acid 255 interact to direct the preference for very low density lipoproteins199627132190531905710.1074/jbc.271.32.190532-s2.0-0029766916WeisgraberK. H.MahleyR. W.Human apolipoprotein E: the Alzheimer's disease connection19961013148514942-s2.0-0029844205GreggR. E.ZechL. A.SchaeferE. J.StarkD.WilsonD.BrewerH. B.Jr.Abnormal in vivo metabolism of apolipoprotein E4 in humans19867838158212-s2.0-0022449937SteinmetzA.JakobsC.MotznyS.KaffarnikH.Differential distribution of apolipoprotein E isoforms in human plasma lipoproteins1989934054112-s2.0-0024395117WeisgraberK. H.Apolipoprotein E distribution among human plasma lipoproteins: role of the cysteine-arginine interchange at residue 1121990318150315112-s2.0-0025171570StrubleR. G.RosarioE. R.KircherM. L.Regionally specific modulation of brain apolipoprotein E in the mouse during the estrous cycle and by exogenous 17β estradiol2003183263864410.1016/S0014-4886(03)00215-22-s2.0-0141671956Levin-AllerhandJ.McEwenB. S.LominskaC. E.LubahnD. B.KorachK. S.SmithJ. D.Brain region-specific up-regulation of mouse apolipoprotein E by pharmacological estrogen treatments200179479680310.1046/j.1471-4159.2001.00627.x2-s2.0-0035184372RozovskyI.HovingS.AndersonC. P.O'CallaghanJ.FinchC. E.Equine estrogens induce apolipoprotein E and glial fibrillary acidic protein in mixed glial cultures2002323319119410.1016/S0304-3940(02)00146-52-s2.0-0037012777InnerarityT. L.PitasR. E.MahleyR. W.Binding of arginine-rich (E) apoprotein after recombination with phospholipid vesicles to the low density lipoprotein receptors of fibroblasts197925441864190NaritaM.HoltzmanD. M.FaganA. M.Cellular catabolism of lipid poor apolipoprotein E via cell surface LDL receptor-related protein200213257437492-s2.0-0141742030OsugaJ. I.YonemotoM.YamadaN.Cholesterol lowering in low density lipoprotein receptor knockout mice overexpressing apolipoprotein E199810223863942-s2.0-0032527612