Lipocalin 2 is a novel immune mediator of experimental autoimmune encephalomyelitis pathogenesis and is modulated in multiple sclerosis

Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model of multiple sclerosis (MS), an inflammatory, demyelinating disease of the central nervous system (CNS). EAE pathogenesis involves various cell types, cytokines, chemokines, and adhesion molecules. Given the complexity of the inflammatory response in EAE, it is likely that many immune mediators still remain to be discovered. To identify novel immune mediators of EAE pathogenesis, we performed an Affymetrix gene array screen on the spinal cords of mice at the onset stage of disease. This screening identified the gene encoding lipocalin 2 (Lcn2) as being significantly upregulated. Lcn2 is a multi-functional protein that plays a role in glial activation, matrix metalloproteinase (MMP) stabilization, and cellular iron flux. As many of these processes have been implicated in EAE, we characterized the expression and role of Lcn2 in this disease in C57BL/6 mice. We show that Lcn2 is significantly upregulated in the spinal cord throughout EAE and is expressed predominantly by monocytes and reactive astrocytes. The Lcn2 receptor, 24p3R, is also expressed on monocytes, macrophages/microglia, and astrocytes in EAE. In addition, we show that EAE severity is increased in Lcn2(-/-) mice as compared with wild-type controls. Finally, we demonstrate that elevated levels of Lcn2 are detected in the plasma and cerebrospinal fluid (CSF) in MS and in immune cells in CNS lesions in MS tissue sections. These data indicate that Lcn2 is a modulator of EAE pathogenesis and suggest that it may also play a role in MS.     

Analysis of T cell receptor β chains in the rat: I. Allelic polymorphism of Vβ8.2 is not a predisposing genetic factor in susceptibility to experimental allergic encephalomyelitis

Previous studies of experimental allergic encephalomyelitis (EAE) in the LER rat have suggested that amino acid differences present in the LER TCR Vβ8.2 chain may be associated with disease resistance. We report here that LEW rats bred to express a Vβ8.2 gene from DA rats, identical to that found in LER, are susceptible to EAE induction. Furthermore, T cells infiltrating the spinal cord of diseased animals primarily utilized Vβ8.2 and the associated AspSer CDR3 motif, typical of TCR Vβ8.2 chains expressed by pathogenic, anti-MBP responsive T cells in the LEW rat. © 1996 Wiley-Liss, Inc.     

In acute experimental autoimmune encephalomyelitis,infiltrating macrophages are immune activated,whereas microglia remain immune suppressed

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) characterized by loss of myelin accompanied by infiltration of T‐lymphocytes and monocytes. Although it has been shown that these infiltrates are important for the progression of MS, the role of microglia, the resident macrophages of the CNS, remains ambiguous. Therefore, we have compared the phenotypes of microglia and macrophages in a mouse model for MS, experimental autoimmune encephalomyelitis (EAE). In order to properly discriminate between these two cell types, microglia were defined as CD11b^pos CD45^int Ly‐6C^neg, and infiltrated macrophages as CD11b^pos CD45^high Ly‐6C^pos. During clinical EAE, microglia displayed a weakly immune‐activated phenotype, based on the expression of MHCII, co‐stimulatory molecules (CD80, CD86, and CD40) and proinflammatory genes [interleukin‐1β (IL‐1β) and tumour necrosis factor‐ α (TNF‐α)]. In contrast, CD11b^pos CD45^high Ly‐6C^pos infiltrated macrophages were strongly activated and could be divided into two populations Ly‐6C^int and Ly‐6C^high, respectively. Ly‐6C^high macrophages contained less myelin than Ly‐6C^int macrophages and expression levels of the proinflammatory cytokines IL‐1β and TNF‐α were higher in Ly‐6C^int macrophages. Together, our data show that during clinical EAE, microglia are only weakly activated whereas infiltrated macrophages are highly immune reactive. GLIA 2014;62:1724–1735     

Polyneuritic onset in multiple sclerosis

A case of definite MS with unusual polyneuritic onset is described. The case is discussed in the light of published data and of experimental studies that have demonstrated a cross reaction between central and peripheral nervous system antigens.

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Sommario Viene presentato un caso di SM definita con inusuale esordio polinevritico dimostrato con EMG. Gli autori discutono tale evenienza alla luce dei dati della letteratura e rispetto a studi sperimentali che dimostrano una reazione crociata tra antigeni del CNS e PNS.

     

Estrogen receptor‐β ligand treatment after disease onset is neuroprotective in the multiple sclerosis model

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation and neurodegeneration. Current MS treatments were designed to reduce inflammation in MS rather than directly to prevent neurodegeneration. Estrogen has well‐documented neuroprotective effects in a variety of disorders of the CNS, including experimental autoimmune encephalomyelitis (EAE), the most widely used mouse model of MS. Treatment with an estrogen receptor‐β (ERβ) ligand is known to ameliorate clinical disease effectively and provide neuroprotection in EAE. However, the protective effects of this ERβ ligand have been demonstrated only when administered prior to disease (prophylactically). Here we tested whether ERβ ligand treatment could provide clinical protection when treatment was initiated after onset of disease (therapeutically). We found that therapeutic treatment effectively ameliorated clinical disease in EAE. Specifically, ERβ ligand‐treated animals exhibited preserved axons and myelin compared with vehicle‐treated animals. We observed no difference in the number of T lymphocytes, macrophages, or microglia in the CNS of vehicle‐ vs. ERβ ligand‐treated animals. Our findings show that therapeutically administered ERβ ligand successfully treats clinical EAE, bearing translational relevance to MS as a candidate neuroprotective agent. © 2013 Wiley Periodicals, Inc.     

Characterization of relapsing–remitting and chronic forms of experimental autoimmune encephalomyelitis in C57BL/6 mice

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). Like MS, the animal model experimental autoimmune encephalomyelitis (EAE) is characterized by CNS inflammation and demyelination and can follow a relapsing–remitting (RR) or chronic (CH) disease course. The molecular and pathological differences that underlie these different forms of EAE are not fully understood. We have compared the differences in RR‐ and CH‐EAE generated in the same mouse strain (C57BL/6) using the same antigen. At the peak of disease when mice in both groups have similar clinical scores, CH‐EAE is associated with increased lesion burden, myelin loss, axonal damage, and chemokine/cytokine expression when compared with RR‐EAE. We further showed that inflammation and myelin loss continue to worsen in later stages of CH‐EAE, whereas these features are largely resolved at the equivalent stage in RR‐EAE. Additionally, axonal loss at these later stages is more severe in CH‐EAE than in RR‐EAE. We also demonstrated that CH‐EAE is associated with a greater predominance of CD8⁺ T cells in the CNS that exhibit MOG_35–55 antigen specificity. These studies therefore showed that, as early as the peak stage of disease, RR‐ and CH‐EAE differ remarkably in their immune cell profile, chemokine/cytokine responses, and histopathological features. These data also indicated that this model of CH‐EAE exhibits pathological features of a chronic‐progressive disease profile and suggested that the sustained chronic phenotype is due to a combination of axonal loss, myelin loss, and continuing inflammation. © 2009 Wiley‐Liss, Inc.     

Macrophage and microglial responses to cytokines in vitro: Phagocytic activity,proteolytic enzyme release,and free radical production

Certain cytokines are believed to play a key role in the development of autoimmune demyelinating diseases. Little is known, however, about the effects of these cytokines in the regulation of the key event in myelin destruction, the phagocytosis of myelin by phagocytic cells. We investigated the effects of certain cytokines and growth factors on cultured peritoneal macrophages and microglia in respect to their various functions, phagocytosis, secreted proteolytic activity, and oxidative activity. Interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and lipopolysaccharide (LPS), all proinflammatory factors, actually decreased (IFN-γ and LPS), or had no effect (TNF-α) on myelin phagocytosis by macrophages, but substantially increased phagocytic activity by microglia. Surprisingly, interleukins 4 and 10 (IL-4 and IL-10), considered to be downregulating cytokines, increased phagocytic activity by macrophages, while with microglia, IL-4 had no effect, but IL-10 almost doubled myelin phagocytosis. Transforming growth factor-β (TGF-β) had no significant effect on either cell. These cytokines did not affect proteolytic secretion in microglia, while IFN-γ and LPS induced a doubling of the secreted proteases. This proteolytic activity was almost completely suppressed by calpain inhibitors, although some gelatinase appeared to be present. Microglia exerted much more oxidative activity on the membranes than macrophages, and granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 1β (IL-1β) significantly increased microglial oxidative activity. The pattern of responses of macrophages and microglia to the cytokine types indicate that in cytokine-driven autoimmune demyelinating disease, microglia may be the more aggressive cell in causing tissue injury by phagocytosis and oxidative injury, while infiltrating macrophages may produce most of the proteolytic activity thought to contribute to myelin destruction. J. Neurosci. Res. 54:68–78, 1998. © 1998 Wiley-Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America.     

Individual differences in the effects of chronic prazosin hydrochloride treatment on hippocampal mineralocorticoid and glucocorticoid receptors

The aim of this study was to investigate the noradrenergic regulation of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in high responder (HR) and low responder (LR) male rats, an animal model of individual differences in hypothalamo-pituitary-adrenal axis activity and vulnerability to drugs of abuse. The effects of a chronic treatment with the noradrenergic alpha(1) antagonist (1-[4-amino-6,7-dimethoxy-2-quinazolinyl]-4-[2-furanylcarbonyl] piperazine) hydrochloride (prazosin) (0.5 mg/kg, i.p., 35 days) were assessed on stress-induced corticosterone (CORT) secretion and on hippocampal MRs and GRs in adrenally intact rats. In order to ascertain whether the effects of chronic prazosin treatment on hippocampal MRs and GRs were direct or indirect, through prazosin-induced CORT secretion, we also assessed the effects of the same treatment on adrenalectomized rats with CORT substitutive therapy. When compared with LR rats, HR rats exhibited a delayed return to the basal level of CORT following acute restraint stress; this was associated with a lower binding of MRs and GRs in HR rats than in LR rats. Chronic prazosin treatment had no effect in HR animals but markedly reduced hippocampal MRs and GRs, and increased stress-induced CORT secretion in LR rats. In LR adrenalectomized rats, prazosin reduced hipppocampal MRs but did not change GRs. Our results provide evidence of a differential regulation by noradrenaline of hippocampal MRs and GRs in HR and LR rats. These data could have clinical implications in terms of individual differences in the resistance to antidepressant treatments and individual differences in drug abuse.     

Upregulation of the stress-associated gene p8 in mouse models of demyelination and in multiple sclerosis tissues

Cuprizone-induced demyelination is a mouse model of multiple sclerosis (MS) as cuprizone-fed mice exhibit neuroinflammation and demyelination in the brain. Upon removal of cuprizone from the diet, inflammation is resolved and reparative remyelination occurs. In an Affymetrix GeneChip analysis, the stress-associated gene p8 was strongly upregulated (>10x) during cuprizone-induced demyelination but not remyelination. We verified this upregulation (>15x) of p8 in the CNS during demyelination by real-time polymerase chain reaction (PCR). This upregulation is brain-specific, as p8 is not elevated in the liver, lung, kidney, spleen, and heart of cuprizone-treated mice. We also localized the cellular source of p8 during cuprizone treatment, and further found elevated expression during embryogenesis but not in normal adult brain. Compared with wild-type controls, the death of oligodendrocytes in p8-/- mice is delayed, as is microglial recruitment to areas of demyelination. The corpus callosum of p8-/- mice demyelinates at a slower rate than wild-type mice, suggesting that p8 exacerbates CNS inflammation and demyelination. Enhanced expression of p8 is also observed in the spinal cords of mice with acute experimental autoimmune encephalomyelitis (EAE) induced by PLP139-151 peptide (10x). Increased expression is detected during disease onset and expression wanes during the remission phase. Finally, p8 is found upregulated (8x) in post-mortem tissue from MS patients and is higher in the plaque tissue compared with adjacent normal-appearing white and gray matter. Thus, p8 is an excellent candidate as a novel biomarker of demyelination.     

Diversity of immune cell types in multiple sclerosis and its animal model: Pathological and therapeutic implications

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system with an autoimmune attack on the components of the myelin sheath and axons. The etiology of the disease remains largely unknown, but it is commonly acknowledged that the development of MS probably results from the interaction of environmental factors in conjunction with a genetic predisposition. Current therapeutic approaches can only ameliorate the clinical symptoms or reduce the frequency of relapse in MS. Most drugs used in this disease broadly suppress the functions of immune effector cells, which can result in serious side effects. Thus, new therapeutic methods resulting in greater efficacy and lower toxicity are needed. Toward this end, cell‐based therapies are of increasing interest in the treatment of MS. Several immunoregulatory cell types, including regulatory T cells, regulatory B cells, M2 macrophages, tolerogenic dendritic cells, and stem cells, have been developed as novel therapeutic tools for the treatment of MS. In this Review, we summarize studies on the application of these cell populations for the treatment of MS and its animal model, experimental autoimmune encephalomyelitis, and call for further research on applications and mechanisms by which these cells act in the treatment of MS. © 2017 The Authors Journal of Neuroscience Research Published by Wiley Periodicals, Inc.     

Astrocyte-induced regulatory T cells mitigate CNS autoimmunity

Although astrocytes presumably participate in maintaining the immune privilege of the central nervous system (CNS), the mechanisms behind their immunoregulatory properties are still largely undefined. In this study, we describe the development of regulatory T cells upon contact with astrocytes. Rat T cells pre-incubated with astrocytes completely lost the ability to proliferate in response to mitogenic stimuli. The cells were blocked in G0/G1 phase of the cell cycle, expressed less IL-2R, and produced significantly lower amounts of interferon-gamma (IFN-gamma), but not interleukin-2 (IL-2), IL-10, or tumor necrosis factor (TNF). These anergic cells completely prevented mitogen-induced growth of normal T lymphocytes, as well as CNS antigen-driven proliferation of autoreactive T cells. The suppressive activity resided in both CD4+ and CD8+ T-cell compartments. Heat-sensitive soluble T-cell factors, not including transforming growth factor-beta (TGF-beta) or IL-10, were solely responsible for the observed suppression, as well as for the transfer of suppressive activity to normal T cells. The administration of astrocyte-induced regulatory T cells markedly alleviated CNS inflammation and clinical symptoms of CNS autoimmunity in rats with experimental allergic encephalomyelitis. Finally, the cells with suppressive properties were readily generated from human lymphocytes after contact with astrocytes. Taken together, these data indicate that astrocyte-induced regulatory T cells might represent an important mechanism for self-limitation of excessive inflammation in the brain.     

FTY720 ameliorates MOG‐induced experimental autoimmune encephalomyelitis by suppressing both cellular and humoral immune responses

FTY720, an oral sphingosine 1‐phosphate (S1P) receptor modulator, has shown efficacy in phase II trials in patients with relapsing‐remitting multiple sclerosis (MS). Although this molecule is thought to immunosuppress by inhibiting lymphocyte egress from the lymph nodes, the full spectrum of FTY720's actions has not yet been uncovered. In this study, we investigated the effects of FTY720 treatment on disease severity and histopathology of MOG‐induced experimental autoimmune encephalomyelitis (EAE) in the dark agouti (DA) rat, a model that closely mimics several features of MS. The effects of FTY720 on T‐cell subsets, anti‐MOG antibody production, and mRNA expression of a number of cytokines and other genes were also examined. Commencement of treatment before disease onset prevented the appearance of clinical disease. Therapeutic treatment after established disease reduced clinical scores and substantially attenuated inflammation, demyelination, and axon loss. EAE suppression was associated with a reduction in all measured T‐cell subsets in blood and spleen and a significant decrease in serum IgG_2a levels. However, in the lymph nodes, all T‐cell subsets except for naïve T cells and recent thymic emigrants remained unaffected. In addition, FTY720 treatment led to a significant inhibition in interferon‐γ, inducible nitric oxide synthase, and glial cell line‐derived neurotrophic factor mRNA expression in the MOG‐EAE spinal cord. In conclusion, our findings indicate that FTY720‐mediated S1P receptor modulation ameliorates chronic relapsing MOG‐EAE by suppressing both cellular and humoral immune responses. © 2009 Wiley‐Liss, Inc.     

Evaluation of Endocrine Profile,Hypothalamic–Pituitary–Testis Axis and Semen Quality in Multiple Sclerosis

Several endocrine and sexual disturbances have been demonstrated in multiple sclerosis (MS) patients of both sexes. The endocrine profile, hypothalamic–pituitary–testis (HPT) axis and semen quality were evaluated in male patients with MS. A total of 68 male MS patients aged 18 years or older were recruited. Forty‐eight age‐matched healthy male volunteers served as controls. All subjects underwent complete physical examination and routine semen analysis. Two blood samples were drawn from each participant at 15‐min intervals for the determination of the resting levels of: luteinising‐hormone (LH), follicle‐stimulating hormone (FSH), prolactin, testosterone, oestradiol and sex hormone binding globulin. The HPT axis was assessed using gonadotrophin‐releasing hormone (GnRH) and human chorionic gonadotrophin tests. The mean basal serum levels for LH, FSH and testosterone in MS patients were significantly lower than the mean for normal controls (P = 0.01). The injection of GnRH analogue did not yield a significant increase in FSH and LH levels in the MS patients compared to normal controls (P = 0.001). Total sperm count, sperm motility and percent normal sperm morphology were lower in MS patients compared to controls. MS subjects with progressive disease had higher and more severe HPT axis abnormalities than that for patients with relapsing remitting MS. Most subjects with MS have hypogonadotrophic hypogonadism state and fertility impairment. It appears that the damage to HPT axis is both in pituitary and testicular levels. Further studies are needed to better elucidate the underlying pathophysiology of HPT axis dysregulation.     

Mouse model mimics multiple sclerosis in the clinico-radiological paradox

The value of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, in deriving novel diagnostic and therapeutic input has been subject to recent debate. This study is the first to report a disseminated distribution of plaques including cranial nerves, prior to or at early stages of disease in murine adoptive transfer EAE, irrespective of the development of clinical symptoms. We induced EAE by adoptive proteolipid protein-specific T-cell transfer in 26 female SJL/J mice, and applied high-field-strength magnetic resonance imaging (MRI) scans longitudinally, assessing blood-brain barrier (BBB) disruption by gadopentate dimeglumine enhancement. We visualized inflammatory nerve injury by gadofluorine M accumulation, and phagocytic cells in inflamed tissue by very small anionic iron oxide particles (VSOP-C184). MRI was correlated with immunohistological sections. In this study, we discovered very early BBB breakdown of white and grey brain matter in 25 mice; one mouse developed exclusively spinal cord inflammation. Widely disseminated contrast-enhancing lesions preceded the onset of disease in 10 animals. Such lesions were present despite the absence of any clinical disease formation in four mice, and coincided with the first detectable symptoms in others. Cranial nerves, predominantly the optic and trigeminal nerves, showed signal intensity changes in nuclei and fascicles of 14 mice. At all sites of MRI lesions we detected cellular infiltrates on corresponding histological sections. The discrepancy between the disease burden visualized by MRI and the extent of disability indeed mimics the human clinico-radiological paradox. MRI should therefore be implemented into evaluational in vivo routines of future therapeutic EAE studies.     

Neuroimmunoprotective effects of estrogen and derivatives in experimental autoimmune encephalomyelitis: therapeutic implications for multiple sclerosis

The extensive literature and the work from our laboratory illustrate the large number of complex processes affected by estrogen that might contribute to the striking ability of 17beta-estradiol (E2) and its derivatives to inhibit clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in mice. These effects require sustained exposure to relatively low doses of exogenous hormone and offer better protection when initiated prior to induction of EAE. However, oral ethinyl estradiol (EE) and fluasterone, which lacks estrogenic side effects, could partially reverse clinical EAE when given after the onset of disease. The three main areas discussed in this review include E2-mediated inhibition of encephalitogenic T cells, inhibition of cell migration into central nervous system tissue, and neuroprotective effects that promote axon and myelin survival. E2 effects on EAE were mediated through Esr1 (alpha receptor for E2) but not Esr2 (beta receptor for E2), as were its antiinflammatory and neuroprotective effects. A novel finding is that E2 up-regulated the expression of Foxp3 and CTLA-4 that contribute to the activity of CD4+CD25+ Treg cells. The protective effects of E2 in EAE suggest its use as therapy for MS, although the risk of cardiovascular disease may complicate treatment in postmenopausal women. This risk could be minimized by using subpregnancy levels of exogenous E2 that produced synergistic effects when used in combination another immunoregulatory therapy. Alternatively, one might envision using EE or fluasterone metabolites alone or in combination therapies in both male and female MS patients.     

Changes in cannabinoid CB(1) receptors in striatal and cortical regions of rats with experimental allergic encephalomyelitis, an animal model of multiple sclerosis

Data, initially anecdotal, but recently supported on more solid experimental evidence, suggest that cannabinoids might be beneficial in the treatment of some of the symptoms of multiple sclerosis (MS). Despite this evidence, there are no data on the possible changes in cannabinoid CB(1) or CB(2) receptors, the main molecular targets for the action of cannabinoids, either in the postmortem brain of patients with MS or in animal models of this disease. The present study addressed this question using the model of experimental allergic encephalomyelitis (EAE) in Lewis rats generated by inoculation of guinea pig myelin basic protein in Freund's adjuvant. After inoculation, animals were examined daily to detect the appearance of neurological signs. The first signs appeared around day 10 after inoculation, reaching the highest degree by day 13, when animals were sacrificed and their brains removed and used for analysis of CB(1) receptor binding, mRNA levels, and activation of GTP-binding proteins. CB(1) receptor binding and mRNA levels were not affected in EAE rats in brain areas such as the hippocampus, limbic structures, and cerebellum. However, there was a marked decrease in both parameters in the caudate-putamen, both in the lateral and medial parts, although this decrease did not correspond with decreases in binding in the nuclei recipient of striatal output neurons, which suggests that changes in CB(1) receptors are exclusively located in the cell bodies of striatal neurons. In addition, CB(1) receptor binding, but not mRNA levels, also decreased in the cerebral cortex, both in the deep and the superficial layers. The analysis of [(35)S]GTPgammaS binding after activation of CB(1) receptors with WIN55,212-2, a synthetic agonist, revealed that, despite the decrease in the number of CB(1) receptors in EAE rats, these were more efficiently coupled to GTP-binding protein-mediated signaling mechanisms in both the caudate-putamen and the cerebral cortex of these animals. In summary, these data suggest that the generation of EAE in Lewis rats would be associated with changes in CB(1) receptors in striatal and cortical neurons, which might be related to the alleviation of some motor signs observed after the treatment with cannabinoid receptor agonists in similar models of MS in rodents.     

CNS-irrelevant T-cells enter the brain, cause blood-brain barrier disruption but no glial pathology

Invasion of autoreactive T-cells and alterations of the blood-brain barrier (BBB) represent early pathological manifestations of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Non-CNS-specific T-cells are also capable of entering the CNS. However, studies investigating the spatial pattern of BBB alterations as well as the exact localization and neuropathological consequences of transferred non-CNS-specific cells have been thus far lacking. Here, we used magnetic resonance imaging and multiphoton microscopy, as well as histochemical and high-precision unbiased stereological analyses to compare T-cell transmigration, localization, persistence, relation to BBB disruption and subsequent effects on CNS tissue in a model of T-cell transfer of ovalbumin (OVA)- and proteolipid protein (PLP)-specific T-cells. BBB alterations were present in both EAE-mice and mice transferred with OVA-specific T-cells. In the latter case, BBB alterations were less pronounced, but the pattern of initial cell migration into the CNS was similar for both PLP- and OVA-specific cells [mean (SEM), 95 x 10(3) (7.6 x 10(3)) and 88 x 10(3) (18 x 10(3)), respectively]. Increased microglial cell density, astrogliosis and demyelination were, however, observed exclusively in the brain of EAE-mice. While mice transferred with non-neural-specific cells showed similar levels of rhodamine-dextran extravasation in susceptible brain regions, EAE-mice presented huge BBB disruption in brainstem and moderate leakage in cerebellum. This suggests that antigen specificity and not the absolute number of infiltrating cells determine the magnitude of BBB disruption and glial pathology.     

Serum sAPO-1/Fas levels in multiple sclerosis

Soluble APO-1 (sAPO-1) may prevent apoptosis of lymphocytes induced by activation of the APO-1/Fas receptor. Objectives – To determine sAPO-1 levels in the serum of multiple sclerosis (MS) patients and controls in order to investigate if abnormal lymphocyte apoptosis occurs in this disease. Methods – Serum samples from patients with MS, other neurological diseases, systemic lupus erythematosus and healthy controls were determined by enzyme-linked immunosorbent assay. Results – We did not detect differences in mean serum sAPO-1 levels between patients with multiple sclerosis and controls. Conclusions – This preliminary study suggests that resistance of peripheral blood lymphocytes to apoptosis mediated by sAPO-1 is not likely to be a major factor in the development of autoreactive cells in MS.