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Background: Brain atrophy (BA) may have a role in acute ischemic stroke (AIS) in mediating outcomes after reperfusion therapy. The extent of this association is not well understood. Purpose: : To examine the impact of pre-existing BA on functional outcome, survival, symptomatic intracerebral hemorrhage (sICH), and early neurological change in patients with AIS treated with intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT). Material and Methods: PubMed, EMBASE, and the Cochrane library were searched for studies on BA in AIS receiving reperfusion therapy. Studies were included if: (i) patients were aged ≥18 years; (ii) patients had been diagnosed with AIS; (iii) patients received IVT and/or EVT; (iv) studies reported on BA; (v) studies reported on post-reperfusion outcomes; and (vi) studies had a sample size of >25 patients. Results: A total of 4444 patients from eight studies were included. Four out of seven studies reporting on 90-day functional outcome found pre-existing BA to be significantly associated with poor functional outcome. Moreover, two out of four studies found BA to be a significant predictor of 90-day mortality. None of the included studies reported a significant association of BA with sICH or early neurological deterioration. Conclusion: This systematic review indicates a potential prognostic role of BA in AIS. Quantitative analysis of association of BA with outcomes in AIS is not possible given the heterogeneity in BA assessment and reporting across studies. Future studies using standardized BA assessment are warranted to clarify its association with clinical and safety outcomes in AIS. [ABSTRACT FROM AUTHOR]

In optic neuritis (ON), transient thickening of the macular retinal nerve fibre layer (RNFL) can be observed. This optical coherence tomography-based observation is not understood. The axonal diameter correlates with the neurofilament (Nf) protein content, but there are no data on the retinal tissue concentration of Nfs. The myelin-oligodendrocyte-glycoprotein (MOG) induced experimental autoimmune encephalomyelitis (EAE) model was used to investigate the retinas of Brown Norway rats with (i) visual evoked potentials (VEP) confirmed ON, (ii) VEP confirmed absence of ON and (iii) control animals. Twenty retinas were collected from MOG-EAE and control rats 27 days after immunisation. Retinal tissue Nf concentrations per total protein (μg/mg) were significantly higher in MOG-EAE rats with ON (median 4.29, interquartile range [IQR] 3.41–5.97) compared with MOG-EAE rats without ON (1.14, IQR 1.10–1.67) or control rats (0.93, IQR 0.45–4.00). The data suggest that up-regulation of Nf expression in the retinal ganglion cells precedes development of RNFL atrophy and plausibly explains the transient increase of axonal diameter and RNFL thickening. [ABSTRACT FROM AUTHOR]

Objectives: Severity of leukoaraiosis may mediate outcomes after reperfusion therapy in acute ischaemic stroke (AIS) patients. However, the level of the association remains poorly understood. We performed a meta‐analysis to investigate the impact of leukoaraiosis severity on functional outcome, survival, haemorrhagic complications, and procedural success in AIS patients treated with intravenous thrombolysis and/or endovascular thrombectomy. Materials and Methods: PubMed, EMBASE and the Cochrane library were searched for studies on leukoaraiosis in AIS receiving reperfusion therapy. A random‐effects meta‐analysis was conducted for post‐reperfusion outcomes in AIS patients with absent‐to‐mild leukoaraiosis and moderate‐to‐severe leukoaraiosis. The strength of association between moderate‐to‐severe leukoaraiosis and poor outcomes was quantified using odds ratios (OR). Results: A total of 15 eligible studies involving 6460 patients (1451 with moderate‐to‐severe leukoaraiosis and 5009 with absent‐to‐mild leukoaraiosis) were included in the meta‐analysis. Moderate‐to‐severe leukoaraiosis was significantly associated with poor 90‐day functional outcome (OR 3.16; 95% confidence interval (CI) 2.69–3.72; p <.0001), 90‐day mortality (OR 3.11; 95% CI 2.27–4.26; p <.0001) and increased risk of symptomatic intracerebral haemorrhage (OR 1.69; 95% CI 1.24–2.32; p =.001) after reperfusion therapy. Overall, no significant association of leukoaraiosis severity with haemorrhagic transformation (HT) and angiographic recanalization status were observed. However, subgroup analysis revealed a significant association of WML severity with HT in patients receiving EVT. Conclusion: Leukoaraiosis is a useful prognostic biomarker in AIS. Patients with moderate‐to‐severe leukoaraiosis on baseline imaging are likely to have worse clinical and safety outcomes after reperfusion therapy. [ABSTRACT FROM AUTHOR]

White matter lesions have been implicated in the setting of stroke, dementia, intracerebral haemorrhage, several other cerebrovascular conditions, migraine, various neuroimmunological diseases like multiple sclerosis, disorders of metabolism, mitochondrial diseases and others. While much is understood vis a vis neuroimmunological conditions, our knowledge of the pathophysiology of these lesions, and their role in, and implications to, management of cerebrovascular diseases or stroke, especially in the elderly, are limited. Several clinical assessment tools are available for delineating white matter lesions in clinical practice. However, their incorporation into clinical decision‐making and specifically prognosis and management of patients is suboptimal for use in standards of care. This article sought to provide an overview of the current knowledge and recent advances on pathophysiology, as well as clinical and radiological assessment, of white matter lesions with a focus on its development, progression and clinical implications in cerebrovascular diseases. Key indications for clinical practice and recommendations on future areas of research are also discussed. Finally, a conceptual proposal on putative mechanisms underlying pathogenesis of white matter lesions in cerebrovascular disease has been presented. Understanding of pathophysiology of white matter lesions and how they mediate outcomes is important to develop therapeutic strategies. [ABSTRACT FROM AUTHOR]

In this article the authors' opines that the concept of non-inflammatory damage to the central nervous system (CNS) is questionable as the immune system has been trained to detect disturbance of homeostasis and responds with an appropriate inflammatory reaction and thus we should not focus more on finding therapeutic targets for the non-inflammatory damage in multiple sclerosis (MS). Topics include there is tissue damage in MS with and without inflammation.

Abstract: Progressive multifocal leukoencephalopathy (PML) is a disease of the central nervous system (CNS) with destructive infection of oligodendrocytes by JC virus. PML belongs to the opportunistic infections. It is observed in patients with HIV infection, lymphoid malignancies, after organ- and stem cell transplantations and more recently in the context of modern immune-therapies with monoclonal antibodies (mAb) like natalizumab, rituximab, infliximab and efalizumab. The natural course of PML is fatal within months. More recently, the Immune Reconstitution Inflammatory Syndrome (IRIS) has been observed in patients with HIV infection treated with combination antiretroviral therapy (cART) as well as patients in whom the PML-inducing immune therapy has been terminated. In PML-IRIS the immune system contributes to the elimination of JC virus from the CNS and if PML-IRIS emerges, PML can be survived but can lead as well to catastrophic outcomes with brain herniation and death. Therefore the management of IRIS requires special knowledge in JC virus biology and patient care. JC virus infection is possibly involved in a variety of additional neurological conditions and cancer. Much will be learned within the next years that could change our view on the understanding of JC virus and human disease. [Copyright &y& Elsevier]

Treosulfan (dihydroxybusulfane, DHB, l-threitol-1,4-bis [methane sulfonate]) is a cytostatic alkylating agent with a favorable profile of side effects. Myelin-oligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) induced in DA (RT1av1) rats resembles multiple sclerosis (MS) in many aspects since central nervous system (CNS) pathology shows inflammation, demyelination and axonal loss. Moreover, DA rats develop a chronic disease course. We here explored the efficacy of treosulfan in the treatment of MOG-induced EAE in DA rats. A single dose of treosulfan (1 g/kg body weight i.p.) at the day of immunization significantly reduced disease severity compared with PBS-treated controls. In addition, after disease had evolved, a single dose of treosulfan (1 g/kg body weight) given i.p. on day 14 post-immunization (p.i.) improved long-term disease outcome. Treatment with treosulfan resulted in reduced mRNA expression of IL-12 and interferon (IFN)-γ in draining lymph nodes and reduced numbers of IFN-γ-secreting MOG-specific T cells. No myelosuppression was observed. Treosulfan was applied to different subsets of cultured human blood mononuclear cells in order to asses the effects on human immune cells in vitro: Treosulfan reduced proliferative capacity and increased apoptosis in T cells and antigen-presenting cells. In light of the beneficial effects in EAE in vivo and the in vitro immunosuppressive and pro-apoptotic capacities in cultured human mononuclear immune effector cells, these data may support a potential role of treosulfan, an agent with high immunosuppressive capacity and low toxicity, in the treatment of MS. [Copyright &y& Elsevier]

Provides information on a study which investigated whether DNA encoding the whole rat myelin basic protein 21.5-kDa sequence can protect against peptide-induced experimental autoimmune encephalomyelitis. Materials and methods; Results and discussion.

Background: The development of permanent disability in multiple sclerosis (MS) is highly variable among patients, and the exact mechanisms that contribute to this disability remain unknown.Methods: Following the idea that the brain has intrinsic network organization, we investigated changes of functional networks in MS patients to identify possible links between network reorganization and remission from clinical episodes in MS. Eighteen relapsing-remitting MS patients (RRMS) in their first clinical manifestation underwent resting-state functional MRI and again during remission. We used ten template networks, identified from independent component analysis, to compare changes in network coherence for each patient compared to those of 44 healthy controls from the Human Connectome Project test-retest dataset (two-sample t-test of pre-post differences). Combining a binomial test with Monte Carlo procedures, we tested four models of how functional coherence might change between the first clinical episode and remission: a network can change its coherence (a) with itself ("one-with-self"), (b) with another network ("one-with-other"), or (c) with a set of other networks ("one-with-many"), or (d) multiple networks can change their coherence with respect to one common network ("many-with-one").Results: We found evidence supporting two of these hypotheses: coherence decreased between the Executive Control Network and several other networks ("one-with-many" hypothesis), and a set of networks altered their coherence with the Cerebellar Network ("many-with-one" hypothesis).Conclusion: Given the unexpected commonality of the Cerebellar Network's altered coherence with other networks (a finding present in more than 70% of the patients, despite their clinical heterogeneity), we conclude that remission in MS may result from learning processes mediated by the Cerebellar Network. [ABSTRACT FROM AUTHOR]

The article presents the case of a 28-year-old Caucasian, otherwise healthy woman presented to the hospital because of a hemiparesis with numbness of the right body side that had developed within several hours. No history of neurological symptoms, antecedent infection or recent vaccination was reported. Medical history otherwise was completely unremarkable. Initial neurological examination revealed a mild right-sided hemiparesis with prominent sensory disturbances affecting light touch, position and vibration sense. Cerebrospinal fluid analysis showed normal cell counts and protein content with an elevated IgG index and positive oligoclonal bands.

It has become increasingly clear that only antibodies recognizing conformation-dependent epitopes of myelin oligodendrocyte glycoprotein (MOG) have a demyelinating potential in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Nevertheless, for the induction of EAE, most studies to date have used MOG peptides or bacterially expressed MOG, neither of which contain the tertiary structure of the native antigen. Non-refolded recombinant human MOG does not induce EAE in DA rats. Therefore, we refolded this protein in order to assess the influence of MOG conformation on its pathogenicity in DA rats. DA rats immunized with refolded human MOG developed severe acute EAE. As expected, rats immunized with the refolded protein had a higher amount of conformational MOG antibodies present in serum. But in addition, a striking effect of MOG refolding on the generation of T-cell responses was found. Indeed, T-cell responses against the encephalitogenic MOG 91-108 epitope were greatly enhanced after refolding. Therefore, we conclude that refolding of MOG increases its pathogenicity both by generating conformation-dependent MOG antibodies and by enhancing its processing or/and presentation on MHC molecules. These data are important in regard to investigations of the pathogenic potential of many (auto)antigens. [ABSTRACT FROM AUTHOR]

The high failure rate of immunotherapies in multiple sclerosis (MS) clinical trials demonstrates problems in translating new treatment concepts from animal models to the patient. One main reason for this ‘immunotherapy gap’ is the usage of immunologically immature, microbiologically clean and genetically homogeneous rodent strains. Another reason is the artificial nature of the experimental autoimmune encephalomyelitis model, which favors CD4+ T cell driven autoimmune mechanisms, whereas CD8+ T cells are prevalent in MS lesions. In this paper, we discuss preclinical models in humanized rodents and non-human primates that are genetically closer to MS. We also discuss models that best reproduce specific aspects of MS pathology and how these can potentially improve preclinical selection of promising therapies from the discovery pipeline. [ABSTRACT FROM AUTHOR]

The Notch receptor and its ligands are involved in myelination in central nervous system (CNS) development. Re-expression of this pathway in the adult CNS has been proposed to hamper remyelination in multiple sclerosis. Previous studies also revealed that pharmacological inhibition of Notch signaling ameliorates experimental autoimmune encephalomyelitis (EAE). However, in a recent study in toxin-induced demyelination constituents of the Notch signaling pathway were demonstrated in remyelinating lesions indicating that remyelination may occur in the presence of Notch signaling. We examined the expression of Notch1-immunoreactivity (IR) and Jagged1-IR in EAE induced by myelin-oligodendrocyte glycoprotein (MOG). In this model, the combined action of T cells, antibodies and the complement cascade yields a pathology closely reflecting multiple sclerosis. Notch1 and its ligand Jagged1 were differentially expressed in the lesions of MOG-EAE. Notch1-IR on macrophages was highest in actively demyelinating and lowest in remyelinating lesions. The amount of Notch1-positive astrocytes increased during the lesion evolution from demyelination to remyelination. Notch1-positive oligodendrocytes were exclusively present in remyelinating lesions and not found in lesions without signs of remyelination. Astrocytes represented the major source of Jagged1-IR in demyelination and remyelination. In conclusion, our study proves that constituents of the Notch pathway are expressed in remyelination in an animal model of T-cell- and antibody-mediated CNS demyelination. Thus, it is unlikely, at least in the paradigm of MOG-EAE, that Notch signaling is responsible for a failure of remyelination. [ABSTRACT FROM AUTHOR]

Background: Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases. Objective: To evaluate the impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD)). Methods: Female-to-male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset. Results: A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p < 0.001). Interval between onset and diagnosis of NMO/SD was longer in women than in men (mean 54 vs 27 months; p = 0.023). In women, attacks occurring ⩽40 years of age were more likely to show complete remission (p = 0.003) and better response to high-dose intravenous steroids (p = 0.005) compared to woman at >40 years. Conclusion: Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD. [ABSTRACT FROM AUTHOR]

Background: Managing multiple sclerosis (MS) treatment presents challenges for both patients and health care professionals. Effective communication between patients with MS and their neurologist is important for improving clinical outcomes and quality of life. Methods: A closed-ended online market research survey was used to assess the current state of MS care from the perspective of both patients with MS ($18 years of age) and neurologists who treat MS from Europe and the US and to gain insight into perceptions of treatment expectations/goals, treatment decisions, treatment challenges, communication, and satisfaction with care, based on current clinical practice. Results: A total of 900 neurologists and 982 patients completed the survey, of whom 46% selfidentified as having remitting-relapsing MS, 29% secondary progressive MS, and 11% primary progressive MS. Overall, patients felt satisfied with their disease-modifying therapy (DMT); satisfaction related to comfort in speaking with their neurologist and participation in their DMT decision-making process. Patients who self-identified as having relapsing-remitting MS were more likely to be very satisfied with their treatment. Top challenges identified by patients in managing their DMT were cost, side effects/tolerability of treatment, and uncertainty if treatment was working. Half of the patients reported skipping doses, but only 68% told their health care provider that they did so. Conclusion: Several important differences in perception were identified between patients and neurologists concerning treatment selection, satisfaction, expectations, goals, and comfort discussing symptoms, as well as treatment challenges and skipped doses. The study results emphasize that patient/neurologist communication and patient input into the treatment decisionmaking process likely influence patient satisfaction with treatment. [ABSTRACT FROM AUTHOR]

Background: Experimental autoimmune encephalomyelitis (EAE) in the common marmoset monkey (Callithrix jacchus) is a relevant preclinical model for translational research into immunopathogenic mechanisms operating in multiple sclerosis (MS). Prior studies showed a core pathogenic role of T and B cells specific for myelin oligodendrocyte glycoprotein (MOG). However, in those studies, the quality of the response against MOG epitopes was strongly biased by bacterial antigens in the complete Freund's adjuvant (CFA), in which the immunizing recombinant human (rh) MOG protein had been formulated. In response to the need of a more refined EAE model, we have tested whether disease could also be induced with rhMOG in incomplete Freund's adjuvant (IFA).Method: Marmosets were immunized with rhMOG emulsified in IFA in the dorsal skin. Monkeys that did not develop neurological deficit were given booster immunizations at 28-day interval with the same antigen preparation. In a second experiment, three marmoset twin pairs were sensitized against MOG peptides in IFA to study a possibility for suppressive activity towards pathogenic T cells directed against the encephalitogenic epitope MOG40-48.Results: Despite the absence of strong danger signals in the rhMOG/IFA inoculum, all monkeys developed clinically evident EAE symptoms. Moreover, in all monkeys, demyelinated lesions were present in the white matter and in two cases also in the cortical grey matter. Immune profiling at height of the disease showed a dominant T cell response against the overlapping peptides 14-36 and 24-46, but reactivity against the pathogenically most relevant peptide 34-56 was conspicuously absent. In the second experiment, there was an indication for a possible suppressive mechanism.Conclusions: Immunization of marmoset monkeys with rhMOG in IFA elicits clinical EAE in all animals. Moreover, rhMOG contains pathogenic and regulatory epitopes, but the pathogenic hierarchy of rhMOG epitopes is strongly influenced by the adjuvant in which the protein is formulated. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the effect of atacicept, a recombinant fusion protein blocking BLyS and APRIL and acting on B cells, on degeneration of retinal ganglion cells (RGCs) during experimental autoimmune encephalomyelitis (EAE). We used myelin oligodendrocyte glycoprotein in Brown Norway rats to induce a variant of EAE which involves B cells and leads to severe optic neuritis. Intraperitoneal treatment with atacicept at some of the studied dose levels (100 or 200μg) resulted in increased apoptosis of retinal ganglion cells whereas at a tenfold lower dose or in vehicle-treated animals no such effect became apparent. Also the extent of inflammation, demyelination, and axonal loss of the optic nerve was more pronounced in rats treated with the higher atacicept dose level. The present study describes observational evidence for adverse effects of atacicept on neuronal survival during EAE. [Copyright &y& Elsevier]

Schwann cell (SC) transplantation is currently being discussed as a strategy that may promote functional recovery in patients with multiple sclerosis (MS) and other inflammatory demyelinating diseases of the central nervous system (CNS). However this assumes they will not only survive but also remyelinate demyelinated axons in the chronically inflamed CNS. To address this question we investigated the fate of transplanted SCs in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in the Dark Agouti rat; an animal model that reproduces the complex inflammatory demyelinating immunopathology of MS. We now report that SCs expressing green fluorescent protein (GFP-SCs) allografted after disease onset not only survive but also migrate to remyelinate lesions in the inflamed CNS. GFP-SCs were detected more frequently in the parenchyma after direct injection into the spinal cord, than via intrathecal delivery into the cerebrospinal fluid. In both cases the transplanted cells intermingled with astrocytes in demyelinated lesions, aligned with axons and by twenty one days post transplantation had formed Pzero protein immunoreactive internodes. Strikingly, GFP-SCs transplantation was associated with marked decrease in clinical disease severity in terms of mortality; all GFP-SCs transplanted animals survived whilst 80% of controls died within 40 days of disease. [ABSTRACT FROM AUTHOR]

Abstract: Cladribine (2-chloro-2′-deoxyadenosine) is a purine nucleoside analogue (PNA) which causes targeted and sustained reduction of peripheral lymphocyte counts. Cladribine tablets produced significant treatment benefit for patients with relapsing–remitting multiple sclerosis in the phase 3 CLARITY study. In addition to the well-characterised cell-specific phosphorylation of PNAs responsible for lymphocyte reduction, the mode of action of cladribine may encompass distinct activities contributing to its overall effects on the immune system. Here we demonstrate that clinically relevant concentrations of cladribine also inhibit cytokine secretion by human peripheral blood T cells in vitro through mechanisms independent of the induction of lymphocyte death. [Copyright &y& Elsevier]

Abstract: The etiology of sarcoidosis remains unknown. Recently, by mass spectrometric sequencing of peptides eluted from HLA-DR molecules of bronchoalveolar lavage (BAL) cells from DRB1⁎0301pos patients, we identified potential self-antigens in sarcoidosis. The aim of the present study was to investigate the capacity of selected peptides to stimulate lung and blood T cells of sarcoidosis patients using an interferon-γ ELISPOT assay. In peripheral blood, there were strong T cell responses to a peptide derived from the cytoskeletal protein vimentin in 6 out of 11 DRB1⁎0301pos patients with active disease but not in patients with other HLA types. BAL T cell responses against peptides derived from ATP synthase or from lysyl-tRNA synthetase were detected in DRB1⁎0301pos as well as DRB1⁎0301neg patients. By using antigenic peptides presented in vivo in the lungs of sarcoidosis patients, we have identified blood and lung T cell autoimmune responses that may help sustain the inflammation in this disease. [Copyright &y& Elsevier]

Polymorphisms in the CTLA4 gene region have been associated with susceptibility to autoimmune diseases. The recently described single nucleotide polymorphism CT60, located in the 3′ untranslated region of CTLA4 is associated with Graves' disease, thyroiditis, autoimmune diabetes and other autoimmune diseases. A case-control association study was conducted in German, Hungarian and Polish multiple sclerosis (MS) patients and regional control individuals for the CTLA4 CT60 and +49A/G polymorphisms. No significant association of these polymorphisms or respective haplotypes with MS was found. No association of CT60 genotypes with T cell expression of ICOS and CTLA-4 after in vitro stimulation was detected. [ABSTRACT FROM AUTHOR]

Sarcoidosis is an inflammatory disease of unknown etiology, most commonly affecting the lungs. Activated CD4+ T cells accumulate in the lungs of individuals with sarcoidosis and are considered to be of central importance for inflammation. We have previously shown that Scandinavian sarcoidosis patients expressing the HLA-DR allele DRB1*0301 are characterized by large accumulations in the lungs of CD4+ T cells expressing the TCR AV2S3 gene segment. This association afforded us a unique opportunity to identify a sarcoidosis-specific antigen recognized by AV2S3+ T cells. To identify candidates for the postulated sarcoidosis-specific antigen, lung cells from 16 HLA-DRB1*0301pos patients were obtained by bronchoalveolar lavage. HLA-DR molecules were affinity purified and bound peptides acid eluted. Subsequently, peptides were separated by reversed-phase HPLC and analyzed by liquid chromatography-mass spectrometry. We identified 78 amino acid sequences from self proteins presented in the lungs of sarcoidosis patients, some of which were well-known autoantigens such as vimentin and ATP synthase. For the first time, to our knowledge, we have identified HLA-bound peptides presented in vivo during an inflammatory condition. This approach can be extended to characterize HLA-bound peptides in various autoimmune settings. [ABSTRACT FROM AUTHOR]

Abstract: FTY720 (fingolimod) is an oral sphingosine 1-phosphate (S1P) receptor modulator under development for the treatment of multiple sclerosis (MS). To elucidate its effects in the central nervous system (CNS), we compared functional parameters of nerve conductance in the DA rat model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) after preventive and therapeutic treatment. We demonstrate that prophylactic therapy protected against the emergence of EAE symptoms, neuropathology, and disturbances to visual and somatosensory evoked potentials (VEP, SEP). Moreover, therapeutic treatment from day 25 to 45 markedly reversed paralysis in established EAE and normalized the electrophysiological responses, correlating with decreased demyelination in the brain and spinal cord. The effectiveness of FTY720 in this model is likely due to several contributing factors. Evidence thus far supports its role in the reduction of inflammation and preservation of blood-brain-barrier integrity. FTY720 may also act via S1P receptors in glial cells to promote endogenous repair mechanisms that complement its immunomodulatory action. [Copyright &y& Elsevier]

Abstract: The role of astrocytes in the pathogenesis of multiple sclerosis (MS) is not well understood. Astrocytes may modulate the activity of pathogenic T cells by presenting myelin antigens in combination with pro- or anti-inflammatory signals. Astrocytes have been shown to present myelin basic protein (MBP) and proteolipid protein (PLP) to T cells, but it has remained unresolved whether astrocytes present myelin oligodendrocyte glycoprotein (MOG), which has been implicated as an important autoantigen in MS. Here, we asked whether astrocytes presented MOG to T cells. To closer model presentation of human MOG by astrocytes in MS patients, we generated astrocytes from transgenic mice expressing the MS-associated MHC class II alleles HLA-DR2 (DRB1*1501) and HLA-DR4 (DRB1*0401). The results show that IFN-γ-activated HLA-DR2 and HLA-DR4 expressing astrocytes efficiently presented immunodominant and subdominant MOG peptides to T cells. The hierarchy of the presented MOG epitopes was comparable to that of professional APCs, including dendritic cells and microglia. Importantly, astrocytes were poor at processing and presenting native MOG protein. Furthermore, astrocytes induced a mixed Th1/Th2 cytokine response in MOG-specific T cells, whereas dendritic cells induced a predominantly Th1 cell response. Collectively, the results suggest that astrocytes may modulate anti-MOG T cell responses in the CNS. [Copyright &y& Elsevier]

Abstract: To investigate the influence of antigen and restricting MHC class II molecule on the T cell repertoire, we varied the peptide source by immunizing either with myelin basic protein (MBP) rat 63-88 or MBPGUINEA PIG (GP)63-88, which differ in the core region of the peptide binding site at position 79 by a single exchange of threonine (T) to serine (S) and by altering the MHC by immunizing MHC congenic LEW (RT1l) and LEW.1W (RT1u) rats. In both MHC haplotypes both peptides lead to oligoclonal dominance of TCRBV8S2 expressing T cells within the central nervous system (CNS) as assessed by complementary determining region 3 (CDR3) spectratyping. In contrast cytofluorometric analysis indicated that only MBPGP63-88 in context with the RT1l haplotype of the LEW rat lead to strong expansions of TCRBV8S2 expressing T cells within the CNS. Importantly, the small conservative change from S to T at position 79 within MBP63-88 had a strong influence both on the encephalitogenic potential of the peptide and on the number of TCRBV8S2+ T cells infiltrating the CNS. These results demonstrate that even minor changes in only one side chain of an amino acid within an (auto)antigen can dramatically alter TCR avidity for certain MHC class II/peptide complexes. [Copyright &y& Elsevier]

Experimental autoimmune encephalomyelitis induced with myelin proteins in DA and LEW.1AV1 rats is a model of multiple sclerosis (MS). It reproduces major aspects of this detrimental disease of the central nervous system. MS is associated with theHLA-DRB1*1501,DRB5*0101, andDQB1*0602haplotype. DA and LEW.1AV1 rats share theRT1 av1 haplotype. So far, no MHC class II peptide motif of RT1.Da molecules has been described. Sequence alignment of the ß chain of the rat MHC class II molecule RT1.Da with human HLA class II molecules revealed strong similarity in the peptide-binding groove of RT1.Da and HLA-DRB1*1501. According to the putative peptide-binding pockets of RT1.Da, after comparison with the pockets of HLA-DRB1*1501, we predicted the peptide motif of RT1.Da. To verify the predicted motif, naturally processed peptides were eluted by acidic treatment from immunoaffinity-purified RT1.Da molecules of lymphoid tissue of DA rats and subsequently analyzed by ESI tandem mass spectrometry. In addition, we performed binding studies with combinatorial nonapeptide libraries to purified RT1.Da molecules. Based on these studies we could define a peptide-binding motif for RT1.Da characterized by aliphatic amino acid residues (L, I, V, M) and of F for the peptide pocket P1, aromatic residues (F, Y, W) for P4, basic residues (K, R) for P6, aliphatic residues (I, L, V) for P7, and aromatic residues (F, Y, W) and L for P9. Both methods revealed similar binding characteristics for peptides to RT1.Da. This data will allow epitope predictions for analysis of peptides, relevant for experimental autoimmune diseases. [ABSTRACT FROM AUTHOR]

With a panel of rat strains, we demonstrate a strong impact of the MHC genotype on susceptibility and disease course in experimental autoimmune neuritis induced with peripheral nerve myelin or the P2 peptide 58–81 (KNTEISFKLGQEFEETTADNRKTK). Beside the MHC genotype, non-MHC genes determined disease susceptibility and resistance. The type of disease induced with P2 58–81 was strongly correlated to the strength of the MHC class II isotype interaction with P2 58–81. These findings suggest a link between susceptibility and acute versus chronic disease courses on one hand and the strength of the MHC class II molecule/peptide affinity on the other hand. [Copyright &y& Elsevier]

The nicotinic acetylcholine receptor (nAChR) is the autoantigen in seropositive myasthenia gravis (MG) that is a T cell-dependent B cell-mediated autoimmune disorder. We tested the immunogenicity and myasthenogenicity of the extracellular and first transmembrane domain of the #x03B5;-chain1–221 of the nAChR in inbred and MHC congenic rat strains. Immunodominant T and B cell determinants did not induce experimental autoimmune myasthenia gravis (EAMG), although immunization resulted in strong Th1 and B cell responses, which could be mapped with overlapping peptides of the nAChR #x03B5;-subunit in eight different rat strains. Our data underscores the concept that immunodominant autoantigen-specific T and B cell responses can lack pathogenicity in autoimmune disease and might be of relevance for the physiological integrity of the organism. [Copyright &y& Elsevier]

The nicotinic acetylcholine receptor (nAChR) is the autoantigen in seropositive myasthenia gravis (MG), a T-cell-dependent B-cell-mediated autoimmune disease. The nAChR is a pentameric transmembrane receptor comprising ααβγδ chains. During early postnatal development the nAChR γ chain is replaced by the nAChR ε chain. We tested the myasthenogenicity in experimental autoimmune myasthenia gravis (EAMG) of the native nAChR derived from the electric ray Torpedo californica (T-nAChR) in various inbred and MHC -congenic rat strains. Differences in the disease course emerged dependent on the MHC haplotype and non-MHC genes. Interestingly, no tested rat strain was completely resistant to EAMG, but there were strong differences in disease severity mainly depending on the MHC haplotype. In the LEW non-MHC genome, the B-cell response and the severity of EAMG were dependent on the expressed MHC haplotype. This study underscores the influence of genetic factors on disease severity, disease course and on the degree of the emerging antibody responses in EAMG. [ABSTRACT FROM AUTHOR]

Epitope spreading has been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS). T cell epitope spreading has been demonstrated in rodents for myelin basic protein (MBP) and proteolipid protein (PLP) determinants, but not for myelin oligodendrocyte glycoprotein (MOG), another important myelin antigen. Moreover, the role of human autoimmunity-associated MHC molecules in epitope spreading, including HLA-DR2 and DR4, has not been formally examined.To address these questions, we investigated epitope spreading to MOG determinants in HLA-DR4 (DRB1*0401) transgenic mice during EAE. The data show that upon induction of EAE in HLA-DR4 transgenic mice with the immunodominant HLA-DR4-restricted MOG peptide 97–108 (MOG97–108; TCFFRDHSYQEE), the T cell response diversifies over time to MOG181–200 (core: MOG183–191; FVIVPVLGP) and MBP. The spreading epitope MOG181–200 binds with high affinity to HLA-DRB1*0401 and is presented by human HLA-DRB1*0401+antigen presenting cells. Moreover, this epitope is encephalitogenic in HLA-DRB1*0401 transgenic mice.This study demonstrates intra- and intermolecular epitope spreading to MOG and MBP in “humanized” HLA-DR4 transgenic mice. [Copyright &y& Elsevier]

Inflammation and demyelination both contribute to the neurological deficits characteristic of multiple sclerosis. Neurological dysfunctions are attributable to inflammatory demyelination and, in addition, to soluble factors such as nitric oxide, cytokines and antibodies. QYNAD, an endogenous pentapeptide identified in the cerebrospinal fluid of patients with demyelinating disorders, has been proposed to promote axonal dysfunction by blocking sodium channels. The present study aimed at characterizing the properties of QYNAD in acutely isolated thalamic neurons in vitro. QYNAD, but not a scrambled peptide (NYDQA), blocked sodium channels in neurons by shifting the steady-state inactivation to more negative potentials. Blocking properties followed a dose–response curve with a maximum effect at 10 µ m. A fluorescently labelled QYNAD analogue with retained biological activity specifically stained thalamic neurons, positive for type II sodium channels, thus demonstrating the specificity of QYNAD binding. Our study confirms and extends previous observations describing QYNAD as a potent sodium channel-blocking agent. These data as well as our preliminary observations in in vivo experiments in an animal model of inflammatory CNS demyelination warrant further in vivo studies in order to clarify the exact pathogenetic role of QYNAD in inflammatory neurological diseases. [ABSTRACT FROM AUTHOR]

Investigates the influence of methylprednisolone therapy on the survival of retinal ganglion cells using a rat model of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. Effect of treatment of methylprednisolone on retinal ganglion cells; Clinical value of methylprednisolane treatment; Negative effects of steroid treatment on neuronal survival.

Costimulatory signals play a key role in regulating T cell activation and are believed to have decisive influence in the inciting and perpetuating cellular effector mechanisms in autoimmune diseases such as multiple sclerosis (MS). Inducible costimulator protein (ICOS), a recently identified member of the CD28-family, presumably affects the differentiation of Th1/Th2 cells after primary activation and modulates the immune response of effector/memory T cells.This study examines the expression and functional role of ICOS costimulation in healthy donors and patients with MS. After nonspecific or antigen-specific stimulation, ICOS is preferentially expressed on CD4 Th2-T cells. ICOS-costimulation affects the production of Th1 and Th2 cytokines both in the absence and presence of B7/CD28 costimulation, thus suggesting that ICOS costimulation can modulate cytokine secretion also in a CD28-independent manner. Levels of constitutive and inducible ICOS expression on human T cell subsets from peripheral blood were quantified in healthy donors and patients with MS. Constitutive expression of ICOS on T cells varies between 0.1% and 42.3%. There were no significant differences between both groups in the baseline expression or inducibility of ICOS on CD4 or CD8 T cells. ICOS expression could be demonstrated on CSF T lymphocytes in patients with acute MS relapses but was not elevated compared with peripheral blood.In essence we show that ICOS is upregulated on human T cells after stimulation and can modulate both Th1 and Th2 cytokine production in the absence and presence of B7-costimulation. In MS patients we demonstrate the functionality of the ICOS costimulatory pathway. Potential implications of ICOSL/ICOS interactions for MS immunopathogenesis are discussed. [Copyright &y& Elsevier]

Abstract: Genetic variation in the intracellular tyrosine phosphatase PTPN22 has been recently associated with susceptibility to various autoimmune diseases. Myasthenia gravis (MG) is a complex genetic disease with a distinct clinical and pathological heterogeneity. We conducted a case–control association study for the PTPN22 1858C/T polymorphism in Hungarian and German MG patients (n = 282) and regional controls (n = 379). We detected an association of the PTPN22 1858T allele with MG in the subgroup of nonthymoma patients with anti-titin antibodies present (n = 50; T allele frequency 21% vs 11% in controls; p = 0.005, odds ratio 2.1, 95% confidence interval 1.23–3.58). This overrepresentation was reported independently in both Hungarian and German MG patients compared with regional controls. We conclude that the common autoimmune polymorphism PTPN22 1858C/T may account for disease susceptibility in a subset of nonthymoma MG patients with anti-titin antibodies present. [Copyright &y& Elsevier]