Re-expression of N-cadherin in remyelinating lesions of experimental inflammatory demyelination.

The cell adhesion molecule N-cadherin is involved in several processes during central nervous system development, but also in certain pathologic conditions in the adult brain, including tumorigenesis and Alzheimer's disease. N-cadherin function in inflammatory demyelinating disease has so far not been investigated. In vitro studies suggest a role of N-cadherin in myelination; on the other hand N-cadherin has been implicated in the formation of the glial scar, which is believed to impede remyelination. The aim of our study was to investigate the expression pattern of N-cadherin immunoreactivity in experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein (MOG-EAE), an animal model closely mimicking multiple sclerosis. It allows a detailed evaluation of all stages of de- and remyelination during lesion development. Immunopathological evaluation was performed on paraffin-embedded CNS sections sampled at days 20 to 120 post immunization. We found a predominant expression of N-cadherin on oligodendrocytes in early remyelinating lesions, while in fully remyelinated shadow plaques there was no detectable immunoreactivity for N-cadherin. This expression pattern indicates a role of N-cadherin in the initiation of remyelination, most likely by providing a guidance between myelin lamellae and oligodendrocytes. Once the initial contact is made N-cadherin is then rapidly downregulated and virtually absent after completion of the repair process, analog to its known role in developmental myelination. Our results show that N-cadherin plays an important role in creating a remyelination-facilitating environment.

Fc receptors are critical for autoimmune inflammatory damage to the central nervous system in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is simulated by various forms of experimental autoimmune encephalomyelitis, in which T cells, antibodies, cytokines and complementary factors interact with the central nervous system (CNS) myelin proteins and lead to inflammatory damage. We investigated the role of Fc receptors (FcRs), which link the cellular and humoral branches of the immune system, in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), using two different FcRgamma knockout DBA/1 mice. The first knockout were the FcRgamma chain-deficient mice, which lack FcgammaRI, FcgammaRIII and Fc(epsilon)RI, while the second knockout mice lack only FcgammaRII. The lack of FcgammaRII enhanced the disease susceptibility with associated increased CNS demyelination. While FcRgamma+/+ DBA/1 mice also developed pronounced CNS infiltration and myelin destruction, FcRgamma-/- littermates were protected despite initial peripheral autoimmune responses to MOG. In vitro analyses revealed equivalent potentials of fluid phase phagocytosis of myelin and MOG in bone-marrow macrophages derived from both FcRgamma+/+ and FcRgamma-/- mice, while MOG-immunoglobulin (Ig)G immune complexes were only internalized by FcRgamma+/+ macrophages. This was associated with cellular activation in FcRgamma+/+ but not FcRgamma-/- macrophages, as assessed by the activation of intracellular mitogen activated protein (MAP)-kinase signalling elements. We propose that protection from EAE in FcRgamma-deficient mice is due to the inefficient antigen processing/presentation of myelin proteins during the induction of secondary immune responses locally in the CNS, which leads to demyelination. This demonstrates the importance of FcR in the promotion of autoimmune inflammation of the CNS and highlights the therapeutic possibility of treatment of MS with FcR-directed modalities.

Anti-MOG and anti-MBP antibody subclasses in multiple sclerosis.

In a subset of multiple sclerosis (MS) patients antibodies against myelin antigens seem to be important in the demyelinating process. In this study we investigated IgM, IgA and IgG serum antibodies against the myelin oligodendrocyte glycoprotein (MOG) and the myelin basic protein (MBP) in 261 MS patients. Seventy-two per cent had anti-MOG antibodies, 59% were anti-MBP seropositive. The dominating antibody was anti-MOG IgM. A significant relationship between IgA and a progressive disease course was found. The predominance of IgGI together with the significantly associated occurrence of IgG3 against MOG corresponds to the prevailing IgGI and IgG3 isotypes in other autoimmune diseases. Patients who actually suffered from a relapse were significant more often anti-MOG and anti-MBP IgG3 seropositive than those in remission. However, patients treated either with intravenous immunoglobulins or interferon-beta showed a significant reduction of anti-MOG IgG3 antibodies.

T- and B-cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis.

The identification of myelin oligodendrocyte glycoprotein (MOG) as a target for autoantibody-mediated demyelination in experimental autoimmune encephalomyelitis (EAE) resulted in the re-evaluation of the role of B cell responses to myelin autoantigens in the immunopathogenesis of multiple sclerosis. MOG is a central nervous system specific myelin glycoprotein that is expressed preferentially on the outermost surface of the myelin sheath. Although MOG is only a minor component of CNS myelin it is highly immunogenic, inducing severe EAE in both rodents and primates. In rat and marmoset models of MOG-induced EAE demyelination is antibody-dependent and reproduces the immunopathology seen in many cases of MS. In contrast, in mice inflammation in the CNS can result in demyelination in the absence of a MOG-specific B cell response, although if present this will enhance disease severity and demyelination. Clinical studies indicate that autoimmune responses to MOG are enhanced in many CNS diseases and implicate MOG-specific B cell responses in the immunopathogenesis of multiple sclerosis. This review provides a summary of our current understanding of MOG as a target autoantigen in EAE and MS, and addresses the crucial question as to how immune tolerance to MOG may be maintained in the healthy individual.

Serum autoantibody responses to myelin oligodendrocyte glycoprotein and myelin basic protein in X-linked adrenoleukodystrophy and multiple sclerosis.

We analyzed the sera of 51 patients with various phenotypes of X-linked adrenoleukodystrophy (X-ALD), 20 patients with multiple sclerosis (MS) and 22 healthy volunteers for the presence of autoantibodies specific for the recombinant extracellular immunoglobulin-like domain of human myelin oligodendrocyte glycoprotein (rhMOG(Igd)) and myelin basic protein (MBP). Anti-rhMOG(Igd) autoantibodies were significantly more frequent in X-ALD and MS patients as opposed to healthy individuals (p<0.05). Anti-MBP autoantibodies were present in about one-fourth of X-ALD and MS patients but in less than 10% of healthy individuals. Anti-rhMOG(Igd) autoantibody responses were not accompanied by increased T cell reactivity against rhMOG(Igd). These findings may have important implications for the understanding of humoral anti-myelin immunoreactivity in demyelinating diseases of the central nervous system such as X-ALD and MS.

Disease progression in chronic relapsing experimental allergic encephalomyelitis is associated with reduced inflammation-driven production of corticosterone.

In this study, we demonstrate that disruption of neuroendocrine signaling is a major factor driving disease progression in myelin oligodendrocyte glycoprotein-induced chronic relapsing experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Although the initial episode of chronic relapsing experimental autoimmune encephalomyelitis is associated with a robust hypothalamic-pituitary-adrenocortical axis response, we show that subsequent disease progression is associated with a selective desensitization of hypothalamic-pituitary-adrenocortical responsiveness to inflammatory mediators. Inflammatory activity in the central nervous system during relapse is therefore unable to produce an endogenous immunosuppressive corticosterone response, and disease progresses into an ultimately lethal phase. However, disease progression is inhibited if the circulating corticosterone level is maintained at levels seen during the initial phase of disease. The effect of hypothalamic-pituitary-adrenocortical axis desensitization on the clinical course of experimental autoimmune encephalomyelitis is aggravated by a marked reduction in proinflammatory cytokine synthesis in the central nervous system in the later stages of disease, reflecting an increasing involvement of antibody, rather than T cell-dependent effector mechanisms, in disease pathogenesis, with time. Thus, our data indicate that distinct immune-endocrine effects play a decisive role in determining disease progression in multiple sclerosis, a concept supported by reports that a subpopulation of multiple sclerosis patients shows evidence of hypothalamic-pituitary-adrenocortical axis desensitization.

Genetic linkage analysis of the antibody responses to myelin basic protein and myelin oligodendrocyte glycoprotein in rats immunized with rat spinal cord homogenate.

The genetic control of the antibody response to myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) was analysed in F1 and F2 crosses of DA and E3 rats, immunized with rat spinal chord homogenate. The DA rats were highly susceptible to encephalomyelitis and made antibody responses to both MBP and MOG, whereas the E3 rats were disease-resistant and responded only to MOG. The anti-MBP response was mainly controlled by the disease-promoting MHC region of the DA strain together with several disease loci outside MHC. In contrast, the anti-MOG response was associated with loci not related to or actually conferring resistance to disease.

MHC class II-regulated central nervous system autoaggression and T cell responses in peripheral lymphoid tissues are dissociated in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis.

We dissected the requirements for disease induction of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis in MHC (RT1 in rat) congenic rats with overlapping MOG peptides. Immunodominance with regard to peptide-specific T cell responses was purely MHC class II dependent, varied between different MHC haplotypes, and was linked to encephalitogenicity only in RT1.B(a)/D(a) rats. Peptides derived from the MOG sequence 91-114 were able to induce overt clinical signs of disease accompanied by demyelinated CNS lesions in the RT1.B(a)/D(a) and RT1(n) haplotypes. Notably, there was no detectable T cell response against this encephalitogenic MOG sequence in the RT1(n) haplotype in peripheral lymphoid tissue. However, CNS-infiltrating lymphoid cells displayed high IFN-gamma, TNF-alpha, and IL-4 mRNA expression suggesting a localization of peptide-specific reactivated T cells in this compartment. Despite the presence of MOG-specific T and B cell responses, no disease could be induced in resistant RT1(l) and RT1(u) haplotypes. Comparison of the number of different MOG peptides binding to MHC class II molecules from the different RT1 haplotypes suggested that susceptibility to MOG-experimental autoimmune encephalomyelitis correlated with promiscuous peptide binding to RT1.B and RT1.D molecules. This may suggest possibilities for a broader repertoire of peptide-specific T cells to participate in disease induction. We demonstrate a powerful MHC class II regulation of autoaggression in which MHC class II peptide binding and peripheral T cell immunodominance fail to predict autoantigenic peptides relevant for an autoaggressive response. Instead, target organ responses may be decisive and should be further explored.

Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis.

Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are immune-mediated diseases of the CNS. They are characterized by widespread inflammation, demyelination and a variable degree of axonal loss. Recent magnetic resonance spectroscopy studies have indicated that axonal damage and loss are a reliable correlate of permanent clinical disability. Accordingly, neuropathological studies have confirmed the presence and timing of axonal injury in multiple sclerosis lesions. The mechanisms of axonal degeneration, however, are unclear. Since calcium influx may mediate axonal damage, we have studied the distribution of the pore-forming subunit of neuronal (N)-type voltage-gated calcium channels in the lesions of multiple sclerosis and EAE. We found that alpha(1B), the pore-forming subunit of N-type calcium channels, was accumulated within axons and axonal spheroids of actively demyelinating lesions. The axonal staining pattern of alpha(1B) was comparable with that of beta-amyloid precursor protein, which is an early and sensitive marker for disturbance of axonal transport. Importantly, within these injured axons, alpha(1B) was not only accumulated, but also integrated in the axoplasmic membrane, as shown by immune electron microscopy on the EAE material. This ectopic distribution of calcium channels in the axonal membrane may result in increased calcium influx, contributing to axonal degeneration, possibly via the activation of neutral proteases. Our data suggest that calcium influx through voltage-dependent calcium channels is one possible candidate mechanism for axonal degeneration in inflammatory demyelinating disorders.

The fine specificity of the myelin oligodendrocyte glycoprotein autoantibody response in patients with multiple sclerosis and normal healthy controls.

Antibodies directed against the extracellular immunoglobulin (Ig)-like domain of the myelin oligodendrocyte glycoprotein (MOG(Igd)) mediate demyelination in experimental autoimmune encephalomyelitis (EAE) and are implicated in the immunopathogenesis of multiple sclerosis (MS). In this study we investigated the epitope specificity of MOG(Igd)-specific autoantibodies immunopurified from MS patients (n=17) and normal healthy controls (HD; n=9). ELISA, using a panel of synthetic MOG(Igd) peptides, revealed that the epitope specificity of this response was heterogeneous in both groups. The most frequently recognised epitopes were located in amino acid sequences (a.a.) 1-26 (13/17) and 63-87 (15/17) in MS patients, and 14-39 (6/9) and 63-87 (6/9) in HDs, but there was no association between MS and any particular peptide specificity. We therefore investigated the ability of the immunopurified antibodies to recognise native MOG(Igd) expressed on at the membrane surface by FACS. Unexpectedly, antibodies fulfilling this essential criterion for a demyelinating antibody response were detected only in one of the MS samples. These results indicate that the epitope specificity of the human B cell response to MOG is not only heterogeneous, but may only mediate demyelination in a limited subset of MS patients.

Analysis of interleukin-4 receptor alpha chain variants in multiple sclerosis.

A recent candidate gene study employing microsatellite markers suggested a possible linkage of multiple sclerosis (MS) with the interleukin-4 receptor (IL4R) gene. Consequently, we investigated the association of different IL4R variants with MS in 341 German MS patients and 305 healthy controls. Analysis of the first 100 MS patients for six IL4R variants showed an increased frequency of the R551 variant in MS patients versus healthy controls and carriage of the same IL4R variant was weakly associated with myelin oligodendrocyte glycoprotein (MOG) autoantibody production. However, further analysis of all 341 MS patients did not confirm the finding that this IL4R variant represents a general genetic risk factor for MS but revealed an increased frequency of the R551 variant in MS patients with primary progressive MS (PPMS, n=48) as compared to patients with relapsing remitting MS or secondary progressive MS (RR/SPMS n=284; P=0.005 for genotype differences) and to 305 healthy controls (P=0.001 for genotype differences). This association was statistically independent of the presence of the well-known MS susceptibility allele HLA-DRB1*15. After correction for multiple comparisons only the genotype differences between PPMS patients and healthy controls remained statistically significant. These results indicate, that the IL4R variant R551 may influence the genetic predisposition for PPMS but does not represent a general genetic risk factor for MS.

The myelin oligodendrocyte glycoprotein (MOG): a model for antibody-mediated demyelination in experimental autoimmune encephalomyelitis and multiple sclerosis.

The myelin oligodendrocyte glycoprotein (MOG) is a major target for autoantibody mediated demyelination in experimental autoimmune encephalomyelitis (EAE). In the current review we discuss the epitope specificity of this antibody response, in particular evidence suggesting that pathogenic anti-MOG antibodies are preferentially directed against conformation-dependent epitopes present on the extracellular immunoglobulin domain of the protein. Surprisingly, recent data suggest that this autoimmune response is in part regulated by polymorphisms in the MOG gene itself, an observation that may have important implications for the genetic and immunological stratification of patients with multiple sclerosis.

Butyrophilin, a milk protein, modulates the encephalitogenic T cell response to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) induced by sensitization with myelin oligodendrocyte glycoprotein (MOG) is a T cell-dependent autoimmune disease that reproduces the inflammatory demyelinating pathology of multiple sclerosis. We report that an encephalitogenic T cell response to MOG can be either induced or alternatively suppressed as a consequence of immunological cross-reactivity, or "molecular mimicry" with the extracellular IgV-like domain of the milk protein butyrophilin (BTN). In the Dark Agouti rat, active immunization with native BTN triggers an inflammatory response in the CNS characterized by the formation of scattered meningeal and perivascular infiltrates of T cells and macrophages. We demonstrate that this pathology is mediated by a MHC class II-restricted T cell response that cross-reacts with the MOG peptide sequence 76-87, I GEG KVA LRIQ N (identities underlined). Conversely, molecular mimicry with BTN can be exploited to suppress disease activity in MOG-induced EAE. We demonstrate that not only is EAE mediated by the adoptive transfer of MOG74-90 T cell lines markedly ameliorated by i.v. treatment with the homologous BTN peptide, BTN74-90, but that this protective effect is also seen in actively induced disease following transmucosal (intranasal) administration of the peptide. These results identify a mechanism by which the consumption of milk products may modulate the pathogenic autoimmune response to MOG.

Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions.

Recent magnetic resonance (MR) studies of multiple sclerosis lesions indicate that axonal injury is a major correlate of permanent clinical deficit. In the present study we systematically quantified acute axonal injury, defined by immunoreactivity for beta-amyloid-precursor-protein in dystrophic neurites, in the central nervous system of 22 multiple sclerosis patients and 18 rats with myelin-oligodendrocyte glycoprotein (MOG)-induced chronic autoimmune encephalomyelitis (EAE). The highest incidence of acute axonal injury was found during active demyelination, which was associated with axonal damage in periplaque and in the normal appearing white matter of actively demyelinating cases. In addition, low but significant axonal injury was also observed in inactive demyelinated plaques. In contrast, no significant axonal damage was found in remyelinated shadow plaques. The patterns of axonal pathology in chronic active EAE were qualitatively and quantitatively similar to those found in multiple sclerosis. Our studies confirm previous observations of axonal destruction in multiple sclerosis lesions during active demyelination, but also indicate that ongoing axonal damage in inactive lesions may significantly contribute to the clinical progression of the disease. The results further emphasize that MOG-induced EAE may serve as a suitable model for testing axon-protective therapies in inflammatory demyelinating conditions.

Myelin oligodendrocyte glycoprotein-DNA vaccination induces antibody-mediated autoaggression in experimental autoimmune encephalomyelitis.

One strategy to reestablish self tolerance in autoimmune diseases is based on the use of DNA vaccination to induce ectopic expression of the target autoantigen. We assessed the potential of vaccination with a DNA construct encoding the myelin oligodendrocyte glycoprotein (MOG), an important candidate autoantigen in multiple sclerosis, to induce tolerance and protect against experimental autoimmune encephalomyelitis (EAE). Unexpectedly, mice vaccinated with MOG-DNA developed an exacerbated form of EAE when challenged with either MOG or an unrelated encephalitogen, myelin proteolipid protein. We demonstrate that this is due to the inability of DNA vaccination to tolerize the MOG-specific T cell response and to the concomitant induction of a cytopathic MOG-specific autoantibody response, which is pathogenic, enhancing demyelination, inflammation and disease severity. Our data suggest that tolerogenic strategies for autoimmune diseases based on DNA vaccination should be approached with caution, as the outcome is unpredictable.

Linkage analysis of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in the rat identifies a locus controlling demyelination on chromosome 18.

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) with a complex etiology comprising a genetically determined predisposition and a suspected auto- immune pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an animal model for MS, which can be used to define susceptibility loci for autoimmune neuroinflammation. We have recently established a chronic relapsing EAE model characterized by inflammation and focal demyelination in the CNS by immunizing a variety of rat strains with the CNS-specific myelin oligodendrocyte glycoprotein (MOG). This model is more MS-like than any other rodent EAE model described up to now. Here we present the first systematic genome search for chromosomal regions linked to phenotypes of MOG-induced EAE in a (DA x ACI) F(2)intercross. A genome-wide significant susceptibility locus linked to demyelination was identified on chromosome 18. This region has not been described in inflammatory diseases affecting other organs and the responsible gene or genes may thus be nervous system specific. Other chromosomal regions showing suggestive linkage to phenotypes of MOG-induced EAE were identified on chromosomes 10, 12 and 13. The chromosome 10 and 12 regions have previously been linked to arthritis in DA rats, suggesting that they harbour immunoregulatory genes controlling general susceptibility to autoimmune diseases. We conclude that identification of susceptibility genes for MOG-induced EAE on rat chromosomes 10, 12, 13 and 18 may disclose important disease pathways for chronic inflammatory demyelinating diseases of the CNS such as MS.

Antibodies against the myelin oligodendrocyte glycoprotein and the myelin basic protein in multiple sclerosis and other neurological diseases: a comparative study.

In experimental animal models of multiple sclerosis demyelinating antibody responses are directed against the myelin oligodendrocyte glycoprotein (MOG). We have investigated whether a similar antibody response is also present in multiple sclerosis patients. Using the recombinant human extracellular immunoglobulin domain of MOG (MOG-Ig) we have screened the sera and CSFs of 130 multiple sclerosis patients, 32 patients with other inflammatory neurological diseases (OIND), 30 patients with other non-inflammatory neurological diseases (ONND) and 10 patients with rheumatoid arthritis. We report that 38% of multiple sclerosis patients are seropositive for IgG antibodies to MOG-Ig compared with 28% seropositive for anti-myelin basic protein (MBP). In contrast, OIND are characterized by similar frequencies of serum IgG antibody responses to MOG-Ig (53%) and MBP (47%), whereas serum IgG responses to MOG-Ig are rare in ONND (3%) and rheumatoid arthritis (10%). Anti-MBP IgG antibodies, however, are a frequent finding in ONND (23%) and rheumatoid arthritis (60%). Our results provide clear evidence that anti-MOG-Ig antibodies are common in CNS inflammation. However, in OIND these antibody responses are transient, whereas they persist in multiple sclerosis. We demonstrate that the serum anti-MOG-Ig response is already established in early multiple sclerosis (multiple sclerosis-R0; 36%). In later multiple sclerosis stages frequencies and titres are comparable with early multiple sclerosis. In contrast, the frequency of anti-MBP antibodies is low in multiple sclerosis-R0 (12%) and increases during disease progression in relapsing-remitting (32%) and chronic progressive multiple sclerosis (40%), thus suggesting that anti-MBP responses accumulate over time. Finally we provide evidence for intrathecal synthesis of IgG antibodies to MOG-Ig in multiple sclerosis.

Multiple sclerosis: B- and T-cell responses to the extracellular domain of the myelin oligodendrocyte glycoprotein.

We report a comparative study of the B- and T-cell responses to the extracellular immunoglobulin (Ig)-like domain of human myelin-oligodendrocyte glycoprotein (MOG(Igd)) in the blood of patients with multiple sclerosis and healthy controls using a bacterial recombinant human protein (rhMOG(Igd)). The frequency of anti-rhMOG(Igd)-seropositive samples, as determined by Western blotting, was significantly higher in the multiple sclerosis group (54%) than in normal random controls (excluding laboratory workers exposed to MOG) (22%; P = 0.02). In contrast, there was no difference in rhMOG(Igd)-induced proliferation indices of peripheral blood T cells between patients and controls. To characterize the rhMOG(Igd)-reactive T-cell repertoire, we isolated a panel of MOG-specific CD4(+) T-cell lines from multiple sclerosis patients and normal subjects, and these revealed a heterogeneous response with respect to epitope specificity, cytokine response, MHC (major histocompatibility complex) restriction and T-cell receptor Vbeta-chain usage. The majority of the T-cell lines recognized epitopes in the N-terminal region of MOG (amino acids 1-60). One epitope (represented by peptide 27-50) was exclusively recognized by T-cell lines from normal controls. Forty per cent of the MOG-specific T-cell lines analysed displayed a Th-2 or Th-0 cytokine profile and could therefore act as helper T cells in vivo.

Susceptibility and resistance to experimental allergic encephalomyelitis: relationship with hypothalamic-pituitary-adrenocortical axis responsiveness in the rat.

Susceptibility to experimental allergic encephalomyelitis (EAE) may be influenced by variations in the production of endogenous glucocorticoids. We investigated whether this concept is consistent across different genotypes and paradigms of EAE. In the major histocompatibility complex-disparate rat strains, Lewis (LEW), Brown Norway (BN), and Dark Agouti (DA), inflammatory and inflammatory-demyelinating variants of EAE were induced by immunization with myelin basic protein and myelin oligodendrocyte glycoprotein, respectively. We analyzed hormone production in EAE and after exposure to novel environment. DA and BN rats showed a robust hypothalamic-pituitary-adrenocortical (HPA) axis response to novelty stress and produced significantly higher ACTH and corticosterone plasma levels compared with LEW rats. However, HPA axis responsiveness was not associated with a generalized resistance to EAE, as both DA and LEW rats were susceptible to myelin basic protein-induced EAE. Moreover, both robust HPA responder strains, DA and the EAE-resistant BN rat, were highly susceptible to myelin oligodendrocyte glycoprotein-induced EAE. In animals of all strains, clinical disease was associated with significantly elevated plasma levels of corticosterone, and no differences in brain glucocorticoid-binding receptors were detected. Therefore, HPA axis characteristics are not a predictor of disease susceptibility in EAE.

Epitope specificity of demyelinating monoclonal autoantibodies directed against the human myelin oligodendrocyte glycoprotein (MOG).

We describe the epitope specificity of a panel of ten demyelinating monoclonal antibodies (mAb) that recognise the extracellular immunoglobulin-like domain of human myelin oligodendrocyte glycoprotein (hMOG(lgd)). All the mAbs bind to the surface of MOG-transfected fibroblasts as assessed in vitro by FACS and immunocytochemistry but failed to recognise overlapping 15-mer MOG peptides when assessed by ELISA. However, increasing peptide length to 25 amino acids revealed that four mAbs recognised epitopes within the amino acid sequence 63-100 of human MOG. In contrast, a non-demyelinating MOG-specific mAb recognised MOG by both ELISA and Western blotting but failed to stain MOG transfected fibroblasts. These observations suggest that assays based on the use of MOG-transfected cell lines will differentiate between pathogenic and non-pathogenic MOG-specific antibody responses in experimental models and human diseases of the nervous system.