Conformational epitopes of myelin oligodendrocyte glycoprotein are targets of potentially pathogenic antibody responses in multiple sclerosis.

Background: Myelin/oligodendrocyte glycoprotein (MOG) is a putative autoantigen in multiple sclerosis (MS). Establishing the pathological relevance and validity of anti-MOG antibodies as biomarkers has yielded conflicting reports mainly due to different MOG isoforms used in different studies. Because epitope specificity may be a key factor determining anti-MOG reactivity we aimed at identifying a priori immunodominant MOG epitopes by monoclonal antibodies (mAbs) and at assessing clinical relevance of these epitopes in MS.

Transient increases in anti-aquaporin-4 antibody titers following rituximab treatment in neuromyelitis optica, in association with elevated serum BAFF levels.

Rituximab is increasingly used for prevention of relapses of neuromyelitis optica (NMO), a condition that is highly associated with serum anti-aquaporin-4 (AQP4) antibodies. However, B-cell depletion also induces systemic B-cell activating factor (BAFF), which may promote antibody production. We collected serial serum samples from a total of seven patients with NMO prior to, and following, treatment with rituximab.

Relevant antibody subsets against MOG recognize conformational epitopes exclusively exposed in solid-phase ELISA.

A pathogenic role for circulating anti-myelin antibodies is difficult to establish in multiple sclerosis (MS). Here, we unravel a broad heterogeneity within the anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in humans and non-human primates, and demonstrate that detection of important epitopes of MOG within the pathogenic repertoire is exclusively dependent on presentation on a solid-phase MOG conformer. Results of ELISA and those of a liquid-phase assay were compared using a MOG protein with identical sequence but different conformations.

Apoptotic effects of Human Herpesvirus-6A on glia and neurons as potential triggers for central nervous system autoimmunity.

Background: Human Herpesvirus type 6 (HHV-6A and/or HHV-6B) has been tentatively associated with multiple sclerosis (MS). However, there is currently no direct proof of pathogenicity.

Objectives: To determine whether exposure to HHV-6 variants is capable of inducing programmed cell death (apoptosis) in representative cell types of the central nervous system (CNS).

Complex alternative splicing of the myelin oligodendrocyte glycoprotein gene is unique to human and non-human primates.

Myelin/oligodendrocyte glycoprotein (MOG) is a minor integral membrane protein specific to CNS myelin, encoded by a gene located in the major histocompatibility complex. MOG is an highly encephalitogenic autoantigen and a target for autoaggressive immune responses in CNS inflammatory demyelinating diseases. We performed transcriptomic analyses for a gene expressed only in mammalian CNS, myelin oligodendrocyte glycoprotein (MOG).

Restrictive and diversifying elements of the anti-myelin/oligodendrocyte glycoprotein antibody response in primate experimental allergic encephalomyelitis.

Autoantibody responses against conformational epitopes of myelin/oligodendrocyte glycoprotein (MOG) possess myelin destructive potential, as demonstrated in the marmoset model of human multiple sclerosis (MS) and in some rodent models of experimental allergic encephalomyelitis. We have previously characterized monoclonal Fab fragments specific for conformational epitopes of MOG that were derived from a combinatorial antibody library generated from a MOG-immune marmoset. In this paper, we address the molecular heterogeneity of humoral responses against MOG in this outbred model of MS by studying additional antibody clones derived from a genetically unrelated animal.

Antibodies to native myelin oligodendrocyte glycoprotein are serologic markers of early inflammation in multiple sclerosis.

Myelin oligodendrocyte glycoprotein (MOG) is an integral membrane protein expressed in CNS oligodendrocytes and outermost myelin lamellae. Anti-MOG Abs cause myelin destruction (demyelination) in animal models of multiple sclerosis (MS); however, such pathogenic Abs have not yet been characterized in humans. Here, a method that specifically detects IgG binding to human MOG in its native, membrane-embedded conformation on MOG-transfected mammalian cells was used to evaluate the significance of these auto Abs.

Antibody responses against galactocerebroside are potential stage-specific biomarkers in multiple sclerosis.

Background: Galactocerebroside, the major glycolipid of central nervous system myelin, is a known target for pathogenic demyelinating antibody responses in experimental allergic encephalomyelitis (EAE), the animal model of multiple sclerosis (MS).

Objective: To address the importance of anti-galactocerebroside (alpha-GalC) antibodies in MS and to evaluate them as biomarkers of disease.

Methods: alpha-GalC IgGs were quantified from sera of patients with MS and in marmoset EAE by a new immunosorbent assay.

Eight-year immunogenicity and safety of interferon beta-1a-Avonex treatment in patients with multiple sclerosis.

An open-label extension study of the phase III trial of intramuscular interferon beta-1a (IFNbeta-1a-Avonex) was conducted to evaluate the immunogenicity and safety of IFNbeta-1a-Avonex over six years in patients with relapsing multiple sclerosis (MS). Patients who participated in the pivotal phase III study were offered enrolment; entry was also open to patients who had not participated. All patients received IFNbeta-1a-Avonex 30 microg intramuscularly once weekly for six years, for a treatment duration of up to eight years in patients who received IFNbeta-1a-Avonex in the phase III trial.

Poly(ADP-ribose) polymerase-1 activation in a primate model of multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated disabling neurological disorder involving inflammation, demyelination, axonal damage, and neurodegeneration. Poly(ADP-ribose)polymerase-1 (PARP-1), a nuclear enzyme linked to DNA repair, has been shown to regulate the cellular inflammatory response through interactions with nuclear factor-kappaB. Extensive PARP-1 activation can, by separate mechanisms, also cause cell death.

An open label study of the effects of rituximab in neuromyelitis optica.

Eight patients with worsening neuromyelitis optica were treated with rituximab to achieve B cell depletion. Treatment was well tolerated. Six of eight patients were relapse free and median attack rate declined from 2.

The unique impact of changes in normal appearing brain tissue on cognitive dysfunction in secondary progressive multiple sclerosis patients.

Objective: The purpose of this study was to examine the relationships between cognitive functioning, whole brain magnetic transfer ratio (MTR) imaging, supratentorial 1H-magnetic resonance spectroscopy imaging (1HMRSI), and conventional T1 and T2 imaging in a homogenous sample of SPMS patients.

Methods: Nineteen patients underwent a single 90-min imaging session that obtained T1-and T2-weighted images and MTR. 1HMRSI was obtained on 14 of these patients.

Social support as a buffer in the relationship between treatment for depression and T-cell production of interferon gamma in patients with multiple sclerosis.

Objective: This study examined the buffering effects of social support on the relationship between depression and autoaggressive immune function in multiple sclerosis (MS).

Methods: Fourteen participants with comorbid diagnoses of MS and major depressive disorder received 16 weeks of psychotherapy or antidepressant medications. Depression and T-cell production of interferon-gamma (IFN-gamma), a lynchpin in MS pathogenesis, were assessed at baseline and posttreatment.

Synergistic interactions of lipids and myelin basic protein.

This report describes force measurements and atomic force microscope imaging of lipid-protein interactions that determine the structure of a model membrane system that closely mimics the myelin sheath. Our results suggest that noncovalent, mainly electrostatic and hydrophobic, interactions are responsible for the multilamellar structure and stability of myelin. We find that myelin basic protein acts as a lipid coupler between two apposed bilayers and as a lipid "hole-filler," effectively preventing defect holes from developing.

Mechanisms of normal appearing corpus callosum injury related to pericallosal T1 lesions in multiple sclerosis using directional diffusion tensor and 1H MRS imaging.

Objectives: To investigate the extent of tissue damage in a region of normal appearing corpus callosum (NACC) for different forms of multiple sclerosis (MS) using diffusion tensor and proton magnetic resonance (MR) spectroscopic imaging.

Methods: A total of 47 patients with MS and 15 controls were included. Regions of interest from the NACC were manually segmented using high resolution anatomical images.

Frontline: Epitope recognition on the myelin/oligodendrocyte glycoprotein differentially influences disease phenotype and antibody effector functions in autoimmune demyelination.

Preliminary observations of humoral immunity against the myelin oligodendrocyte glycoprotein (MOG) in experimental allergic encephalomyelitis (EAE) and human multiple sclerosis (MS) suggest that a subset of anti-MOG autoantibodies directed against conformational epitopes is of pathogenic predominance. Here, we provide proof that in marmoset EAE, autoantibodies reactive against conformational epitopes of MOG are not only responsible for aggravating demyelination, but also an essential factor for disease dissemination in space within the central nervous system, a hallmark for typical forms of human MS. In terms of effector mechanisms, IgG deposition and complement activation occur exclusively in association with presence of these conformational antibodies, while microglial/macrophage activation appears to be a common immunopathological finding regardless of the fine determinant specificity of anti-MOG antibodies.

Role of lipid interactions in autoimmune demyelination.

A morphological transformation involving loss of adhesion between myelin lamellae and formation of myelin vesicles has been described as a mechanism for demyelination in multiple sclerosis and marmoset experimental allergic encephalomyelitis (EAE). Although protein interactions are involved in maintaining normal myelin structure, we describe here how lipids contribute to myelin stability and how lipid changes in EAE, including increases in lipid polyunsaturation and negatively charged phosphatidylserine (PS), promote demyelination. Three physico-chemical techniques were used to identify these changes: (1) Langmuir monolayer isotherms indicated that EAE white matter lipids were significantly more "expanded" (fluid) than controls.

Role of nerve growth factor and other trophic factors in brain inflammation.

Inflammation in the brain is a double-edged process that may be beneficial in promoting homeostasis and repair, but can also result in tissue injury through the damaging potential of inflammatory mediators. Thus, control mechanisms that minimize the extent of the inflammatory reaction are necessary in order to help preserve brain architecture and restore function. The expression of neurotrophic factors such as nerve growth factor (NGF) is increased after brain injury, in part mediated by effects on astrocytes of pro-inflammatory mediators and cytokines produced by immune cells.

Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis.

The diversity of autoimmune responses poses a formidable challenge to the development of antigen-specific tolerizing therapy. We developed 'myelin proteome' microarrays to profile the evolution of autoantibody responses in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). Increased diversity of autoantibody responses in acute EAE predicted a more severe clinical course.

Approved and future pharmacotherapy for multiple sclerosis.

Background: Pharmacotherapy for relapsing-remitting multiple sclerosis (MS) advanced with the demonstration that interferon beta and glatiramer acetate improve the clinical course of this disease. Mitoxantrone is the first drug approved by the Food and Drug Administration for treatment of secondary progressive MS. Despite this progress, the agents presently available are only partially effective, are difficult to administer, and may have significant side effects.

3-D echo planar (1)HMRS imaging in MS: metabolite comparison from supratentorial vs. central brain.

Unlabelled: To determine if metabolite ratios as measured by 3-dimensional echo planar spectroscopy imaging (3D-EPSI) from central brain regions of interest (ROI) centered at the corpus callosum reflect imaging metrics of large volumes of supratentorial brain (STB) from patients with multiple sclerosis.

Methods: 48 MS patients with relapsing-remitting, secondary progressive, and primary progressive disease underwent a 3D-EPSI sequence covering large volumes of STB. Metabolite ratios were first estimated from all voxels within a STB mask using a linear regression of N-acetylaspartate (NAA) over Creatine (Cr), NAA over choline (Cho) and Cho over Cr.

Molecular characterization of antibody specificities against myelin/oligodendrocyte glycoprotein in autoimmune demyelination.

Myelin/oligodendrocyte glycoprotein (MOG) is a target antigen for myelin-destructive Abs in autoimmune central nervous system demyelinating disorders. Little is known about the molecular and structural basis of these pathogenic Ab responses. Here, we have characterized anti-MOG Ab specificities in the marmoset model of experimental allergic encephalomyelitis, by means of a combinatorial IgG-Fab library.

The human T cell response to myelin oligodendrocyte glycoprotein: a multiple sclerosis family-based study.

Myelin oligodendrocyte glycoprotein (MOG) is an encephalitogenic myelin protein and a likely autoantigen in human multiple sclerosis (MS). In this work, we describe the fine specificity and cytokine profile of T cell clones (TCC) directed against MOG in three nuclear families, comprised of four individuals affected with MS and their HLA-identical siblings. TCC were generated from PBMC by limiting dilution against a mixture of eleven 20-mer overlapping peptides corresponding to the encephalitogenic extracellular domain of human MOG (aa 1-120).

Activity of a newly identified serine protease in CNS demyelination.

We have identified a novel serine protease, myelencephalon-specific protease (MSP), which is preferentially expressed in the adult CNS, and therein, is abundant in both neurones and oligodendroglia. To determine the potential activity of MSP in CNS demyelination, we examined its expression in multiple sclerosis lesions and in two animal models of multiple sclerosis: Theiler's murine encephalomyelitis virus (TMEV) and myelin oligodendrocyte glycoprotein (MOG)-induced experimental allergic encephalomyelitis (EAE) in marmosets. High levels of MSP were present within infiltrating mononuclear cells, including macrophages and T cells, which characteristically fill sites of demyelination, both in multiple sclerosis lesions and in animal models of this disease.