Epitope Analysis of Cerebrospinal Fluid IgG in Japanese Multiple Sclerosis Patients Using Phage Display Method

To investigate the antigen recognized by cerebrospinal fluid (CSF) high affinity IgG in patients with multiple sclerosis (MS), the phage display method was applied to the CSF from 15 MS and 10 control patients. Peptide sequences recognized by MS and control CSF IgG were individual specific, and no common motif was found. Peptide sequences frequently showed homology to various kinds of amino acid sequences of ubiquitous viruses such as epstein barr virus (EBV) and herpes simplex virus (HSV), although the frequency was not specific to MS patients. MS CSF IgG may recognize various types of ubiquitous viral antigen and may be increased by a bystander response

Pathology of myelin oligodendrocyte glycoprotein antibody-associated disease: a comparison with multiple sclerosis and aquaporin 4 antibody-positive neuromyelitis optica spectrum disorders

Myelin oligodendrocyte glycoprotein (MOG) is expressed on the outermost layer of the myelin sheath in the central nervous system. Recently, the clinical concept of MOG antibody-associated disease (MOGAD) was established based on the results of human MOG-transfected cell-based assays which can detect conformation-sensitive antibodies against MOG. In this review, we summarized the pathological findings of MOGAD and discussed the issues that remain unresolved. MOGAD pathology is principally inflammatory demyelination without astrocyte destruction, characterized by perivenous demyelination previously reported in acute disseminated encephalomyelitis and by its fusion pattern localized in both the white and gray matter, but not by radially expanding confluent demyelination typically seen in multiple sclerosis (MS). Some of demyelinating lesions in MOGAD show severe loss of MOG staining compared with those of other myelin proteins, suggesting a MOG-targeted pathology in the disease. Perivascular cuffings mainly consist of macrophages and T cells with CD4-dominancy, which is also different from CD8+ T-cell-dominant inflammation in MS. Compared to aquaporin 4 (AQP4) antibody-positive neuromyelitis optica spectrum disorders (NMOSD), perivenous complement deposition is less common, but can be seen on myelinated fibers and on myelin degradation products within macrophages, resembling MS Pattern II pathology. Thus, the pathogenetic contribution of complements in MOGAD is still debatable. Together, these pathological features in MOGAD are clearly different from those of MS and AQP4 antibody-positive NMOSD, suggesting that MOGAD is an independent autoimmune demyelinating disease entity. Further research is needed to clarify the exact pathomechanisms of demyelination and how the pathophysiology relates to the clinical phenotype and symptoms leading to disability in MOGAD patients

Intrastriatal injection of interleukin-1 beta triggers the formation of neuromyelitis optica-like lesions in NMO-IgG seropositive rats

BACKGROUND: Neuromyelitis optica (NMO) is a severe, disabling disease of the central nervous system (CNS) characterized by the formation of astrocyte-destructive, neutrophil-dominated inflammatory lesions in the spinal cord and optic nerves. These lesions are initiated by the binding of pathogenic aquaporin 4 (AQP4)-specific autoantibodies to astrocytes and subsequent complement-mediated lysis of these cells. Typically, these lesions form in a setting of CNS inflammation, where the blood–brain barrier is open for the entry of antibodies and complement. However, it remained unclear to which extent pro-inflammatory cytokines and chemokines contribute to the formation of NMO lesions. To specifically address this question, we injected the cytokines interleukin-1 beta, tumor necrosis factor alpha, interleukin-6, interferon gamma and the chemokine CXCL2 into the striatum of NMO-IgG seropositive rats and analyzed the tissue 24 hours later by immunohistochemistry. RESULTS: All injected cytokines and chemokines led to profound leakage of immunoglobulins into the injected hemisphere, but only interleukin-1 beta induced the formation of perivascular, neutrophil-infiltrated lesions with AQP4 loss and complement-mediated astrocyte destruction distant from the needle tract. Treatment of rat brain endothelial cells with interleukin-1 beta, but not with any other cytokine or chemokine applied at the same concentration and over the same period of time, caused profound upregulation of granulocyte-recruiting and supporting molecules. Injection of interleukin-1 beta caused higher numbers of blood vessels with perivascular, cellular C1q reactivity than any other cytokine tested. Finally, the screening of a large sample of CNS lesions from NMO and multiple sclerosis patients revealed large numbers of interleukin-1 beta-reactive macrophages/activated microglial cells in active NMO lesions but not in MS lesions with comparable lesion activity and location. CONCLUSIONS: Our data strongly suggest that interleukin-1 beta released in NMO lesions and interleukin-1 beta-induced production/accumulation of complement factors (like C1q) facilitate neutrophil entry and BBB breakdown in the vicinity of NMO lesions, and might thus be an important secondary factor for lesion formation, possibly by paving the ground for rapid lesion growth and amplified immune cell recruitment to this site

Presence of six different lesion types suggests diverse mechanisms of tissue injury in neuromyelitis optica

Neuromyelitis optica (NMO) is an autoimmune disease targeting aquaporin 4 (AQP4), localized mainly at the astrocytic foot processes. Loss of AQP4 and glial fibrillary acidic protein (GFAP) was reported, but the pathological significance of astrocytopathy is still controversial. Here we show that active lesions in NMO display a wide spectrum of pathology even within a single tissue block of an individual patient. We have distinguished six different lesion types. The first reflects complement deposition at the surface of astrocytes, associated with granulocyte infiltration and astrocyte necrosis and followed by demyelination, global tissue destruction and the formation of cystic, necrotic lesions (lesion type 2). Such destructive lesions lead to Wallerian degeneration in lesion-related tracts (lesion type 3). Around active NMO lesions AQP4 may selectively be lost in the absence of aquaporin 1 (AQP1) loss or other structural damage (lesion type 4). Another pattern is characterized by clasmatodendrosis of astrocytes, defined by cytoplasmic swelling and vacuolation, beading and dissolution of their processes and nuclear alterations resembling apoptosis, which was associated with internalization of AQP4 and AQP1 and astrocyte apoptosis in the absence of complement activation. Such lesions give rise to extensive astrocyte loss, which may occur in part in the absence of any other tissue injury, such as demyelination or axonal degeneration (lesion type 5). Finally, lesions with a variable degree of astrocyte clasmatodendrosis are found, which show plaque-like primary demyelination that is associated with oligodendrocyte apoptosis, but with preservation of axons (lesion type 6). In active multiple sclerosis (MS) lesions astrocytes reveal changes of reactive protoplasmatic or fibrillary gliosis. Only in a subset of lesions, in patients with aggressive disease, loss of AQP4 is observed in the initial stage of their formation, which is associated with retraction of astrocyte processes in the absence of complement deposition, granulocyte infiltration or loss of AQP1 or astrocytes. Our data underline the primary assault of astrocytes in NMO lesions, but also indicate that different mechanisms of tissue injury operate in parallel in the same patient and even within the same lesion. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-013-1116-7) contains supplementary material, which is available to authorized users

Leukoencephalopathy resolution after atypical mycobacterial treatment: a case report

Abstract\ud \ud Background\ud Association of leukoencephalopathy and atypical mycobacteriosis has been rarely reported. We present a case that is relevant for its unusual presentation and because it may shed further light on the pathogenic mechanisms underlying reversible encephalopathies.\ud \ud \ud Case report\ud We report the case of a Hispanic 64-year-old woman with cognitive decline and extensive leukoencephalopathy. Magnetic resonance imaging revealed white-matter lesions with increased water diffusivity, without blood–brain-barrier disruption. Brain biopsy showed tissue rarefaction with vacuolation, mild inflammation, few reactive astrocytes and decreased aquaporin water-channel expression in the lesions. Six months later, she was diagnosed with atypical mycobacterial pulmonary infection. Brain lesions resolved after antimycobacterial treatment.\ud \ud \ud Conclusion\ud We hypothesize leukoencephalopathic changes and vasogenic edema were associated with decreased aquaporin expression. Further studies should clarify if reversible leukoencephalopathy has a causal relationship with decreased aquaporin expression and atypical mycobacterial infection, and mechanisms underlying leukoencephalopathy resolution after antimycobacterial treatment. This article may contribute to the understanding of pathogenic mechanisms underlying magnetic resonance imaging subcortical lesions and edema, which remain incompletely understood.Ministry of Education, Culture, Sports, Science and Technology (MEXT) of JapanHealth and Labor Sciences Research Grant on Intractable Diseases\ud (Neuroimmunological Diseases) from the Ministry of Health, Labor and\ud Welfare of Japa

Clinical and MRI features of Japanese MS patients with NMO-IgG

ABSTRACT Background: NMO-IgG is a disease-specific serum marker autoantibody of neuromyelitis optica (NMO) and may distinguish NMO from multiple sclerosis (MS). NMO-IgG has also been frequently detected in Japanese patients with the optic-spinal form of MS (OSMS) suggesting that NMO and OSMS may be the same entity

Pathogenic T cell responses against aquaporin 4

Inflammatory lesions in the central nervous system of patients with neuromyelitis optica are characterized by infiltration of T cells and deposition of aquaporin-4-specific antibodies and complement on astrocytes at the glia limitans. Although the contribution of aquaporin-4-specific autoantibodies to the disease process has been recently elucidated, a potential role of aquaporin-4-specific T cells in lesion formation is unresolved. To address this issue, we raised aquaporin-4-specific T cell lines in Lewis rats and characterized their pathogenic potential in the presence and absence of aquaporin-4-specific autoantibodies of neuromyelitis optica patients. We show that aquaporin-4-specific T cells induce brain inflammation with particular targeting of the astrocytic glia limitans and permit the entry of pathogenic anti-aquaporin-4-specific antibodies to induce NMO-like lesions in spinal cord and brain. In addition, transfer of aquaporin-4-specific T cells provoked mild (subclinical) myositis and interstitial nephritis. We further show that the expression of the conformational epitope, recognized by NMO patient-derived aquaporin-4-specific antibodies is induced in kidney cells by the pro-inflammatory cytokine gamma-interferon. Our data provide further support for the view that NMO lesions may be induced by a complex interplay of T cell mediated and humoral immune responses against aquaporin-4