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The Role of B Cells and Antibodies in Multiple Sclerosis, Neuromyelitis Optica, and Related Disorders.

ABSTRACT: Our pathophysiological concept of the most common central nervous system demyelinating disease, multiple sclerosis, strikingly evolved by recent discoveries suggesting that B lymphocytes substantially contribute in its initiation and chronic propagation. In this regard, activated B cells are nowadays considered to act as important antigen-presenting cells for the activation of T cells and as essential source of pro-inflammatory cytokines. Hereby, they create a milieu in which other immune cells differentiate and join an orchestrated inflammatory infiltration of the CNS. Without a doubt, this scientific leap was critically pioneered by the empirical use of anti-CD20 antibodies in recent clinical MS trials, which revealed that the therapeutic removal of immature and mature B cells basically halted development of new inflammatory flares in otherwise relapsing MS patients. This stabilization occurred largely independent of any indirect effect on plasma cell-produced antibody levels. On the contrary, peripherally produced autoantibodies are probably the most important B cell component in two other CNS demyelinating diseases which are currently in the process of being delineated as separate disease entities. The first one is neuromyelitis optica in which an antibody response against aquaporin-4 targets and destroys astrocytes, the second, likely distinct entity embraces a group of patients containing antibodies against myelin oligodendrocyte glycoprotein. In this review, we will describe and summarize pro-inflammatory B cell properties in these three CNS demyelinating disorders; we will however also provide an overview on the emerging concept that B cells or B cell subsets may exert immunologically counterbalancing properties, which may be therapeutically desirable to maintain and foster in inflammatory CNS demyelination. In an outlook, we will discuss accordingly, how this potentially important aspect can be harnessed to advance future B cell-directed therapeutic approaches in multiple sclerosis and related diseases.

SUBMITTER: Hausser-Kinzel S

PROVIDER: S-EPMC6375838 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Role of B Cells and Antibodies in Multiple Sclerosis, Neuromyelitis Optica, and Related Disorders.

Häusser-Kinzel Silke S Weber Martin S MS

Frontiers in immunology 20190208

Our pathophysiological concept of the most common central nervous system demyelinating disease, multiple sclerosis, strikingly evolved by recent discoveries suggesting that B lymphocytes substantially contribute in its initiation and chronic propagation. In this regard, activated B cells are nowadays considered to act as important antigen-presenting cells for the activation of T cells and as essential source of pro-inflammatory cytokines. Hereby, they create a milieu in which other immune cells ...[more]

PMID: 30800132

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Project description:BACKGROUND: Serum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved. RESULTS: We analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels. CONCLUSIONS: We could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response.

Project description:BACKGROUND AND PURPOSE:Both clinical and imaging criteria must be met to diagnose neuromyelitis optica spectrum disorders and multiple sclerosis. However, neuromyelitis optica spectrum disorders are often misdiagnosed as MS because of an overlap in MR imaging features. The purpose of this study was to confirm imaging differences between neuromyelitis optica spectrum disorders and MS with visually detailed quantitative analyses of large-sample data. MATERIALS AND METHODS:We retrospectively examined 89 consecutive patients with neuromyelitis optica spectrum disorders (median age, 51 years; range, 16-85 years; females, 77; aquaporin 4 immunoglobulin G-positive, 93%) and 89 with MS (median age, 36 years; range, 18-67 years; females, 68; relapsing-remitting MS, 89%; primary-progressive MS, 7%; secondary-progressive MS, 2%) from 9 institutions across Japan (April 2008 to December 2012). Two neuroradiologists visually evaluated the number, location, and size of all lesions using the Mann-Whitney U test or the Fisher exact test. RESULTS:We enrolled 79 patients with neuromyelitis optica spectrum disorders and 87 with MS for brain analysis, 57 with neuromyelitis optica spectrum disorders and 55 with MS for spinal cord analysis, and 42 with neuromyelitis optica spectrum disorders and 14 with MS for optic nerve analysis. We identified 911 brain lesions in neuromyelitis optica spectrum disorders, 1659 brain lesions in MS, 86 spinal cord lesions in neuromyelitis optica spectrum disorders, and 102 spinal cord lesions in MS. The frequencies of periventricular white matter and deep white matter lesions were 17% and 68% in neuromyelitis optica spectrum disorders versus 41% and 42% in MS, respectively (location of brain lesions, P < .001). We found a significant difference in the distribution of spinal cord lesions between these 2 diseases (P = .024): More thoracic lesions than cervical lesions were present in neuromyelitis optica spectrum disorders (cervical versus thoracic, 29% versus 71%), whereas they were equally distributed in MS (46% versus 54%). Furthermore, thoracic lesions were significantly longer than cervical lesions in neuromyelitis optica spectrum disorders (P = .001), but not in MS (P = .80). CONCLUSIONS:Visually detailed quantitative analyses confirmed imaging differences, especially in brain and spinal cord lesions, between neuromyelitis optica spectrum disorders and MS. These observations may have clinical implications.

Dataset Information

The Role of B Cells and Antibodies in Multiple Sclerosis, Neuromyelitis Optica, and Related Disorders.

Publications

The Role of B Cells and Antibodies in Multiple Sclerosis, Neuromyelitis Optica, and Related Disorders.

Similar Datasets

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