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      Autoantibodies in neurological disease

      review-article
      1 , 2 ,
      Nature Reviews. Immunology
      Nature Publishing Group UK
      Neuroimmunology, Autoimmunity

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          Abstract

          The realization that autoantibodies can contribute to dysfunction of the brain has brought about a paradigm shift in neurological diseases over the past decade, offering up important novel diagnostic and therapeutic opportunities. Detection of specific autoantibodies to neuronal or glial targets has resulted in a better understanding of central nervous system autoimmunity and in the reclassification of some diseases previously thought to result from infectious, ‘idiopathic’ or psychogenic causes. The most prominent examples, such as aquaporin 4 autoantibodies in neuromyelitis optica or NMDAR autoantibodies in encephalitis, have stimulated an entire field of clinical and experimental studies on disease mechanisms and immunological abnormalities. Also, these findings inspired the search for additional autoantibodies, which has been very successful to date and has not yet reached its peak. This Review summarizes this rapid development at a point in time where preclinical studies have started delivering fundamental new data for mechanistic understanding, where new technologies are being introduced into this field, and — most importantly — where the first specifically tailored immunotherapeutic approaches are emerging.

          Abstract

          Here, Harald Prüss discusses how autoantibodies can contribute to neurological diseases. The identification of specific autoantibodies to neuronal and glial targets has increased our understanding of autoimmunity in the central nervous system and led to the reclassification of some diseases previously thought to result from infection or ‘idiopathic’ causes.

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          Most cited references201

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          A clinical approach to diagnosis of autoimmune encephalitis.

          Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders. However, existing criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy, which might delay the diagnosis. We reviewed the literature and gathered the experience of a team of experts with the aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis and providing guidelines to navigate through the differential diagnosis. Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians. Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.
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            Alzheimer Disease: An Update on Pathobiology and Treatment Strategies

            Alzheimer disease (AD) is a heterogeneous disease with a complex pathobiology. The presence of extracellular amyloid-β deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles remain the primary neuropathologic criteria for AD diagnosis. However, a number of recent fundamental discoveries highlight important pathological roles for other critical cellular and molecular processes. Despite this, no disease modifying treatment currently exists and numerous phase 3 clinical trials have failed to demonstrate benefit. We review here recent advances in our understanding of AD pathobiology and discuss current treatment strategies, highlighting recent clinical trials and opportunities for developing future disease modifying therapies.
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              The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.

              Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.
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                Author and article information

                Contributors
                harald.pruess@charite.de
                Journal
                Nat Rev Immunol
                Nat Rev Immunol
                Nature Reviews. Immunology
                Nature Publishing Group UK (London )
                1474-1733
                1474-1741
                11 May 2021
                : 1-16
                Affiliations
                [1 ]German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany
                [2 ]GRID grid.6363.0, ISNI 0000 0001 2218 4662, Department of Neurology and Experimental Neurology, , Charité — Universitätsmedizin Berlin, ; Berlin, Germany
                Author information
                http://orcid.org/0000-0002-8283-7976
                Article
                543
                10.1038/s41577-021-00543-w
                8111372
                33976421
                7d1420db-ef64-4f52-a926-f431c75ebb84
                © Springer Nature Limited 2021

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 19 March 2021
                Categories
                Review Article

                neuroimmunology,autoimmunity
                neuroimmunology, autoimmunity

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