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      Diagnostic Utility of Auto Antibodies in Inflammatory Nerve Disorders

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          Abstract

          A wide range of autoantibodies have been described in immune-mediated nerve disorders that target glycans borne by glycolipids and glycoproteins enriched in the peripheral nerves. Their use as diagnostic biomarkers is very widespread, despite some limitations on sensitivity and specificity, and the lack of standardized assays and access to quality assurance schemes. Although many methods have been applied to measurement, ELISA, in the form of commercial kits or in-house assays, still remains the most widely available and convenient assay methodology.

          Some antibodies have a particularly robust and widely appreciated clinical significance. Thus, the anti-MAG IgM antibodies that are found in IgM paraprotein related neuropathies define a relatively uniform clinical and prognostic phenotype. IgG antibodies against gangliosides GM1 and GD1a are strongly associated with motor axonal variants of Guillain-Barré syndrome, and anti-GQ1b with Miller Fisher syndrome. In other chronic neuropathies, antibodies against disialylated gangliosides including GD1b and GD3 are detected in ataxic neuropathies, usually associated with an IgM paraprotein, and antibodies against GM1 and the complex GM1:GalC are frequently found in multifocal motor neuropathy. Unfortunately, autoantibodies strongly associated with the diagnosis of chronic inflammatory demyelinating polyneuropathies and with demyelinating forms of GBS are still lacking.

          Identification of autoantibodies that map onto a specific clinical phenotype not only allows for improved classification, but also provides better understanding of the pathophysiology of inflammatory neuropathies and the potential for therapeutic interventions.

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          Most cited references47

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          Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy.

          Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a frequent autoimmune neuropathy with a heterogeneous clinical spectrum. Clinical and experimental evidence suggests that autoantibodies may be involved in its pathogenesis, but the target antigens are unknown. Axoglial junction proteins have been proposed as candidate antigens. We examined the reactivity of CIDP patients' sera against neuronal antigens and used immunoprecipitation for antigen unraveling. Primary cultures of hippocampal neurons were used to select patients' sera that showed robust reactivity with the cell surface of neurons. The identity of the antigens was established by immunoprecipitation and mass spectrometry, and subsequently confirmed with cell-based assays, immunohistochemistry with teased rat sciatic nerve, and immunoabsorption experiments. Four of 46 sera from patients with CIDP reacted strongly against hippocampal neurons (8.6%) and paranodal structures on peripheral nerve. Two patients' sera precipitated contactin-1 (CNTN1), and 1 precipitated both CNTN1 and contactin-associated protein 1 (CASPR1). Reactivity against CNTN1 was confirmed in 2 cases, whereas the third reacted only when CNTN1 and CASPR1 were cotransfected. No other CIDP patient or any of the 104 controls with other neurological diseases tested positive. All 3 patients shared common clinical features, including advanced age, predominantly motor involvement, aggressive symptom onset, early axonal involvement, and poor response to intravenous immunoglobulin. Antibodies against the CNTN1/CASPR1 complex occur in a subset of patients with CIDP who share common clinical features. The finding of this biomarker may help to explain the symptoms of these patients and the heterogeneous response to therapy in CIDP. Copyright © 2012 American Neurological Association.
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            Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg.

            To describe the frequency of antibodies against neurofascin in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and the associated clinical features. Immunocytochemistry was used to identify antibodies to neurofascin 155 (NF155) and 186. Serum reactivity with paranodes and brain tissue was tested with immunohistochemistry of teased-nerve fibers and rat brain. Antibody titers and immunoglobulin (Ig) G isotypes were determined using ELISA. Clinical information was obtained retrospectively. Two of 53 patients, but none of 204 controls, had antibodies to NF155 (p = 0.041). The 2 patients with NF155 antibodies developed severe polyradiculoneuropathy with predominant distal weakness that was refractory to IVIg. Eight additional patients with IVIg-refractory CIDP were then identified from a national database; 2 of them with the same clinical features also had NF155 antibodies. Overall, 3 of the 4 patients with NF155 antibodies had a disabling and characteristic tremor (high amplitude, low frequency, postural, and intention). Patients' antibodies reacted with the paranodes in teased-nerve fibers and with the neuropil of rat cerebellum, brain, and brainstem. Anti-NF155 antibodies were predominantly of the IgG4 isotype in all patients. Patients with CIDP positive for IgG4 NF155 antibodies constitute a specific subgroup with a severe phenotype, poor response to IVIg, and disabling tremor. Autoantibodies against paranodal structures associate with distinct clinical features in CIDP and their identification has diagnostic, prognostic, and therapeutic implications. This study provides Class IV evidence that autoantibodies to NF155 identify a CIDP subtype characterized by severe neuropathy, poor response to IVIg, and disabling tremor.
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              Peripheral neuropathies and anti-glycolipid antibodies.

              This review charts the progress of anti-glycolipid antibodies in neuropathy, from their original discovery 20 years ago in immunoglobulin M paraproteinaemic neuropathy through to current discoveries mapping their relationship to subtypes of Guillain-Barré syndrome. Antibodies to >20 different glycolipids have now been associated with a wide range of clinically identifiable acute and chronic neuropathy syndromes. Particular progress has been achieved in understanding the link between acute motor axonal neuropathy and antibodies to GM1, GD1a, GM1b and GalNAc-GD1a, and between the cranial, bulbar and sensory variants of GBS and antibodies to the disialylated gangliosides GQ1b, GT1a, GD1b and GD3. In addition to clinical and serological studies, the origins and measurement of anti-glycolipid antibodies and their relationships to similar carbohydrate structures on infectious organisms, particularly Campylobacter jejuni, are discussed in the context of a molecular mimicry hypothesis. The structure and nomenclature of relevant glycolipids are outlined, along with information on their localization in nerve, and the influence this has on clinical phenotypes. Major advances have been made in animal modelling of anti-glycolipid antibody-associated diseases, both in vitro and in vivo. This has advanced our understanding of the role of anti-GQ1b antibodies in Miller Fisher syndrome with particular respect to the motor nerve terminal as a potential site of injury, and led to the creation of rabbit models of anti-GD1b and anti-GM1 antibody-mediated sensory and motor neuropathy, respectively. With such information in place, it will now be possible to determine the precise mechanisms by which antibodies injure the different compartments of peripheral nerve and establish how a range of immunomodulating therapies, including current treatments, exert their therapeutic effects. Despite these very significant advances, considerable gaps in our knowledge persist, and it is likely that other pathogenic pathways operate in inflammatory neuropathy that are unrelated to glycolipid antibodies, although these are outside the scope of this review.
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                Author and article information

                Journal
                J Neuromuscul Dis
                J Neuromuscul Dis
                JND
                Journal of Neuromuscular Diseases
                IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )
                2214-3599
                2214-3602
                4 June 2015
                : 2
                : 2
                : 107-112
                Affiliations
                [a ]Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
                [b ]Referral centre for ALS and Neuromuscular diseases, hospital La Timone, Marseille, France
                Author notes
                [* ]Correspondence to: Delmont Emilien, Reference centre for ALS and Neuromuscular diseases, hospital La Timone, 264 rue Saint Pierre, 13005 Marseille, France. Tel.: +33 4 91 38 65 79; Fax: +33 4 91 42 68 55; emilien.delmont@ 123456ap-hm.fr
                Article
                JND150078
                10.3233/JND-150078
                5271420
                27858733
                2eda8023-c94b-4276-8a27-8fbc1ad1fc4a
                IOS Press and the authors. All rights reserved

                This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License.

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                inflammatory neuropathy,anti-ganglioside antibodies,anti-mag antibodies,autoantibodies

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