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L'atteinte du système nerveux périphérique (SNP) concerne environ 15 % des patients ayant une maladie de Sjögren (Sjo). Des études ont mis en évidence une association entre les anticorps anti-fibroblast Growth Factor Receptor 3 (Ac anti-FGFR3) et anti-argonaute (Ac anti-AGO) et les neuropathies sensitives, notamment chez des patients ayant un contexte auto-immun. L'objectif de notre étude était d'évaluer la fréquence de ces anticorps, dans une cohorte de patients ayant une neuropathie périphérique associée à la Sjo. Nous avons inclus les patients de la cohorte nationale française ASSESS (Assessment of Systemic Signs and Evolution in Sjögren's Syndrome) présentant une neuropathie périphérique à l'inclusion ou au cours du suivi (défini comme cas). Nous avons sélectionné pour chaque cas un patient contrôle issu d'ASSESS, apparié sur le sexe et l'âge. Le dosage des anticorps anti-FGFR3 et anti-AGO a été réalisé sur le sérum des cas et des contrôles. Sur un suivi de 5 ans, sur 395 patients avec Sjo, 83 (21,0 %) patients ont présenté une atteinte du SNP, dont 80 patients avec du sérum disponible pour l'analyse. Les principaux tableaux cliniques observés étaient des neuropathies sensitives pures (n = 50, 62,5 %), dont des ganglionopathies (n = 7, 8,8 %), des neuropathies sensitivomotrices (n = 24, 30,0 %), des mononeuropathies multiples (n = 5, 6,3 %), des polyradiculonévrites (n = 1, 1,3 %), et/ou une atteinte des nerfs crâniens (n = 10, 12,5 %). L'atteinte des nerfs crâniens était associée à un autre type de neuropathie dans 60 % des cas. L'Ac anti-FGFR3 était détecté chez 4/80 (5,0 %) patients avec atteinte du SNP versus 2/80 (2,5 %) patients contrôles sans atteinte du SNP (p = 0,68). Il s'agissait d'une neuropathie sensitive pure chez les 4 patients avec atteinte du SNP. L'Ac anti-AGO était détecté chez 4/80 (5,0 %) patients avec atteinte du SNP versus 2/80 (2,5 %) des patients contrôles (p = 0,68). Il s'agissait de neuropathies sensitives pures pour 3 patients et d'une neuropathie sensitivomotrice avec atteinte des nerfs crâniens pour 1 patient. Aucun patient n'était positif pour les deux anticorps. On retrouvait la présence d'un des deux anticorps chez 7 (14,0 %) patients ayant une neuropathie sensitive pure versus 1 (3,3 %) patient ayant une neuropathie autre (p = 0,247) versus 4 (5,0 %) patients n'ayant pas de neuropathie (p = 0,105). Nous avons ensuite comparé les patients ayant une positivité d'un des deux anticorps (n = 12) aux autres patients (n = 148). Il n'y avait pas de différence significative concernant le sexe, l'âge, la présence d'Ac anti-SSA/SSB. En revanche, ils présentaient un taux plus élevé de gammaglobulines (21,7 ± 6,6 g/L versus 17,1 ± 7,4 g/L, p = 0,01) et un taux plus bas de lymphocytes (1,1 ± 0,6 G/L versus 1,5 ± 0,7 G/L, p = 0,04). Les Ac anti-FGFR3 ou anti-AGO sont mis en évidence chez 14 % des patients ayant une neuropathie sensitive associée à la Sjo, et chez 5 % des patients ayant une Sjo sans neuropathie périphérique. Il serait intéressant d'évaluer si ces auto-Ac pourraient être associés à un pronostic et/ou une sensibilité particulière à certains traitements de fond, notamment ceux ciblant le lymphocyte B. [ABSTRACT FROM AUTHOR]

Background and Objectives: Autoantibodies (Abs) improve diagnosis and treatment decisions of idiopathic neurologic disorders. Recently, we identified Abs against Argonaute (AGO) proteins as potential autoimmunity biomarkers in neurologic disorders. In this study, we aim to reveal (1) the frequency of AGO1 Abs in sensory neuronopathy (SNN), (2) titers and IgG subclasses, and (3) their clinical pattern including response to treatment., Methods: This retrospective multicentric case/control study screened 132 patients with SNN, 301 with non-SNN neuropathies, 274 with autoimmune diseases (AIDs), and 116 healthy controls (HCs) for AGO1 Abs through ELISA. Seropositive cases were also tested for IgG subclasses, titers, and conformation specificity., Results: AGO1 Abs occurred in 44 patients, comprising significantly more of those with SNN (17/132 [12.9%]) than those with non-SNN neuropathies (11/301 [3.7%]; p = 0.001), those with AIDs (16/274 [5.8%]; p = 0.02), or HCs (0/116; p < 0.0001). Ab titers ranged from 1:100 to 1:100,000. IgG subclass was mainly IgG1, and 11/17 AGO1 Ab-positive SNN (65%) had a conformational epitope. AGO1 Ab-positive SNN was more severe than AGO1 Ab-negative SNN (e.g., SNN score: 12.2 vs 11.0, p = 0.004), and they more frequently and more efficiently responded to immunomodulatory treatments than AGO1 Ab-negative SNN (7/13 [54%] vs 6/37 [16%], p = 0.02). Regarding the type of treatments more precisely, this significant difference was confirmed for the use of IV immunoglobulins (IVIg) but not for steroids or second-line treatments. Multivariate logistic regression adjusted for potential confounders showed that AGO1 Ab positivity was the only predictor of response to treatment (OR 4.93, 1.10-22.24 95% CI, p = 0.03)., Discussion: Although AGO Abs are not specific for SNN, based on our retrospective data, they may identify a subset of cases with SNN with more severe features and a possibly better response to IVIg. The significance of AGO1 Abs in clinical practice needs to be explored on a larger series., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Autoantibodies (Abs) are biomarkers for many disease conditions and are increasingly used to facilitate diagnosis and treatment decisions. To guarantee high sensitivity and specificity, the choice of their detection method is crucial. Via cell-based assays, we recently found 21 patients with neurological diseases positive for antibodies against argonaute (AGO), 10 of which having a neuropathy (NP). Here, we established a simple and conformation-sensitive ELISA with the aim to distinguish between AGO1 Abs against conformational epitopes and non-conformational epitopes and to reveal further characteristics of AGO1 antibodies in NP and autoimmune disease (AID). In a retrospective multicenter case/control and observational study, we tested 434 patients with NP, 274 disease controls with AID, and 116 healthy controls (HC) for AGO1 Abs via conformation-stabilizing ELISA. Seropositive patients were also tested for conformation-specificity via comparative denaturing/stabilizing ELISA (CODES-ELISA), CBA positivity, AGO1 titers and IgG subclasses, and AGO2 reactivity. These parameters were statistically compared among different epitope-specific patient groups. We found Abs in 44 patients, including 28/434 (6.5%) NP, 16/274 (5.8%) AID, and 0/116 (0%) HC. Serum reactivity was consistently higher for AGO1 than AGO2. Globally among the 44 AGO1 Abs-positive patients, 42 were also tested in CBA for AGO1 Abs positivity and 15 (35.7%) were positive. Furthermore, 43 were tested for conformation-specificity and 32 (74.4%) bound a conformational epitope. Among the subgroups of highly positive patients (ELISA z-score >14) with sera binding conformational epitopes (n=23), 14 patient sera were also CBA positive and 9 bound a second conformational but CBA-inaccessible epitope. A third, non-conformational epitope was bound by 11/43 (15.6%). Among the epitope-specific patient subgroups, we found significant differences regarding the Abs titers, IgG subclass, and AGO2 reactivity. When comparing AGO1 Abs-positive NP versus AID patients, we found the conformation-specific and CBA inaccessible epitope significantly more frequently in AID patients. We conclude that 1) conformational ELISA was more sensitive than CBA in detecting AGO1 Abs, 2) serum reactivity is higher for AGO1 than for AGO2 at least for NP patients, 3) AGO1 Abs might be a marker-of-interest in 6.5% of NP patients, 4) distinguishing epitopes might help finding different patient subgroups., Competing Interests: CPM, L-DD, J-PC, JH, J-CA have submitted a patent application for the application of AGO antibodies as biomarkers for autoimmune neurological diseases. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Moritz, Do, Tholance, Vallayer, Rogemond, Joubert, Ferraud, La Marca, Camdessanché, Honnorat and Antoine.)

Antibodies against FGFR3 define a subgroup of sensory neuropathy (SN). The aim of this study was to identify the epitope(s) of anti-FGFR3 autoantibodies and potential epitope-dependent clinical subtypes. Using SPOT methodology, five specific candidate epitopes, three in the juxtamembrane domain (JMD) and two in the tyrosine kinase domain (TKD), were screened with 68 anti-FGFR3-positive patients and 35 healthy controls. The identified epitopes cover 6/15 functionally relevant sites of the protein. Four patients reacted with the JMD and 11 with the TKD, partly even in a phosphorylation-state dependent manner. The epitope could not be identified in the others. Patients with antibodies recognizing TKD exhibited a more severe clinical and electrophysiological impairment than others., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To identify and characterize autoantibodies (Abs) as novel biomarkers for an autoimmune context in patients with central and peripheral neurologic diseases., Methods: Two distinct approaches (immunoprecipitation/mass spectrometry-based proteomics and protein microarrays) and patients' sera and CSF were used. The specificity of the identified target was confirmed by cell-based assay (CBA) in 856 control samples., Results: Using the 2 methods as well as sera and CSF of patients with central and peripheral neurologic involvement, we identified Abs against the family of Argonaute proteins (mainly AGO1 and AGO2), which were already reported in systemic autoimmunity. AGO-Abs were mostly of immunoglobulin G 1 subclass and conformation dependent. Using CBA, AGO-Abs were detected in 21 patients with a high suspicion of autoimmune neurologic diseases (71.4% were women; median age 57 years) and only in 4/856 (0.5%) controls analyzed by CBA (1 diagnosed with small-cell lung cancer and the other 3 with Sjögren syndrome). Among the 21 neurologic patients identified, the main clinical presentations were sensory neuronopathy (8/21, 38.1%) and limbic encephalitis (6/21, 28.6%). Fourteen patients (66.7%) had autoimmune comorbidities and/or co-occurring Abs, whereas AGO-Abs were the only autoimmune biomarker for the remaining 7/21 (33.3%). Thirteen (61.9%) patients were treated with immunotherapy; 8/13 (61.5%) improved, and 3/13 (23.1%) remained stable, suggesting an efficacy of these treatments., Conclusions: AGO-Abs might be potential biomarkers of autoimmunity in patients with central and peripheral nonparaneoplastic neurologic diseases. In 7 patients, AGO-Abs were the only biomarkers; thus, their identification may be useful to suspect the autoimmune character of the neurologic disorder., Classification of Evidence: This study provides Class III evidence that AGO-Abs are more frequent in patients with autoimmune neurologic diseases than controls., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To discover systemic characteristics in the repertoires of targeted autoantigens in chronic inflammatory demyelinating polyneuropathy (CIDP), we detected the entire autoantigen repertoire of patients and controls and analyzed them systematically., Methods: We screened 43 human serum samples, of which 22 were from patients with CIDP, 12 from patients with other neuropathies, and 9 from healthy controls via HuProt Human Proteome microarrays testing about 16,000 distinct human bait proteins. Autoantigen repertoires were analyzed via bioinformatical autoantigenomic approaches: principal component analysis, analysis of the repertoire sizes in disease groups and clinical subgroups, and overrepresentation analyses using Gene Ontology and PantherDB., Results: The autoantigen repertoires enabled the identification of a subgroup of 10/22 patients with CIDP with a younger age at onset and a higher frequency of mixed motor and sensory CIDP. IV immunoglobulin therapy responders targeted 3 times more autoantigens than nonresponders. No CIDP-specific autoantibody is present in all patients; however, anchoring junction components were significantly targeted by 86.4% of patients with CIDP. There are potential novel CIDP-specific autoantigens such as the myelination- or axo-glial structure-related proteins actin-related protein 2/3 complex subunit 1B, band 4.1-like protein 2, cadherin-15, cytohesin-1, epidermal growth factor receptor, ezrin, and radixin., Conclusions: The repertoire of targeted autoantigens of patients with CIDP differs in a systematic degree from those of controls. Systematic autoantigenomic approaches can help to understand the disease and to discover novel bioinformatical tools and novel autoantigen panels to improve diagnosis, treatment, prognosis, or patient stratification., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: Sensory neuropathies (SNs) are often classified as idiopathic even if immunological mechanisms can be suspected. Antibodies against the intracellular domain of the fibroblast growth factor receptor 3 (FGFR3) possibly identify a subgroup of SN affecting mostly the dorsal root ganglion (DRG). The aim of this study was to identify the frequency of anti-FGFR3 antibodies and the associated clinical pattern in a large cohort of patients with SN., Methods: A prospective, multicentric, European and Brazilian study included adults with pure SN. Serum anti-FGRF3 antibodies were analysed by ELISA. Detailed clinical and paraclinical data were collected for each anti-FGFR3-positive patient and as control for anti-FGFR3-negative patients from the same centres ('center-matched')., Results: Sixty-five patients out of 426 (15%) had anti-FGFR3 antibodies, which were the only identified autoimmune markers in 43 patients (66%). The neuropathy was non-length dependent in 89% and classified as sensory neuronopathy in 64%, non-length-dependent small fibre neuropathy in 17% and other neuropathy in 19%. Specific clinical features occurred after 5-6 years of evolution including frequent paresthesia, predominant clinical and electrophysiological involvement of the lower limbs, and a less frequent mixed large and small fibre involvement. Brazilians had a higher frequency of anti-FGFR3 antibodies than Europeans (36% vs 13%, p<0.001), and a more frequent asymmetrical distribution of symptoms (OR 169, 95% CI 3.4 to 8424)., Conclusions: Anti-FGFR3 antibodies occur in a subgroup of SN probably predominantly affecting the DRG. Differences between Europeans and Brazilians could suggest involvement of genetic or environmental factors., Competing Interests: Competing interests: YT reports personal fees from The Binding Site and Alexion, outside of the submitted work. CPM received travel grants from CSL Behring (France), outside of the submitted work. J-PC reports personal fees for lectures, consulting, writing of articles, or training courses from Akcea, Alnylam, Biogen, CSL Behring, Genzyme, Laboratoire Français des Biotechnologies (LFB), Merck, Novartis, Pfizer, Pharmalliance, Teva, Editions Scientifiques L&C, Edimark, Expression Santé, Natus, Scien, SNF-Floerger, outside of the submitted work. J-CA received honoraria for scientific counseling from Pfizer and from a license on diagnostic test for the detection of anti-CRMP5 antibodies, and travel grants from LFB. J-CA and J-PC also participated to a patent on the detection of FGFR3 antibodies. CR, KF, FL, ER-F, MCFJ and ARMM report no disclosure relevant to the manuscript., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess the clinicopathological and therapeutic features of patients with low (≥1000 to <10 000 Bühlmann Titre Units) (BTU), medium (10 000-70 000) or high (≥70 000) anti-myelin-associated glycoprotein (anti-MAG) antibody titres., Methods: We retrospectively and prospectively analysed standardised report forms and medical records of 202 patients from 14 neuromuscular centres., Results: Mean age at onset and mean time between symptom onset to last follow-up were respectively 62.6 years (25-91.4) and 8.4 years (0.3-33.3). Anti-MAG antibody titres at diagnosis were low, medium or high in 11%, 51% and 38% of patients. Patients presented with monoclonal gammopathy of undetermined significance in 68% of cases. About 17% of patients presented with 'atypical' clinical phenotype independently of anti-MAG titres, including acute or chronic sensorimotor polyradiculoneuropathies (12.4%), and asymmetric or multifocal neuropathy (3%). At the most severe disease stage, 22.4% of patients were significantly disabled. Seventy-eight per cent of patients received immunotherapies. Transient clinical worsening was observed in 12% of patients treated with rituximab (11/92). Stabilisation after rituximab treatment during the 7-12-month follow-up period was observed in 29% of patients. Clinical response to rituximab during the 6-month and/or 7-12-month follow-up period was observed in 31.5% of patients and correlated with anti-MAG titre ≥10 000 BTU., Conclusion: Our study highlights the extended clinical spectrum of patients with anti-MAG neuropathy, which appears unrelated to antibody titre. Besides, it may also suggest beneficial use of rituximab in the early phase of anti-MAG neuropathy., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Collapsin response mediator protein 5 (CRMP5) is one of the rare peripheral nerve antigens that is a target of autoantibodies in a paraneoplastic peripheral neuropathy. The pattern of axonal and myelin alterations suggests that CRMP5 is involved in axon-Schwann cell interaction. We examined CRMP5 expression and function in primary cultures of Schwann cells and neurons and at various developmental and regenerating stages of rat sciatic nerve and in CRMP5-deficient mice in vivo. Collapsin response mediator protein 5 was strongly expressed during postnatal development and regeneration and decreased with myelination. It was mainly expressed by immature Schwann cells and persisted in Remak cells in the adult; however, a subpopulation of Schwann cells that were induced to myelinate also expressed CRMP5. We identified 2 axonal molecular cues regulating CRMP5 expression: human neuregulin type 1, which induces CRMP5 expression in immature and premyelinating Schwann cells, and cyclic adenosine monophosphate, which inhibits CRMP5 expression when Schwann cells begin myelination. Collapsin response mediator protein 5-deficient mice showed abnormal Schwann process extension resulting in abnormal cell-axon segregation, indicating that CRMP5 is involved in the morphologic adaptation of Schwann cells to surround axons. These results demonstrate the importance of CRMP5 in axon-Schwann cell cooperation during development and regeneration.