RESUMEN
BACKGROUND AND OBJECTIVES: Autoimmune nodopathies with antibodies against the paranodal proteins show a distinct phenotype of a severe sensorimotor neuropathy. In some patients, complete remission can be achieved after treatment with rituximab whereas others show a chronic course. For optimal planning of treatment, predicting the course of disease and therapeutic response is crucial. METHODS: We stimulated peripheral blood mononuclear cells in vitro to find out whether secretion of specific autoantibodies may be a predictor of the course of disease and response to rituximab. RESULTS: Three patterns could be identified: In most patients with anti-Neurofascin-155-, anti-Contactin-1-, and anti-Caspr1-IgG4 autoantibodies, in vitro production of autoantibodies was detected, indicating autoantigen-specific memory B cells and short-lived plasma cells/plasmablasts as the major source of autoantibodies. These patients generally showed a good response to rituximab. In a subgroup of patients with anti-Neurofascin-155-IgG4 autoantibodies and insufficient response to rituximab, no in vitro autoantibody production was found despite high serum titers, indicating autoantibody secretion by long-lived plasma cells outside the peripheral blood. In the patients with anti-pan-Neurofascin autoantibodies-all with a monophasic course of disease-no in vitro autoantibody production could be measured, suggesting a lack of autoantigen-specific memory B cells. In some of them, autoantibody production by unstimulated cells was detectable, presumably corresponding to high amounts of autoantigen-specific plasmablasts-well in line with a severe but monophasic course of disease. DISCUSSION: Our data suggest that different B-cell responses may occur in autoimmune nodopathies and may serve as markers of courses of disease and response to rituximab.
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Autoanticuerpos , Leucocitos Mononucleares , Rituximab , Humanos , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Femenino , Masculino , Adulto , Leucocitos Mononucleares/inmunología , Rituximab/farmacología , Persona de Mediana Edad , Factores de Crecimiento Nervioso/inmunología , Adulto Joven , Contactina 1/inmunología , Anciano , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Adolescente , Moléculas de Adhesión Celular/inmunologíaRESUMEN
Background: Contactin-1 (CNTN1) antibody-positive nodopathy is rare and exhibits distinct clinical symptoms such as tremors and ataxia. However, the mechanisms of these symptoms and the characteristics of the cerebral spinal fluid (CSF) remain unknown. Case presentation: Here, we report a case of recurrent CNTN1 antibody-positive nodopathy. Initially, a 45-year-old woman experiencing numbness in the upper limbs and weakness in the lower limbs was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Eleven years later, her symptoms worsened, and she began to experience tremors and ataxia. Tests for serum CNTN1, GT1a, and GQ1b antibodies returned positive. Subsequently, she was diagnosed with CNTN1 antibody-positive nodopathy and underwent plasmapheresis therapy, although the treatment's efficacy was limited. To gain a deeper understanding of the disease, we conducted a comprehensive literature review, identifying 52 cases of CNTN1 antibody-positive nodopathy to date, with a tremor prevalence of 26.9%. Additionally, we found that the average CSF protein level in CNTN1 antibody-positive nodopathy was 2.57 g/L, with 87% of patients exhibiting a CSF protein level above 1.5 g/L. Conclusion: We present a rare case of recurrent CNTN1 antibody-positive nodopathy. Our findings indicate a high prevalence of tremor (26.9%) and elevated CSF protein levels among patients with CNTN1 antibody-positive nodopathy.
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Autoanticuerpos , Contactina 1 , Humanos , Femenino , Persona de Mediana Edad , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Contactina 1/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/terapia , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/sangre , Recurrencia , Temblor/inmunología , Temblor/etiología , PlasmaféresisRESUMEN
BACKGROUND: To investigate Ranvier's autoantibodies prevalence and isotypes in various peripheral neuropathy variants, compare clinical features between seronegative and seropositive patients, and elucidate immune mechanisms underlying antibody generation. METHODS: Antibodies against anti-neurofascin-155 (NF155), NF186, contactin-1 (CNTN1), CNTN2, contactin-associated protein 1 (CASPR1), and CASPR2 were identified through cell-based assays. Plasma cytokines were analyzed in anti-NF155 antibody-positive chronic inflammatory demyelinating polyneuropathy (NF155+ CIDP) and Ranvier's antibodies-negative CIDP (Ab- CIDP) patients using a multiplexed fluorescent immunoassay, validated in vitro in a cell culture model. RESULTS: In 368 plasma samples, 50 Ranvier's autoantibodies were found in 45 individuals, primarily in CIDP cases (25 out of 69 patients) and in 10 out of 122 Guillain-Barré syndrome patients. Anti-NF155 and CNTN1-IgG were exclusive to CIDP. Fourteen samples were NF155-IgG, primarily IgG4 subclass, linked to CIDP features including early onset, tremor, sensory disturbance, elevated CSF protein, prolonged motor latency, conduction block, and poor treatment response. NF155-IgG had low sensitivity (20.28%) but high specificity (100%) for CIDP, rising to 88.88% with tremor and prolonged motor latency. Cytokine profiling in NF155+ CIDP revealed distinct immune responses involving helper T cells, toll-like receptor pathways. Some NF155+ CIDP patients had circulating NF155-specific B cells producing NF155-IgG without antigen presence, suggesting therapeutic potential. CONCLUSION: The study emphasizes the high specificity and sensitivity of NF155-IgG for diagnosing CIDP characterized by distinctive features. Further investigation into circulating NF155-specific B cell phenotypes may pave the way for B cell directed therapy.
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Autoanticuerpos , Moléculas de Adhesión Celular , Factores de Crecimiento Nervioso , Fenotipo , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/sangre , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Masculino , Femenino , Moléculas de Adhesión Celular/sangre , Moléculas de Adhesión Celular/inmunología , Factores de Crecimiento Nervioso/inmunología , Factores de Crecimiento Nervioso/sangre , Persona de Mediana Edad , Autoanticuerpos/sangre , Anciano , Adulto , Citocinas/sangre , Nódulos de Ranvier/inmunología , Contactina 1/inmunologíaRESUMEN
Autoimmune nodopathy (AN) is a group of peripheral neuropathies caused by antibodies targeting the nodes of Ranvier or paranodes. It typically presents with sensory ataxia, distal limb weakness, and tremor, and often has a subacute onset, with limited response to immunoglobulin or corticosteroids. We report a case of anti-contactin-1 neuropathy initially manifesting as isolated superior oblique palsy, aiming to broaden the clinical spectrum of the disease. A 68-year-old male with well-controlled diabetes, hypertension, and hyperlipidemia developed acute binocular vertical diplopia, progressing over two months to include distal paresthesia, sensory ataxia, ageusia, and dysarthria. Concurrent nephrotic syndrome was identified. Nerve conduction studies supported demyelination. Despite treatment with intravenous methylprednisolone followed by long-term immunosuppression, some disability persisted. Serum archived during his admission tested positive for anti-contactin-1 IgG, with IgG4 as the predominant subclass, in the flow cytometry assay for AN. This case extends the clinical spectrum of AN. Some cases of isolated cranial nerve palsies, especially in the relevant context like nephrotic syndrome, may be attributed to AN. Prompt initiation of more effective therapies, such as rituximab, could significantly improve outcomes.
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Contactina 1 , Inmunoglobulina G , Humanos , Masculino , Anciano , Inmunoglobulina G/sangre , Contactina 1/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Enfermedades del Nervio Troclear/tratamiento farmacológico , Enfermedades del Nervio Troclear/etiologíaRESUMEN
Background: Autoimmune nodopathy (AN) has emerged as a novel diagnostic category that is pathologically different from classic chronic inflammatory demyelinating polyneuropathy. Clinical manifestations of AN include sensory or motor neuropathies, sensory ataxia, tremor, and cranial nerve involvement. AN with a serum-positive contactin-1 (CNTN1) antibody usually results in peripheral nerve demyelination. In this study, we reported a rare case of AN with CNTN1 antibodies characterized by the presence of CNTN1 antibodies in both serum and cerebrospinal fluid, which is associated with cerebellar dysarthria. Methods: A 25-year-old man was admitted to our hospital due to progressive dysarthria with limb tremors. The patient was initially diagnosed with peripheral neuropathy at a local hospital. Three years after onset, he was admitted to our hospital due to dysarthria, apparent limb tremor, and limb weakness. At that time, he was diagnosed with spinocerebellar ataxia. Eight years post-onset, during his second admission, his condition had notably deteriorated. His dysarthria had evolved to typical distinctive cerebellar characteristics, such as tremor, loud voice, stress, and interrupted articulation. Additionally, he experienced further progression in limb weakness and developed muscle atrophy in the distal limbs. Magnetic resonance imaging (MRI), nerve conduction studies (NCS), and autoimmune antibody tests were performed. Results: The results of the NCS suggested severe demyelination and even axonal damage to the peripheral nerves. MRI scans revealed diffuse thickening of bilateral cervical nerve roots, lumbosacral nerve roots, cauda equina nerve, and multiple intercostal nerve root sheath cysts. Furthermore, anti-CNTN1 antibody titers were 1:10 in the cerebrospinal fluid (CSF) and 1:100 in the serum. After one round of rituximab treatment, the patient showed significant improvement in limb weakness and dysarthria, and the CSF antibodies turned negative. Conclusion: Apart from peripheral neuropathies, cerebellar dysarthria (central nervous system involvement) should not be ignored in AN patients with CNTN1 antibodies.
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Disartria , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Masculino , Humanos , Adulto , Disartria/complicaciones , Temblor/complicaciones , Contactina 1 , AtaxiaRESUMEN
Clemastine (CLM) is repurposed to enhance remyelination in multiple sclerosis (MS) patients. CLM blocks histamine and muscarinic receptors as negative regulators to oligodendrocyte differentiation. These receptors are linked to the canonical and non-canonical Notch-1 signaling via specific ligands; Jagged-1 and F3/Contactin-1, respectively. Yet, there are no previous studies showing the influence of CLM on Notch entities. Herein, the study aimed to investigate to which extent CLM aligns to one of the two Notch-1 arms in experimental autoimmune encephalomyelitis (EAE) rat model. Three groups were utilized where first group received vehicles. The second group was injected by spinal cord homogenate mixed with complete Freund's adjuvant on days 0 and 7. In the third group, CLM (5 mg/kg/day; p.o) was administered for 15 days starting from the day of the first immunization. CLM ameliorated EAE-associated motor and gripping impairment in rotarod, open-field, and grip strength arena beside sensory anomalies in hot plate, cold allodynia, and mechanical Randall-Selitto tests. Additionally, CLM alleviated depressive mood observed in tail suspension test. These findings harmonized with histopathological examinations of Luxol-fast blue stain together with enhanced immunostaining of myelin basic protein and oligodendrocyte lineage gene 2 in corpus callosum and spinal cord. Additionally, CLM enhanced oligodendrocyte myelination and maturation by increasing 2',3'-cyclic nucleotide 3'-phosphodiesterase, proteolipid protein, aspartoacylase as well. CLM restored the level of F3/Contactin-1 in the diseased rats over Jagged-1 level; the ligand of the canonical pathway. This was accompanied by elevated gene expression of Deltex-1 and reduced hairy and enhancer-of-split homologs 1 and 5. Additionally, CLM suppressed microglial and astrocyte activation via reducing the expression of ionized calcium-binding adaptor molecule-1 as well as glial fibrillary acidic protein, respectively. These results outlined the remyelinating beneficence of CLM which could be due to augmenting the non-canonical Notch-1 signaling over the canonical one.
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Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Humanos , Ratas , Animales , Proteína Jagged-1 , Clemastina , Contactina 1 , Receptores Notch , Modelos TeóricosAsunto(s)
Autoanticuerpos , Contactina 1 , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/tratamiento farmacológico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/sangre , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Contactina 1/inmunología , Masculino , Femenino , Persona de Mediana Edad , Corticoesteroides/uso terapéutico , AdultoRESUMEN
Axon initial segment (AIS) cell surface proteins mediate key biological processes in neurons including action potential initiation and axo-axonic synapse formation. However, few AIS cell surface proteins have been identified. Here, we use antibody-directed proximity biotinylation to define the cell surface proteins in close proximity to the AIS cell adhesion molecule Neurofascin. To determine the distributions of the identified proteins, we use CRISPR-mediated genome editing for insertion of epitope tags in the endogenous proteins. We identify Contactin-1 (Cntn1) as an AIS cell surface protein. Cntn1 is enriched at the AIS through interactions with Neurofascin and NrCAM. We further show that Cntn1 contributes to assembly of the AIS extracellular matrix, and regulates AIS axo-axonic innervation by inhibitory basket cells in the cerebellum and inhibitory chandelier cells in the cortex.
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Segmento Inicial del Axón , Fenómenos Biológicos , Segmento Inicial del Axón/metabolismo , Contactina 1/metabolismo , Biotinilación , Sinapsis/metabolismo , Axones/metabolismo , Proteínas de la Membrana/metabolismo , Anticuerpos/metabolismoRESUMEN
BACKGROUND: The aim of this study was to determine treatment response and whether it is associated with antibody titre change in patients with autoimmune nodopathy (AN) previously diagnosed as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and to compare clinical features and treatment response between AN and CIDP. METHODS: Serum IgG antibodies to neurofascin-155 (NF155), contactin-1 (CNTN1) and contactin-associated protein 1 (CASPR1) were detected with cell-based assays in patients diagnosed with CIDP. Clinical improvement was determined using the modified Rankin scale, need for alternative and/or additional treatments and assessment of the treating neurologist. RESULTS: We studied 401 patients diagnosed with CIDP and identified 21 patients with AN (10 anti-NF155, 6 anti-CNTN1, 4 anti-CASPR1 and 1 anti-NF155/anti-CASPR1 double positive). In patients with AN ataxia (68% vs 28%, p=0.001), cranial nerve involvement (34% vs 11%, p=0.012) and autonomic symptoms (47% vs 22%, p=0.025) were more frequently reported; patients with AN improved less often after intravenous immunoglobulin treatment (39% vs 80%, p=0.002) and required additional/alternative treatments more frequently (84% vs 34%, p<0.001), compared with patients with CIDP. Antibody titres decreased or became negative in patients improving on treatment. Treatment withdrawal was associated with a titre increase and clinical deterioration in four patients. CONCLUSIONS: Distinguishing CIDP from AN is important, as patients with AN need a different treatment approach. Improvement and relapses were associated with changes in antibody titres, supporting the pathogenicity of these antibodies.
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Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/tratamiento farmacológico , Relevancia Clínica , Autoanticuerpos , Inmunoglobulinas Intravenosas/uso terapéutico , Contactina 1RESUMEN
BACKGROUND: The frequency of nodal-paranodal antibodies in HIV-infected patients with chronic immune-mediated radiculo-neuropathies (IMRN) has not been previously described. METHODS: HIV-infected patients who met the inclusion criteria for chronic IMRN were screened for immunoglobulin G (IgG) antibodies directed against nodal (neurofascin (NF)186) and paranodal (NF155, contactin-1 (CNTN1) and contactin-associated protein(Caspr1)) cell adhesion molecules, using a live, cell-based assay. To explore potential pathogenicity, binding of human IgG to myelinated co-cultures was assessed by incubation with patients' sera positive for nodal or paranodal antibodies. Normal human serum was added as a source of complement to assess for complement activation as a mechanism for myelin injury. RESULTS: Twenty-four HIV-infected patients with IMRN were included in the study, 15 with chronic inflammatory demyelinating polyneuropathy (CIDP), 4 with ventral root radiculopathies (VRR), and 5 with dorsal root ganglionopathies (DRG). Five patients with CIDP had combined central and peripheral demyelination (CCPD). Three patients (12.7%) tested positive for neurofascin IgG1 antibodies in the following categories: 1 patient with VRR was NF186 positive, and 2 patients were NF155 positive with DRG and mixed sensory-motor demyelinating neuropathy with optic neuritis, respectively. CONCLUSION: The frequency of nodal-paranodal antibodies is similar among IMRN regardless of HIV status. Interpretation of the results in the context of HIV is challenging as there is uncertainty regarding pathogenicity of the antibodies, especially at low titres. Larger prospective immune studies are required to delineate pathogenicity in the context of HIV, and to establish a panel of antibodies to predict for a particular clinical phenotype.
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Infecciones por VIH , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Autoanticuerpos , Factores de Crecimiento Nervioso , Estudios Prospectivos , Inmunoglobulina G , Contactina 1RESUMEN
PURPOSE: Immunotherapy has been widely used in bladder cancer (BCa) in recent years and has significantly improved the prognosis of patients with BCa. However, further identification of immunotherapy-sensitive individuals to improve the efficacy of immunotherapy remains an important unmet need. MATERIALS AND METHODS: The key genes were screened and identified from Gene Expression Omnibus database and The Cancer Genome Atlas database to construct the risk prediction function (risk scores). Real-time polymerase chain reaction, immunohistochemistry, and IMvigor210 data sets were used to verify the roles of key molecules and efficacy of risk scores. The biologic function of CNTN1 and EMP1 was further explored through cell proliferation experiments. RESULTS: Five key genes, CNTN1, MAP1A, EMP1, MFAP5, and PTGIS, which were significantly related to the prognosis and immune checkpoint molecules of patients, were screened out. CNTN1 and EMP1 were further experimentally confirmed for their significant tumor-promoting effects. Besides, the constructed risk scores on the basis of these five key genes can accurately predict the prognosis and immunotherapy efficacy of patients with BCa. Interestingly, the high-risk patients identified by the risk scores have significantly worse prognosis and immunotherapy effects than low-risk patients. CONCLUSION: The key genes we screened can affect the prognosis of BCa, tumor microenvironment immune infiltration, and the efficacy of immunotherapy. The risk scores tool we constructed will contribute to the development of individualized treatment for BCa.
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Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/terapia , Pronóstico , Inmunoterapia , Pacientes , Factores de Riesgo , Microambiente Tumoral/genética , Contactina 1RESUMEN
Introduction: IgG4 autoantibodies against paranodal proteins are known to induce acute-onset and often severe sensorimotor autoimmune neuropathies. How autoantibodies reach their antigens at the paranode in spite of the myelin barrier is still unclear. Methods: We performed in vitro incubation experiments with patient sera on unfixed and unpermeabilized nerve fibers and in vivo intraneural and intrathecal passive transfer of patient IgG to rats, to explore the access of IgG autoantibodies directed against neurofascin-155 and contactin-1 to the paranodes and their pathogenic effect. Results: We found that in vitro incubation resulted in weak paranodal binding of anti-contactin-1 autoantibodies whereas anti-neurofascin-155 autoantibodies bound to the nodes more than to the paranodes. After short-term intraneural injection, no nodal or paranodal binding was detectable when using anti-neurofascin-155 antibodies. After repeated intrathecal injections, nodal more than paranodal binding could be detected in animals treated with anti-neurofascin-155, accompanied by sensorimotor neuropathy. In contrast, no paranodal binding was visible in rats intrathecally injected with anti-contactin-1 antibodies, and animals remained unaffected. Conclusion: These data support the notion of different pathogenic mechanisms of anti-neurofascin-155 and anti-contactin-1 autoantibodies and different accessibility of paranodal and nodal structures.
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Autoanticuerpos , Axones , Animales , Ratas , Contactina 1 , Inmunoglobulina G , Vaina de Mielina , Factor de Crecimiento Transformador betaRESUMEN
Methamphetamine (Meth), a commonly used central nervous system stimulant, is highly addictive. Currently, there is no effective treatment for Meth dependence and abuse, although cell adhesion molecules (CAMs) have been shown to play an important role in the formation and remodeling of synapses in the nervous system while also being involved in addictive behavior. Contactin 1 (CNTN1) is a CAM that is widely expressed in the brain; nevertheless, its role in Meth addiction remains unclear. Therefore, in the present study, we established mouse models of single and repeated Meth exposure and subsequently determined that CNTN1 expression in the nucleus accumbens (NAc) was upregulated in mice following single or repeated Meth exposure, whereas CNTN1 expression in the hippocampus was not significantly altered. Intraperitoneal injection of the dopamine receptor 2 antagonist haloperidol reversed Meth-induced hyperlocomotion and upregulation of CNTN1 expression in the NAc. Additionally, repeated Meth exposure also induced conditioned place preference (CPP) in mice and upregulated the expression levels of CNTN1, NR2A, NR2B, and PSD95 in the NAc. Using an AAV-shRNA-based approach to specifically silence CNTN1 expression in the NAc via brain stereotaxis reversed Meth-induced CPP and decreased the expression levels of NR2A, NR2B, and PSD95 in the NAc. These findings suggest that CNTN1 expression in the NAc plays an important role in Meth-induced addiction, and the underlying mechanism may be related to the expression of synapse-associated proteins in the NAc. The results of this study improved our understanding of the role of cell adhesion molecules in Meth addiction.
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Trastornos Relacionados con Anfetaminas , Estimulantes del Sistema Nervioso Central , Metanfetamina , Ratones , Animales , Metanfetamina/farmacología , Núcleo Accumbens , Contactina 1/metabolismo , Estimulantes del Sistema Nervioso Central/farmacología , Encéfalo/metabolismo , Trastornos Relacionados con Anfetaminas/metabolismoRESUMEN
Membranous glomerulonephritis (MGN) is a common cause of nephrotic syndrome in adults, mediated by glomerular antibody deposition to an increasing number of newly recognised antigens. Previous case reports have suggested an association between patients with anti-contactin-1 (CNTN1)-mediated neuropathies and MGN. In an observational study we investigated the pathobiology and extent of this potential cause of MGN by examining the association of antibodies against CNTN1 with the clinical features of a cohort of 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 256 controls. Neuronal and glomerular binding of patient IgG, serum CNTN1 antibody and protein levels, as well as immune-complex deposition were determined. We identified 15 patients with immune-mediated neuropathy and concurrent nephrotic syndrome (biopsy proven MGN in 12/12), and 4 patients with isolated MGN from an idiopathic MGN cohort, all seropositive for IgG4 CNTN1 antibodies. CNTN1-containing immune complexes were found in the renal glomeruli of patients with CNTN1 antibodies, but not in control kidneys. CNTN1 peptides were identified in glomeruli by mass spectroscopy. CNTN1 seropositive patients were largely resistant to first-line neuropathy treatments but achieved a good outcome with escalation therapies. Neurological and renal function improved in parallel with suppressed antibody titres. The reason for isolated MGN without clinical neuropathy is unclear. We show that CNTN1, found in peripheral nerves and kidney glomeruli, is a common target for autoantibody-mediated pathology and may account for between 1 and 2% of idiopathic MGN cases. Greater awareness of this cross-system syndrome should facilitate earlier diagnosis and more timely use of effective treatment.
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Glomerulonefritis Membranosa , Glomerulonefritis , Enfermedades Renales , Síndrome Nefrótico , Enfermedades del Sistema Nervioso Periférico , Adulto , Humanos , Glomerulonefritis Membranosa/patología , Síndrome Nefrótico/patología , Contactina 1 , Glomérulos Renales/patología , Riñón/patología , Enfermedades Renales/patología , Enfermedades del Sistema Nervioso Periférico/patología , Glomerulonefritis/patologíaRESUMEN
Introduction: Autoimmune nodopathies (AN) have been diagnosed in a subset of patients fulfilling criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who display no or poor response to intravenous immunoglobulins. Biomarkers of AN are autoantibodies, mainly IgG4, directed against the ternary paranodal complex composed by neurofascin-155, contactin-1 (CNTN1), and Contactin-associated-protein-1 (CASPR1) or against the nodal isoforms of neurofascin. IgG4 can undergo a Fab-arm exchange (FAE) which results in functionally monovalent antibody. This phenomenon differentially affects the pathogenicity of IgG4 depending on the target of autoantibodies. Here, we have evaluated this issue by examining the impact of valency on anti-CNTN1 IgG4 which induces paranodal destruction through a function blocking activity. Methods: Sera were obtained from 20 patients with AN associated with anti-CNTN1 antibodies. The proportion of monospecific/bispecific anti-CNTN1 antibodies was estimated in each patient by ELISA by examining the ability of serum antibodies to cross-link untagged CNTN1 with biotinylated CNTN1. To determine the impact of monovalency, anti-CNTN1 IgG4 were enzymatically digested into monovalent Fab and tested in vitro on cell aggregation assay. Also, intraneural injections were performed to determine whether monovalent Fab and native IgG4 may penetrate paranode, and antibody infiltration was monitored 1- and 3-days post injection. Results and discussion: We found that the percentage of monospecific antibodies were lower than 5% in 14 out of 20 patients (70%), suggesting that IgG4 have undergone extensive FAE in situ. The levels of monospecific antibodies correlated with the titers of anti-CNTN1 antibodies. However, no correlation was found with clinical severity, and patients with low or high percentage of monospecific antibodies similarly showed a severe phenotype. Native anti-CNTN1 IgG4 were shown to inhibit the interaction between cells expressing CNTN1/CASPR1 and cells expressing neurofascin-155 using an in vitro aggregation assay. Similarly, monovalent Fab significantly inhibited the interaction between CNTN1/CASPR1 and neurofascin-155. Intraneural injections of Fab and native anti-CNTN1 IgG4 indicated that both mono- and bivalent anti-CNTN1 IgG4 potently penetrated the paranodal regions and completely invaded this region by day 3. Altogether, these data indicate anti-CNTN1 IgG4 are mostly bispecific in patients, and that functionally monovalent anti-CNTN1 antibodies have the pathogenic potency to alter paranode.
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Anticuerpos Biespecíficos , Inmunoglobulina G , Factores de Crecimiento Nervioso , Contactina 1 , Moléculas de Adhesión Celular , AutoanticuerposRESUMEN
The expression levels of the synaptic-related proteins contactin 1/2 (CNTN1/2) are down-regulated in the brain of Alzheimer's disease (AD), but the mechanism has not been clarified. γ-Aminobutyric acid (GABA) is considered a biologically active ingredient in food. Our previous research revealed that GABA can regulate CEBPα expression in Aß-treated U251 cells. However, it is uncertain whether GABA can antagonize the pathogenesis of AD. Whether GABA can inhibit the reduction in CNTN1/2 expression by regulating CEBPα/circAPLP2/miR-671-5p in the AD brain remains unclear yet. Here, we demonstrate that GABA could attenuate the deposition of Aß in the brain and ameliorate cognitive impairments in AD model mice. The expressions of CEBPα, circAPLP2, and CNTN1/2 were decreased and that of miR-671-5p was increased in AD model mouse brains and Aß-induced SH-SY5Y cells. These alterations were partly reversed by GABA. The CNTN1/2 expression was down-regulated and up-regulated in SH-SY5Y cells treated with miR-671-5p mimics and miR-671-5p inhibitors, respectively. The results from the luciferase reporter assay revealed that miR-671-5p could bind to the 3'-untranslated region of circAPLP2. The silencing of circAPLP2 with the siRNA duplex caused an up-regulation of miR-671-5p and a down-regulation of CNTN1/2 in SH-SY5Y cells. The silencing of CEBPα with the siRNA duplex caused a down-regulation of circAPLP2 or CNTN1/2 and an up-regulation of miR-671-5p. In conclusion, GABA may decrease the deposition of Aß in the brain, inhibit the down-regulation of CNTN1/2 expression, and ameliorate the cognitive deficits of AD model mice. The CEBPα/circAPLP2/miR-671-5p pathway plays a role in regulating CNTN1/2 expression by GABA in AD.
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Enfermedad de Alzheimer , MicroARNs , Neuroblastoma , Animales , Humanos , Ratones , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Contactina 1 , MicroARNs/genética , ARN Interferente PequeñoRESUMEN
We herein report a 77-year-old man with a 4-month history of progressive gait and sensory disturbances of the extremities. A nerve conduction study indicated demyelinating polyneuropathy. Serum IgG4 levels and anti-contactin 1 IgG4 antibodies were markedly increased. The sural nerve biopsy specimen showed IgG4-positive plasma cell infiltration in the epineurium. Treatment with steroids resulted in an amelioration of functional status, improvement of nerve conduction parameters, decreased serum IgG4 levels, and negative conversion of anti-contactin 1 antibody. Further studies are needed to clarify the significance of IgG4-positive plasma cell infiltration in anti-contactin 1 antibody-positive neuropathies.
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Enfermedades del Sistema Nervioso Periférico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Masculino , Humanos , Anciano , Inmunoglobulina G , Contactina 1 , Nervios Periféricos , Inflamación , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Conducción Nerviosa/fisiología , AutoanticuerposRESUMEN
Diabetes is frequently accompanied by cognitive impairment with insidious onset, and progressive cognitive and behavioral changes. ß-1, 3-galactosyltransferase 2 (B3galt2) contributes to glycosylation, showing a clue for neuronal apoptosis, proliferation and differentiation. However, the role of B3galt2 in diabetic cognitive dysfunction (DCD) has not been investigated. In the present study, we aimed to explore the role of B3galt2 in DCD. Additionally, the potential therapeutic effects of salidroside on DCD was also explored. Diabetic C57BL/6J mice showed cognitive dysfunction together with down-regulated B3galt2. Overexpression of B3galt2 reversed the cognitive decline of diabetic C57BL/6J. Moreover, cognitive impairment was aggravated in B3galt2+/- diabetic mice compared with C57BL/6J diabetic mice. Immunohistochemistry fluorescence indicated that B3galt2 and F3/Contactin were co-localized in the hippocampal regions. Importantly, the expression of F3/Contactin can be regulated by the manipulation of B3galt2, overexpression of which assuaged hippocampal neuronal damage, protected the synapsin, and reduced neuronal apoptosis in diabetic mice. Interestingly, SAL alleviated DCD and reversed the expression of B3galt2 in diabetic C57BL/6J mice. These findings indicate that inhibition of B3galt2/F3/Contactin pathway contributes to DCD, and participates in SAL reversed DCD.
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Disfunción Cognitiva , Diabetes Mellitus Experimental , Ratones , Animales , Contactina 1/metabolismo , Ratones Endogámicos C57BL , Contactinas , Transducción de SeñalRESUMEN
Cell-surface expressed contactin 1 and neurofascin 155 control wiring of the nervous system and interact across cells to form and maintain paranodal myelin-axon junctions. The molecular mechanism of contactin 1 - neurofascin 155 adhesion complex formation is unresolved. Crystallographic structures of complexed and individual contactin 1 and neurofascin 155 binding regions presented here, provide a rich picture of how competing and complementary interfaces, post-translational glycosylation, splice differences and structural plasticity enable formation of diverse adhesion sites. Structural, biophysical, and cell-clustering analysis reveal how conserved Ig1-2 interfaces form competing heterophilic contactin 1 - neurofascin 155 and homophilic neurofascin 155 complexes whereas contactin 1 forms low-affinity clusters through interfaces on Ig3-6. The structures explain how the heterophilic Ig1-Ig4 horseshoe's in the contactin 1 - neurofascin 155 complex define the 7.4 nm paranodal spacing and how the remaining six domains enable bridging of distinct intercellular distances.
Asunto(s)
Moléculas de Adhesión Celular , Contactina 1 , Moléculas de Adhesión Celular/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Contactinas , Axones/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismoRESUMEN
BACKGROUND: Despite highly effective treatment strategies for patients with relapsing-remitting multiple sclerosis (RRMS), long-term neurodegeneration and disease progression are often considerable. Accurate blood-based biomarkers that predict long-term neurodegeneration are lacking. OBJECTIVE: To assess the predictive value of serum neurofilament-light (sNfL) and serum contactin-1 (sCNTN1) for long-term magnetic resonance imaging (MRI)-derived neurodegeneration in natalizumab-treated patients with RRMS. METHODS: sNfL and sCNTN1 were measured in an observational cohort of natalizumab-treated patients with RRMS at baseline (first dose) and at 3 months, Year 1, Year 2, and last follow-up (median = 5.2 years) of treatment. Disability progression was quantified using "EDSS-plus" criteria. Neurodegeneration was measured by calculating annualized percentage brain, ventricular, and thalamic volume change (PBVC, VVC, and TVC, respectively). Linear regression analysis was performed to identify longitudinal predictors of neurodegeneration. RESULTS: In total, 88 patients (age = 37 ± 9 years, 75% female) were included, of whom 48% progressed. Year 1 sNfL level (not baseline or 3 months) was associated with PBVC (standardized (std.) ß = -0.26, p = 0.013), VVC (standardized ß = 0.36, p < 0.001), and TVC (standardized ß = -0.24, p = 0.02). For sCNTN1, only 3-month level was associated with VVC (standardized ß = -0.31, p = 0.002). CONCLUSION: Year 1 (but not baseline) sNfL level was predictive for long-term brain atrophy in patients treated with natalizumab. sCNTN1 level did not show a clear predictive value.