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BACKGROUND: Contactin-associated protein-2(CASPR2) antibody-associated autoimmune encephalitis(AE) is rare in children. This study aimed to report the clinical characteristics and long-term outcome of CASPR2 autoimmunity in children to expand the disease spectrum. METHODS: Children who were hospitalized in our hospital with clinically suspected AE from May 2015 to April 2022 and underwent neuronal surface antibodies detections were retrospectively analyzed. Clinical data of patients with CASPR2 autoimmunity were collected. RESULTS: Patients who were positive for NMDAR-IgG, CASPR2-IgG, LGI1-IgG and IgLON5-IgG occupied 95.2%(119/125),3.2%(4/125),0.8%(1/125) and 0.8%(1/125), respectively.The median onset age of the 4 patients with CASPR2-IgG was 5.6 years. The most common symptoms were psychiatric symptoms/abnormal behavior(3/4) and sleep dysfunction(3/4). One patient developed a phenotype of Rasmussen encephalitis(RE). Tumor was absent in our patients. Two patients showed abnormal findings on initial brain magnetic resonance imaging(MRI) scans. All the patients showed favorable response to immunotherapy except the patient with RE experienced recurrent symptoms who finally achieved remission after surgery. All the patients had a favorable long-term outcome at the last follow-up(33-58months). CONCLUSIONS: CASPR2 autoimmunity may be the second most common anti-neuronal surface antibodies associated neurological disease in children. Psychiatric symptoms/abnormal behavior and sleep disorder were common in children with CASPR2-associated AE. Tumor was rare in those patients. Most pediatric patients had a favorable long-term outcome.
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Autoanticuerpos , Encefalitis , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Humanos , Masculino , Femenino , Niño , Encefalitis/inmunología , Encefalitis/diagnóstico , Estudios Retrospectivos , Proteínas del Tejido Nervioso/inmunología , Proteínas de la Membrana/inmunología , Preescolar , Enfermedad de Hashimoto/inmunología , Enfermedad de Hashimoto/diagnóstico , AdolescenteRESUMEN
Anti-contactin associated protein receptor 2 (CASPR2) encephalitis is a severe autoimmune encephalitis with a variable clinical phenotype including behavioral abnormalities, cognitive decline, epileptic seizures, peripheral nerve hyperexcitability and neuropathic pain. The detailed mechanisms of how CASPR2 autoantibodies lead to synaptic dysfunction and clinical symptoms are largely unknown. Aiming for analyses from the molecular to the clinical level, we isolated antibody-secreting cells from the cerebrospinal fluid of two patients with CASPR2 encephalitis. From these we cloned four anti-CASPR2 human monoclonal autoantibodies (mAbs) with strong binding to brain and peripheral nerves. All were highly hypermutated and mainly of the IgG4 subclass. Mutagenesis studies determined selective binding to the discoidin domain of CASPR2. Surface plasmon resonance revealed affinities with dissociation constants KD in the pico- to nanomolar range. CASPR2 mAbs interrupted the interaction of CASPR2 with its binding partner contactin 2 in vitro and were internalized after binding to CASPR2-expressing cells. Electrophysiological recordings of rat hippocampal slices after stereotactic injection of CASPR2 mAbs showed characteristic afterpotentials following electrical stimulation. In vivo experiments with intracerebroventricular administration of human CASPR2 mAbs into mice and rats showed EEG-recorded brain hyperexcitability but no spontaneous recurrent seizures. Behavioral assessment of infused mice showed a subtle clinical phenotype, mainly affecting sociability. Mouse brain MRI exhibited markedly reduced resting-state functional connectivity without short-term structural changes. Together, the experimental data support the direct pathogenicity of CASPR2 autoantibodies. The minimally invasive EEG and MRI techniques applied here may serve as novel objective, quantifiable tools for improved animal models, in particular for subtle neuropsychiatric phenotypes or repeated measurements.
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Anticuerpos Monoclonales , Autoanticuerpos , Encefalitis , Imagen por Resonancia Magnética , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Animales , Autoanticuerpos/inmunología , Autoanticuerpos/metabolismo , Ratas , Humanos , Ratones , Imagen por Resonancia Magnética/métodos , Proteínas del Tejido Nervioso/inmunología , Proteínas del Tejido Nervioso/metabolismo , Masculino , Encefalitis/inmunología , Encefalitis/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/inmunología , Modelos Animales de Enfermedad , Femenino , Encéfalo/metabolismo , Hipocampo/metabolismo , Conducta Animal/fisiologíaRESUMEN
Synaptic ribbons are the eponymous specializations of continuously active ribbon synapses. They are primarily composed of the RIBEYE protein that consists of a unique amino-terminal A-domain and carboxy-terminal B-domain that is largely identical to the ubiquitously expressed transcriptional regulator protein CtBP2. Both RIBEYE A-domain and RIBEYE B-domain are essential for the assembly of the synaptic ribbon, as shown by previous analyses of RIBEYE knockout and knockin mice and related investigations. How exactly the synaptic ribbon is assembled from RIBEYE subunits is not yet clear. To achieve further insights into the architecture of the synaptic ribbon, we performed analytical post-embedding immunogold-electron microscopy with direct gold-labelled primary antibodies against RIBEYE A-domain and RIBEYE B-domain for improved ultrastructural resolution. With direct gold-labelled monoclonal antibodies against RIBEYE A-domain and RIBEYE B-domain, we found that both domains show a very similar localization within the synaptic ribbon of mouse photoreceptor synapses, with no obvious differential gradient between the centre and surface of the synaptic ribbon. These data favour a model of the architecture of the synaptic ribbon in which the RIBEYE A-domain and RIBEYE B-domain are located similar distances from the midline of the synaptic ribbon.
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Anticuerpos Monoclonales , Sinapsis , Animales , Ratones , Sinapsis/ultraestructura , Sinapsis/metabolismo , Anticuerpos Monoclonales/inmunología , Oxidorreductasas de Alcohol/metabolismo , Oxidorreductasas de Alcohol/química , Proteínas Co-Represoras/metabolismo , Inmunohistoquímica/métodos , Dominios Proteicos , Microscopía Inmunoelectrónica/métodos , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/inmunologíaRESUMEN
RATIONALE: The phenomenon of hypercoagulability has not been previously documented in individuals with Morvan's syndrome, especially in those associated with contactin-associated protein-like receptor 2 (CASPR2). PATIENT CONCERNS: A previously healthy 32-year-old Chinese male was admitted to the hospital with central and peripheral neurologic symptoms. The patient was tested positive for anti-CASPR2 antibodies, and also presented with an activated coagulation state on admission, characterized by a low activated partial thromboplastin time and a high platelet count. With gradual improvement of clinical symptoms, activated partial thromboplastin time, and platelet count returned to normal. Simultaneously, anti-CASPR2 antibody titers significantly decreased and eventually became undetectable. DIAGNOSES: The patient was diagnosed as Morvan's syndrome with positive anti-CASPAR2 antibodies accompanied with hypercoagulable state. INTERVENTIONS: Plasmapheresis was administered to improve the symptoms combined with prednisolone acetate therapy. OUTCOMES: The patient experienced complete resolution of all symptoms during hospitalization and generally recovery after 2 months of discharge. LESSONS: Emphasis should be directed towards hypercoagulability in individuals diagnosed with Morvan's syndrome, particularly those presenting with positive anti-CASPR2 antibodies. Anticoagulant therapy may represent a novel therapeutic approach for individuals afflicted with Morvan's syndrome and exhibiting positivity for anti-CASPR2 antibodies.
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Autoanticuerpos , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Trombofilia , Humanos , Masculino , Adulto , Trombofilia/inmunología , Trombofilia/tratamiento farmacológico , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Proteínas de la Membrana/inmunología , Proteínas del Tejido Nervioso/inmunología , PlasmaféresisRESUMEN
BACKGROUND: We have previously identified auto-antibody (Ab) to collapsin response mediator protein 2 (CRMP2) in patients with encephalitis. The present study aims to evaluate the pathogenic effects of anti-CRMP2 Ab. METHODS: Recombinant CRMP2 protein was injected subcutaneously into mice to establish an active immune mouse model with anti-CRMP2 Ab. Behavioral assessments, histopathological staining, and electrophysiological testing were performed to identify any pathogenic changes. RESULTS: The mice exhibited signs of impaired motor coordination four weeks post-immunization of CRMP2 protein. Moreover, CRMP2 immunized mice for eight weeks showed anxiety-like behaviors indicating by tests of open field and the elevated plus maze. After incubating the CA1 region of hippocampal brain section with the sera from CRMP2 immunized mice, the whole-cell path-clamp recordings showed increased excitability of pyramidal neurons. However, no obvious inflammation and infiltration of immune cells were observed by histopathological analysis. Western blot showed that the phosphorylation levels of CRMP2-Thr514 and -Ser522 were not affected. CONCLUSION: In an active immunization model with CRMP2 protein, impaired coordination and anxiety-like behaviors were observed. Also, anti-CRMP2 Abs containing sera heightened the excitability of hippocampal pyramidal neurons in vitro, which imply the pathogenic effects of anti-CRMP2 Ab.
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Ansiedad , Péptidos y Proteínas de Señalización Intercelular , Proteínas del Tejido Nervioso , Células Piramidales , Animales , Células Piramidales/patología , Células Piramidales/metabolismo , Células Piramidales/inmunología , Ansiedad/inmunología , Ansiedad/patología , Ratones , Proteínas del Tejido Nervioso/inmunología , Péptidos y Proteínas de Señalización Intercelular/inmunología , Masculino , Autoanticuerpos/inmunología , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Fosforilación , Hipocampo/patología , Hipocampo/inmunología , Hipocampo/metabolismoRESUMEN
Chorea is a very commonly encountered movement disorder; it has various etiologies, and it can have autoimmune, vascular, degenerative, or paraneoplastic etiology. Our patient had acute onset chorea and a strong history of smoking, which made us suspect first vascular followed by paraneoplastic cause. After ruling out common vascular and metabolic causes, his whole body positron emission tomography (PET) scan revealed a mass in the right upper lobe, a biopsy revealed a small cell carcinoma lung and a paraneoplastic panel showed antibodies positive for collapsin response mediator protein 5 antigen (CRMP-5/CV2); the patient was started on immunomodulation, chemotherapy with the variable response, he succumbed to a cardiac event after treatment.
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Corea , Neoplasias Pulmonares , Humanos , Corea/etiología , Corea/diagnóstico , Masculino , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/diagnóstico , Proteínas del Tejido Nervioso/inmunología , Carcinoma Pulmonar de Células Pequeñas/complicaciones , Resultado Fatal , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Hidrolasas , Proteínas Asociadas a MicrotúbulosRESUMEN
BACKGROUND AND OBJECTIVES: Patients with ongoing seizures are usually not allowed to drive. The prognosis for seizure freedom is favorable in patients with autoimmune encephalitis (AIE) with antibodies against NMDA receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the gamma-aminobutyric-acid B receptor (GABABR). We hypothesized that after a seizure-free period of 3 months, patients with AIE have a seizure recurrence risk of <20% during the subsequent 12 months. This would render them eligible for noncommercial driving according to driving regulations in several countries. METHODS: This retrospective multicenter cohort study analyzed follow-up data from patients aged 15 years or older with seizures resulting from NMDAR-, LGI1-, CASPR2-, or GABABR-AIE, who had been seizure-free for ≥3 months. We used Kaplan-Meier (KM) estimates for the seizure recurrence risk at 12 months for each antibody group and tested for the effects of potential covariates with regression models. RESULTS: We included 383 patients with NMDAR-, 440 with LGI1-, 114 with CASPR2-, and 44 with GABABR-AIE from 14 international centers. After being seizure-free for 3 months after an initial seizure period, we calculated the probability of remaining seizure-free for another 12 months (KM estimate) as 0.89 (95% confidence interval [CI] 0.85-0.92) for NMDAR, 0.84 (CI 0.80-0.88) for LGI1, 0.82 (CI 0.75-0.90) for CASPR2, and 0.76 (CI 0.62-0.93) for GABABR. DISCUSSION: Taking a <20% recurrence risk within 12 months as sufficient, patients with NMDAR-AIE and LGI1-AIE could be considered eligible for noncommercial driving after having been seizure-free for 3 months.
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Autoanticuerpos , Encefalitis , Péptidos y Proteínas de Señalización Intracelular , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Receptores de GABA-B , Recurrencia , Humanos , Femenino , Masculino , Adulto , Péptidos y Proteínas de Señalización Intracelular/inmunología , Autoanticuerpos/sangre , Persona de Mediana Edad , Encefalitis/inmunología , Estudios Retrospectivos , Receptores de GABA-B/inmunología , Proteínas del Tejido Nervioso/inmunología , Adulto Joven , Proteínas de la Membrana/inmunología , Receptores de N-Metil-D-Aspartato/inmunología , Convulsiones/etiología , Convulsiones/inmunología , Enfermedad de Hashimoto/inmunología , Enfermedad de Hashimoto/sangre , Anciano , Adolescente , Estudios de Seguimiento , Proteínas/inmunología , Estudios de CohortesRESUMEN
OBJECTIVES: To demonstrate treatment efficacy on composite and non-length-dependent (NLD) punch biopsy specimens from intravenous immunoglobulin (IVIG) in pure small-fiber neuropathy (SFN) with trisulfated heparin disaccharide (TS-HDS), fibroblast growth factor-3 (FGFR-3), or Plexin D1 antibodies. SFN has an increasing prevalence, and over 30% of cases may be immune-mediated. TS-HDS, FGFR-3, and Plexin D1 autoantibodies have been shown to be present in 44%-55% of cryptogenic SFN cases, suggesting an immune mechanism. Reports have shown IVIG to be effective for this condition, but some controversy exists based on length-dependent (LD) post-IVIG treatment data in a recent trial. METHODS: In a retrospective review, all pure SFN cases tested for the 3 antibodies from January 2021 to May 2022 were tabulated, and patients who underwent IVIG treatment were separated and analyzed for changes in epidermal nerve fiber density (ENFD) on skin biopsy, as well as SFN-specific questionnaire and pain scores. RESULTS: Ninety-one patients with pure SFN had antibody testing. Sixty of these (66%) were seropositive, and 31 (34%) were seronegative. Seventeen seropositive patients (13 female patients, 4 male patients, 6 FGFR-3, 2 TS-HDS, 4 Plexin D1, 2 with all 3 antibodies, 1 with FGFR-3 and Plexin D1, 1 with FGFR-3 and TS-HDS, and 1 with TS-HDS and Plexin D1) underwent IVIG treatment. Of these, 2 patients stopped treatment due to side effects, and the remaining 15 completed at least 6 months of IVIG. Of these, 12 had a post-IVIG skin biopsy, and of these, 11 (92%) had a 55.1% improved mean composite ENFD (P = 0.01). NLD-ENFD specimens improved by 42.3% (P = 0.02), and LD-ENFD specimens improved by 99.7% (P = 0.01). Composite ENFD in Plexin D1-SFN patients improved by 139% (P = 0.04). In addition, 14 patients had questionnaires pre-IVIG/post-IVIG, and average pain decreased by 2.7 (P = 0.002). CONCLUSIONS: IVIG shows disease-modifying effect in immune SFN with novel antibodies, especially Plexin D1-SFN, as well as significantly improved pain. NLD-ENFD should be examined as well as LD-ENFD to see this effect. Further randomized controlled trials looking at NLD-ENFD as well as LD-ENFD improvement, along with pain and SFN-specific questionnaires, are needed to confirm these findings.
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Autoanticuerpos , Inmunoglobulinas Intravenosas , Piel , Neuropatía de Fibras Pequeñas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Autoanticuerpos/sangre , Biopsia , Disacáridos , Heparina/análogos & derivados , Heparina/inmunología , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Proteínas del Tejido Nervioso/inmunología , Receptores de Superficie Celular , Estudios Retrospectivos , Piel/patología , Neuropatía de Fibras Pequeñas/tratamiento farmacológico , Resultado del Tratamiento , Glicoproteínas de Membrana/inmunología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/inmunologíaRESUMEN
Introduction: Anti-NMDA receptor encephalitis is an autoimmune disorder caused by autoantibodies (abs) against the conformational epitope on GluN1 subunits. GluN1-abs have been determined with cell-based assay (CBA) co-expressing GluN1/GluN2 subunits. However, commercial fixed CBA expressing only GluN1 subunit has increasingly been used in clinical practice. The ab titers can be determined with serial dilutions, but its clinical significance remains unclear. We aimed to develop an H-intensity scale (HIS) score to estimate GluN1-ab titers in cerebrospinal fluid (CSF) with one-time immunostaining using both commercial CBA and immunohistochemistry and report its usefulness. "H" is the initial of a patient with high CSF GluN1-ab titers (1:2,048). Methods: We first determined the reliability of CBA in 370 patients with suspected autoimmune encephalitis by comparing the results between commercial CBA and established assay in Dalmau's Lab. Then, we made positive control panels using the patient H's CSF diluted in a fourfold serial dilution method (1:2, 1:8, 1:32, 1:128, 1:512, and 1:2,048). Based on the panels, we scored the intensity of ab reactivity of 79 GluN1-ab-positive patients' CSF (diluted at 1:2) on a scale from 0 to 6 (with ≥1 considered positive). To assess inter-assay reliability, we performed immunostaining twice in 21 patients' CSF. We investigated an association between the score of CSF obtained at diagnosis and the clinical/paraclinical features. Results: The sensitivity and specificity of CBA were 93.7% (95% CI: 86.0-97.3) and 98.6% (95% CI: 96.5-99.5), respectively. Linear regression analysis showed a good agreement between the scores of the first and second assays. Patients with a typical spectrum, need for mechanical ventilation support, autonomic symptoms/central hypoventilation, dyskinesias, speech dysfunction, decreased level of consciousness, preceding headache, ovarian teratoma, and CSF leukocyte count >20 cells/µL had a higher median HIS score than those without, but HIS score was not associated with sex, age at onset, or seizure. HIS score at diagnosis had a significant effect on 1-year functional status. Discussion: The severity of disease and four of the six core symptoms were associated with higher GluN1-ab titers in CSF at diagnosis, which may play a role in poor 1-year functional status. An incomplete phenotype can be attributed to low CSF GluN1-ab titers.
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Encefalitis Antirreceptor N-Metil-D-Aspartato , Inmunohistoquímica , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico , Encefalitis Antirreceptor N-Metil-D-Aspartato/líquido cefalorraquídeo , Encefalitis Antirreceptor N-Metil-D-Aspartato/inmunología , Autoanticuerpos/líquido cefalorraquídeo , Autoanticuerpos/inmunología , Biomarcadores/líquido cefalorraquídeo , Proteínas del Tejido Nervioso/inmunología , Receptores de N-Metil-D-Aspartato/inmunología , Reproducibilidad de los ResultadosRESUMEN
A substantial number of patients recovering from acute SARS-CoV-2 infection present serious lingering symptoms, often referred to as long COVID (LC). However, a subset of these patients exhibits the most debilitating symptoms characterized by ongoing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). We specifically identified and studied ME/CFS patients from two independent LC cohorts, at least 12 months post the onset of acute disease, and compared them to the recovered group (R). ME/CFS patients had relatively increased neutrophils and monocytes but reduced lymphocytes. Selective T cell exhaustion with reduced naïve but increased terminal effector T cells was observed in these patients. LC was associated with elevated levels of plasma pro-inflammatory cytokines, chemokines, Galectin-9 (Gal-9), and artemin (ARTN). A defined threshold of Gal-9 and ARTN concentrations had a strong association with LC. The expansion of immunosuppressive CD71+ erythroid cells (CECs) was noted. These cells may modulate the immune response and contribute to increased ARTN concentration, which correlated with pain and cognitive impairment. Serology revealed an elevation in a variety of autoantibodies in LC. Intriguingly, we found that the frequency of 2B4+CD160+ and TIM3+CD160+ CD8+ T cells completely separated LC patients from the R group. Our further analyses using a multiple regression model revealed that the elevated frequency/levels of CD4 terminal effector, ARTN, CEC, Gal-9, CD8 terminal effector, and MCP1 but lower frequency/levels of TGF-ß and MAIT cells can distinguish LC from the R group. Our findings provide a new paradigm in the pathogenesis of ME/CFS to identify strategies for its prevention and treatment.
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COVID-19 , Eritropoyesis , Síndrome de Fatiga Crónica , SARS-CoV-2 , Humanos , Síndrome de Fatiga Crónica/inmunología , Síndrome de Fatiga Crónica/sangre , COVID-19/inmunología , COVID-19/sangre , COVID-19/complicaciones , Femenino , Masculino , Persona de Mediana Edad , SARS-CoV-2/inmunología , Adulto , Eritropoyesis/inmunología , Galectinas/sangre , Galectinas/inmunología , Citocinas/sangre , Citocinas/metabolismo , Síndrome Post Agudo de COVID-19 , Inflamación/inmunología , Proteínas del Tejido Nervioso/inmunología , Proteínas del Tejido Nervioso/sangreRESUMEN
This comprehensive research review explores the complex interplay between the Sema-3E/PlexinD1 axis and dendritic cells (DCs), highlighting its critical role in immune modulation with implications for clinical application Critical regulators of immune responses Dendritic cells are central to adaptive immunity, and the Sema-3E /PlexinD1 axis emerges as a key modulator affecting their phenotypes and functions Review delineates the impact of this signaling axis on DC maturation, migration, antigen presentation, and cytokine production, unravels its multifaceted role in shaping the immune response. Recognizing the limitations and gaps in current knowledge, the study highlights the need for further studies to condition downstream signaling events and related information experienced by the Sema-3E/PlexinD1 axis emphasizes the clarity of the immune system. The review concludes by identifying opportunities for translation, focusing on therapeutic and diagnostic potential. It highlights the importance of collaborative, interdisciplinary efforts to address the challenges and harness the therapeutic and pathological potential of targeting the Sema-3E/PlexinD1 axis, thus opening the way for transformative advances in immunology and clinical medicine.
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Células Dendríticas , Fenotipo , Semaforinas , Transducción de Señal , Células Dendríticas/inmunología , Humanos , Semaforinas/metabolismo , Semaforinas/inmunología , Animales , Presentación de Antígeno , Diferenciación Celular/inmunología , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/inmunología , Proteínas del Tejido Nervioso/genética , Inmunomodulación , Citocinas/metabolismo , Glicoproteínas de Membrana , Péptidos y Proteínas de Señalización IntracelularAsunto(s)
Hipoglucemia , Necrosis , Humanos , Hipoglucemia/etiología , Hipoglucemia/complicaciones , Proteínas Asociadas a Microtúbulos , Proteínas del Tejido Nervioso/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Masculino , Femenino , Persona de Mediana Edad , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Imagen por Resonancia Magnética , HidrolasasRESUMEN
The activity-regulated cytoskeleton-associated protein (Arc) is a complex regulator of synaptic plasticity in glutamatergic neurons. Understanding its molecular function is key to elucidate the neurobiology of memory and learning, stress regulation, and multiple neurological and psychiatric diseases. The recent development of anti-Arc nanobodies has promoted the characterization of the molecular structure and function of Arc. This study aimed to validate two anti-Arc nanobodies, E5 and H11, as selective modulators of the human Arc N-lobe (Arc-NL), a domain that mediates several molecular functions of Arc through its peptide ligand binding site. The structural characteristics of recombinant Arc-NL-nanobody complexes were solved at atomic resolution using X-ray crystallography. Both anti-Arc nanobodies bind specifically to the multi-peptide binding site of Arc-NL. Isothermal titration calorimetry showed that the Arc-NL-nanobody interactions occur at nanomolar affinity, and that the nanobodies can displace a TARPγ2-derived peptide from the binding site. Thus, both anti-Arc-NL nanobodies could be used as competitive inhibitors of endogenous Arc ligands. Differences in the CDR3 loops between the two nanobodies indicate that the spectrum of short linear motifs recognized by the Arc-NL should be expanded. We provide a robust biochemical background to support the use of anti-Arc nanobodies in attempts to target Arc-dependent synaptic plasticity. Function-blocking anti-Arc nanobodies could eventually help unravel the complex neurobiology of synaptic plasticity and allow to develop diagnostic and treatment tools.
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Proteínas del Citoesqueleto , Proteínas del Tejido Nervioso , Anticuerpos de Dominio Único , Humanos , Anticuerpos de Dominio Único/química , Anticuerpos de Dominio Único/inmunología , Anticuerpos de Dominio Único/metabolismo , Sitios de Unión , Proteínas del Citoesqueleto/metabolismo , Proteínas del Citoesqueleto/química , Proteínas del Citoesqueleto/inmunología , Ligandos , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/inmunología , Cristalografía por Rayos X , Unión Proteica , Modelos Moleculares , Secuencia de AminoácidosRESUMEN
GCN5L1, also known as BLOC1S1 and BLOS1, is a small intracellular protein involved in many key biological processes. Over the last decade, GCN5L1 has been implicated in the regulation of protein lysine acetylation, energy metabolism, endo-lysosomal function, and cellular immune pathways. An increasing number of published papers have used commercially-available reagents to interrogate GCN5L1 function. However, in many cases these reagents have not been rigorously validated, leading to potentially misleading results. In this report we tested several commercially-available antibodies for GCN5L1, and found that two-thirds of those available did not unambiguously detect the protein by western blot in cultured mouse cells or ex vivo liver tissue. These data suggest that previously published studies which used these unverified antibodies to measure GCN5L1 protein abundance, in the absence of other independent methods of corroboration, should be interpreted with appropriate caution.
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Anticuerpos , Animales , Ratones , Anticuerpos/inmunología , Anticuerpos/metabolismo , Hígado/metabolismo , Hígado/inmunología , Ratones Noqueados , Proteínas Mitocondriales/inmunología , Proteínas del Tejido Nervioso/inmunologíaRESUMEN
PURPOSE OF REVIEW: To describe relevant advances in nonparaneoplastic autoimmune cerebellar ataxias (ACA) with neuronal antibodies. RECENT FINDINGS: Apart from metabotropic glutamate receptor 1(mGluR1) antibodies, in recent years, the number of neuronal antibodies against surface antigens in ACA has increased with the description of glutamate kainate receptor subunit 2 (GluK2) antibodies in young patients with cerebellitis. Around 20% of patients with contactin-associated protein-like 2 (CASPR2) encephalitis also present prominent cerebellar ataxia. However, isolate cerebellar ataxia is unusual (<4%). Outcome in patients with neuronal antibodies against surface antigens remains suboptimal despite the cerebellar ataxia probably is antibody-mediated.Concerning neuronal antibodies against intracellular antigens, up to 25% of patients with glutamic acid decarboxylase (GAD) antibodies present transient episodes of vertigo or diplopia that antedate the development of the ACA. There is in-vitro evidence that septin-5 is partially exposed to the membrane and the antibodies may interfere with septin-5 function. The clinical significance of the remaining antibodies against intracellular antigens remains unclear. SUMMARY: The number of antibodies against surface antigens is increasing in ACA, but the response to the immunotherapy remains suboptimal. More studies are needed to clarify the role of most of the antibodies against intracellular antigens described in these patients.
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Autoanticuerpos , Ataxia Cerebelosa , Humanos , Ataxia Cerebelosa/inmunología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Neuronas/inmunología , Enfermedades Autoinmunes/inmunología , Proteínas del Tejido Nervioso/inmunologíaAsunto(s)
Autoanticuerpos , Inmunidad Innata , Péptidos y Proteínas de Señalización Intracelular , Encefalitis Límbica , Imagen por Resonancia Magnética , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Tomografía de Emisión de Positrones , Pirazoles , Humanos , Encefalitis Límbica/inmunología , Encefalitis Límbica/diagnóstico por imagen , Pirazoles/farmacología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Inmunidad Innata/inmunología , Proteínas del Tejido Nervioso/inmunología , Autoanticuerpos/inmunología , Proteínas de la Membrana/inmunología , Pirimidinas , Femenino , Masculino , Persona de Mediana EdadRESUMEN
Importance: Rapid and accurate diagnosis of autoimmune encephalitis encourages prompt initiation of immunotherapy toward improved patient outcomes. However, clinical features alone may not sufficiently narrow the differential diagnosis, and awaiting autoantibody results can delay immunotherapy. Objective: To identify simple magnetic resonance imaging (MRI) characteristics that accurately distinguish 2 common forms of autoimmune encephalitis, LGI1- and CASPR2-antibody encephalitis (LGI1/CASPR2-Ab-E), from 2 major differential diagnoses, viral encephalitis (VE) and Creutzfeldt-Jakob disease (CJD). Design, Setting, and Participants: This cross-sectional study involved a retrospective, blinded analysis of the first available brain MRIs (taken 2000-2022) from 192 patients at Oxford University Hospitals in the UK and Mayo Clinic in the US. These patients had LGI1/CASPR2-Ab-E, VE, or CJD as evaluated by 2 neuroradiologists (discovery cohort; n = 87); findings were validated in an independent cohort by 3 neurologists (n = 105). Groups were statistically compared with contingency tables. Data were analyzed in 2023. Main Outcomes and Measures: MRI findings including T2 or fluid-attenuated inversion recovery (FLAIR) hyperintensities, swelling or volume loss, presence of gadolinium contrast enhancement, and diffusion-weighted imaging changes. Correlations with clinical features. Results: Among 192 participants with MRIs reviewed, 71 were female (37%) and 121 were male (63%); the median age was 66 years (range, 19-92 years). By comparison with VE and CJD, in LGI1/CASPR2-Ab-E, T2 and/or FLAIR hyperintensities were less likely to extend outside the temporal lobe (3/42 patients [7%] vs 17/18 patients [94%] with VE; P < .001, and 3/4 patients [75%] with CJD; P = .005), less frequently exhibited swelling (12/55 [22%] with LGI1/CASPR2-Ab-E vs 13/22 [59%] with VE; P = .003), and showed no diffusion restriction (0 patients vs 16/22 [73%] with VE and 8/10 [80%] with CJD; both P < .001) and rare contrast enhancement (1/20 [5%] vs 7/17 [41%] with VE; P = .01). These findings were validated in an independent cohort and generated an area under the curve of 0.97, sensitivity of 90%, and specificity of 95% among cases with T2/FLAIR hyperintensity in the hippocampus and/or amygdala. Conclusions and Relevance: In this study, T2 and/or FLAIR hyperintensities confined to the temporal lobes, without diffusion restriction or contrast enhancement, robustly distinguished LGI1/CASPR2-Ab-E from key differential diagnoses. These observations should assist clinical decision-making toward expediting immunotherapy. Their generalizability to other forms of autoimmune encephalitis and VE should be examined in future studies.
Asunto(s)
Autoanticuerpos , Encefalitis , Péptidos y Proteínas de Señalización Intracelular , Imagen por Resonancia Magnética , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Humanos , Masculino , Femenino , Anciano , Péptidos y Proteínas de Señalización Intracelular/inmunología , Persona de Mediana Edad , Imagen por Resonancia Magnética/métodos , Estudios Transversales , Autoanticuerpos/inmunología , Encefalitis/diagnóstico por imagen , Encefalitis/inmunología , Encefalitis/patología , Estudios Retrospectivos , Proteínas del Tejido Nervioso/inmunología , Proteínas de la Membrana/inmunología , Adulto , Anciano de 80 o más Años , Síndrome de Creutzfeldt-Jakob/diagnóstico por imagen , Síndrome de Creutzfeldt-Jakob/inmunología , Síndrome de Creutzfeldt-Jakob/patología , Diagnóstico Diferencial , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Enfermedad de Hashimoto/diagnóstico por imagen , Enfermedad de Hashimoto/inmunología , Adulto JovenRESUMEN
Autoantibodies against contactin-associated protein 2 (Caspr2) not only induce limbic autoimmune encephalitis but are also associated with pain conditions. Here, we analyzed clinical data on pain in a large cohort of patients included into the German Network for Research in Autoimmune Encephalitis. Out of 102 patients in our cohort, pain was a frequent symptom (36% of all patients), often severe (63.6% of the patients with pain) and/or even the major symptom (55.6% of the patients with pain). Pain phenotypes differed between patients. Cluster analysis revealed two major phenotypes including mostly distal-symmetric burning pain and widespread pain with myalgia and cramps. Almost all patients had IgG4 autoantibodies and some additional IgG1, 2, and/or 3 autoantibodies, but IgG subclasses, titers, and presence or absence of intrathecal synthesis were not associated with the occurrence of pain. However, certain pre-existing risk factors for chronic pain like diabetes mellitus, peripheral neuropathy, or preexisting chronic back pain tended to occur more frequently in patients with anti-Caspr2 autoantibodies and pain. Our data show that pain is a relevant symptom in patients with anti-Caspr2 autoantibodies and support the idea of decreased algesic thresholds leading to pain. Testing for anti-Caspr2 autoantibodies needs to be considered in patients with various pain phenotypes.