RESUMEN
We propose the finger drop sign as a new clinical variant of acute motor axonal neuropathy (AMAN) defined by immunological and radiological evidence. We identified eight consecutive patients who had AMAN. All of them developed prominent involvement of the finger extensors. We performed magnetic resonance imaging (MRI) of the extremity muscles and serological assays for antiganglioside antibodies and Campylobacter jejuni. Patients with AMAN showed characteristic and a markedly sustained weakness of the finger extensors with a distinctive pattern of the finger drop sign. Limb MRI revealed unevenly distributed abnormal signals in the muscles mainly innervated by the posterior interosseous nerve. All tested patients showed positivity for immunoglobulin G antibody against ganglioside complex of GM1 and phosphatidic acid. A pathophysiological understanding of this unique syndrome can provide further insight into antiganglioside-antibody-mediated axonal injury in Guillain-Barré syndrome.
Asunto(s)
Autoanticuerpos/inmunología , Axones , Dedos/fisiopatología , Gangliósido G(M1)/inmunología , Síndrome de Guillain-Barré/clasificación , Debilidad Muscular/fisiopatología , Conducción Nerviosa , Ácidos Fosfatidicos/inmunología , Anciano , Anticuerpos Antibacterianos , Campylobacter jejuni/inmunología , Electrodiagnóstico , Electromiografía , Femenino , Dedos/inervación , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/inmunología , Síndrome de Guillain-Barré/fisiopatología , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Examen Neurológico , Examen Físico , Estudios RetrospectivosRESUMEN
A series of tetrahydroisoquinoline-based benzodiazepine dimers were synthesized and tested for in vitro cytotoxicity against a panel of cancer cell lines. Structure-activity relationship investigation of various spacers guided by molecular modeling studies helped to identify compounds with picomolar activity. Payload 17 was conjugated to anti-mesothelin and anti-fucosylated monosialotetrahexosylganglioside (FucGM1) antibodies using lysosome-cleavable valine-citrulline dipeptide linkers via heterogeneous lysine conjugation and bacterial transglutaminase-mediated site-specific conjugation. In vitro, these antibody drug conjugates (ADCs) exhibited significant cytotoxic and target-mediated selectivity on human cancer cell lines. The pharmacokinetics and efficacy of these ADCs were further evaluated in gastric and lung cancer xenograft models in mice. Consistent pharmacokinetic profiles, high target specificity, and robust antitumor activity were observed in these models after a single dose of the ADC-46 (0.02 µmol/kg).
Asunto(s)
Anticuerpos Monoclonales/química , Antineoplásicos/farmacología , Benzodiazepinas/química , Diseño de Fármacos , Inmunoconjugados/farmacología , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Tetrahidroisoquinolinas/química , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Antineoplásicos/química , Apoptosis , Benzodiazepinas/metabolismo , Proliferación Celular , Femenino , Gangliósido G(M1)/análogos & derivados , Gangliósido G(M1)/inmunología , Proteínas Ligadas a GPI/inmunología , Humanos , Inmunoconjugados/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Mesotelina , Ratones , Ratones SCID , Carcinoma Pulmonar de Células Pequeñas/patología , Neoplasias Gástricas/patología , Relación Estructura-Actividad , Tetrahidroisoquinolinas/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoAsunto(s)
Infecciones por Coronavirus/complicaciones , Síndrome de Guillain-Barré/fisiopatología , Síndrome de Guillain-Barré/virología , Neumonía Viral/complicaciones , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Betacoronavirus , COVID-19 , Infecciones por Coronavirus/inmunología , Gangliósido G(M1)/inmunología , Gangliósidos/inmunología , Síndrome de Guillain-Barré/inmunología , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/inmunología , SARS-CoV-2RESUMEN
OBJECTIVE: Approximately 15%-20% of patients with Guillain-Barré syndrome (GBS) are unable to walk independently at 6 months from the onset of neurological symptom. The modified Erasmus GBS outcome score (mEGOS) has been reported as a prognostic tool.Herein we investigated the association between a poor outcome, inability to walk independently at 6 months and presence of antiganglioside antibodies. METHODS: The clinical and serological data of 177 patients with GBS were retrospectively collected in Japan to assess the associations between a poor outcome and serum IgG antibodies against each ganglioside (GM1, GD1a, GalNAc-GD1a, GQ1b and GT1a). In addition, we investigated whether the combination of mEGOS and serum IgG antibodies against gangliosides is useful in predicting a poor outcome. RESULTS: The patients with IgG anti-GD1a antibodies more frequently showed poor outcomes than those without these antibodies (9 (36%) of 25 vs 8 (6%) of 127 patients, p<0.001). Particularly, 80% showed a poor outcome when they had both serum IgG anti-GD1a antibody and a high mEGOS of ≥10 on day 7 of admission. CONCLUSIONS: The combination of serum IgG anti-GD1a antibodies and a high mEGOS could help in making a more accurate prognosis of patients than mEGOS alone, especially for predicting poor outcomes.
Asunto(s)
Gangliósidos/inmunología , Síndrome de Guillain-Barré/inmunología , Inmunoglobulina G/inmunología , Limitación de la Movilidad , Factores de Edad , Autoanticuerpos , Diarrea , Electrodiagnóstico , Gangliósido G(M1)/inmunología , Síndrome de Guillain-Barré/fisiopatología , Síndrome de Guillain-Barré/terapia , Humanos , Pronóstico , Respiración Artificial , Estudios RetrospectivosRESUMEN
BACKGROUND: Antibodies against ganglioside complexes (GSCs) are associated with various clinical features and subtypes of Guillain-Barré syndrome (GBS). METHODS: One-hundred patients were evaluated for antibodies to GSCs formed by combination of GM1, GM2, GD1a, GD1b, GT1b, and GQ1b using manual enzyme linked immuno-sorbent assay (ELISA). RESULTS: Twenty-six patients were GSC antibody-positive, most frequent being against GM1-containing GSC (76.9%). Gender distribution, mean age, symptom-duration, antecedent events, electrophysiological subtypes, requirement for mechanical ventilation, and median duration of hospital stay were comparable between the GSC antibody-positive and negative groups. There was no association between specific GSC antibody and electrophysiological subtypes or clinical variants. After controlling for false discovery rate (FDR) using the Benjamini-Hochberg method, the number of subjects who improved in overall disability sum score, modified Erasmus GBS outcome score, and neuropathy symptom score at discharge was significantly higher in the GSC antibody-positive group. Improvements in Medical Research Council sum scores and Hughes Disability Scale during the hospital stay between the GSC antibody-positive and negative groups were not significantly different after controlling for FDR. CONCLUSIONS: The GSC antibody-positive group had better outcome at hospital discharge in some of the disability scores. Pathophysiological pathways among patients without GSC antibodies may be different and this requires further evaluation.
Asunto(s)
Autoanticuerpos/inmunología , Gangliósidos/inmunología , Síndrome de Guillain-Barré/inmunología , Adolescente , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Femenino , Gangliósido G(M1)/inmunología , Gangliósido G(M2)/inmunología , Síndrome de Guillain-Barré/fisiopatología , Síndrome de Guillain-Barré/terapia , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , India , Masculino , Persona de Mediana Edad , Plasmaféresis , Respiración Artificial , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Bickerstaff's brainstem encephalitis (BBE) is a Guillain-Barré syndrome (GBS) spectrum disorder associated with predominantly central nervous system predilection. Patients exhibit a variable constellation of depressed consciousness, bilateral external ophthalmoplegia, ataxia and long tract signs. Although the pathophysiology is not fully understood, it has been associated with anti-GQ1b antibodies in two-thirds of patients. We present a patient with clinical features consistent with BBE and positive anti-GM1 and anti-GD1a antibodies. A diagnostic approach to the acutely unwell patient with brainstem encephalitis is explored in this clinical context with a literature review of the aforementioned ganglioside antibody significance. Intravenous immunoglobulin therapy is highlighted in BBE using up-to-date evidence-based extrapolation from GBS.
Asunto(s)
Ataxia/inmunología , Autoanticuerpos/sangre , Tronco Encefálico/inmunología , Encefalitis/diagnóstico , Oftalmoplejía/inmunología , Adulto , Ataxia/sangre , Autoanticuerpos/inmunología , Diagnóstico Diferencial , Electroencefalografía , Encefalitis/sangre , Encefalitis/complicaciones , Encefalitis/inmunología , Gangliósido G(M1)/inmunología , Gangliósidos/inmunología , Escala de Coma de Glasgow , Humanos , Masculino , Oftalmoplejía/sangreRESUMEN
Guillain-Barré syndrome, an autoimmune neuropathy characterized by acute limb weakness, is often preceded by Campylobacter jejuni infection. Molecular mimicry exists between the bacterial lipo-oligosaccharide and human ganglioside. Such C. jejuni infection induces production of immunoglobulin G1 (IgG1) autoantibodies against GM1 and causes complement-mediated motor nerve injury. For elucidating the molecular mechanisms linking autoantigen recognition and complement activation, we characterized the dynamic interactions of anti-GM1 IgG autoantibodies on ganglioside-incorporated membranes. Using high-speed atomic force microscopy, we found that the IgG molecules assemble into a hexameric ring structure on the membranes depending on their specific interactions with GM1. Complement component C1q was specifically recruited onto these IgG rings. The ring formation was inhibited by an IgG-binding domain of staphylococcal protein A bound at the cleft between the CH2 and CH3 domains. These data indicate that the IgG assembly is mediated through Fc-Fc interactions, which are promoted under on-membrane conditions due to restricted translational diffusion of IgG molecules. Reduction and alkylation of the hinge disulfide impaired IgG ring formation, presumably because of an increase in conformational entropic penalty. Our findings provide mechanistic insights into the molecular processes involved in Guillain-Barré syndrome and, more generally, into antigen-dependent interplay between antibodies and complement components on membranes.
Asunto(s)
Complemento C1q/metabolismo , Gangliósido G(M1)/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Síndrome de Guillain-Barré/inmunología , Síndrome de Guillain-Barré/metabolismo , Humanos , Microscopía de Fuerza Atómica , Unión ProteicaAsunto(s)
Autoanticuerpos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Gangliósido G(M1)/inmunología , Adulto , Anemia Hemolítica Autoinmune/diagnóstico , Anemia Hemolítica Autoinmune/inmunología , Antiinflamatorios/uso terapéutico , Ataxia/diagnóstico , Ataxia/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , Diagnóstico Diferencial , Femenino , Humanos , Oftalmoplejía/diagnóstico , Oftalmoplejía/inmunología , Prednisona/uso terapéuticoRESUMEN
Vaccination strategy that induce efficient antibody responses polytopically in most lymph nodes (LNs) against infections has not been established yet. Because donor-specific blood transfusion induces anti-donor class I MHC antibody production in splenectomized rats, we examined the mechanism and significance of this response. Among the donor blood components, T cells were the most efficient immunogens, inducing recipient T cell and B cell proliferative responses not only in the spleen, but also in the peripheral and gut LNs. Donor T cells soon migrated to the splenic T cell area and the LNs, with a temporary significant increase in recipient NK cells. XCR1+ resident dendritic cells (DCs), but not XCR1- DCs, selectively phagocytosed donor class I MHC+ fragments after 1 day. After 1.5 days, both DC subsets formed clusters with recipient CD4+ T cells, which proliferated within these clusters. Inhibition of donor T cell migration or depletion of NK cells by pretreatment with pertussis toxin or anti-asialoGM1 antibody, respectively, significantly suppressed DC phagocytosis and subsequent immune responses. Three allogeneic strains with different NK activities had the same response but with different intensity. Donor T cell proliferation was not required, indicating that the graft vs. host reaction is dispensable. Intravenous transfer of antigen-labeled and mitotic inhibitor-treated allogeneic, but not syngeneic, T cells induced a polytopical antibody response to labeled antigens in the LNs of splenectomized rats. These results demonstrate a novel mechanism of alloresponses polytopically in the secondary lymphoid organs (SLOs) induced by allogeneic T cells. Donor T cells behave as self-migratory antigen ferries to be delivered to resident XCR1+ DCs with negligible commitment of migratory DCs. Allogeneic T cells may be clinically applicable as vaccine vectors for polytopical prophylactic antibody production even in asplenic or hyposplenic individuals.
Asunto(s)
Células Dendríticas/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Isoanticuerpos/biosíntesis , Ganglios Linfáticos/inmunología , Receptores Acoplados a Proteínas G/análisis , Linfocitos T/inmunología , Animales , Donantes de Sangre , Transfusión Sanguínea , Movimiento Celular , Células Dendríticas/química , Epítopos/inmunología , Gangliósido G(M1)/inmunología , Gangliósido G(M1)/farmacología , Isoanticuerpos/inmunología , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Transfusión de Linfocitos , Toxina del Pertussis/inmunología , Toxina del Pertussis/farmacología , Ganglios Linfáticos Agregados/inmunología , Fagocitosis , Ratas , Ratas Endogámicas ACI , Ratas Endogámicas Lew , Bazo/inmunología , EsplenectomíaRESUMEN
RATIONALE: The occurrence of peripheral neuropathy associated with non-Hodgkin's lymphoma (NHL) is uncommon. And autoimmunity may play an important role. We report a case of the patient with NHL, has sensorimotor demyelinating polyneuropathy. PATIENT CONCERNS: The patient presented with a 1-month history of progressive numbness at the distal extremities and motor weakness of the lower limbs. Meanwhile, patient also endorsed a painful lump on her right cheek. And then the enlarged cervical and supra clavicular lymph nodes were observed on admission. Biopsy of the lymph nodes showed NHL. Serum IgM antibodies against GM1 and GD1b were also positive. DIAGNOSIS: Biopsy of the lymph nodes showed NHL. Serum IgM antibodies against GM1 and GD1b were also positive. Thus, the patience was diagnosed with lymphoma and sensorimotor polyneuropathy. INTERVENTIONS: Patient refused the further treatment. OUTCOMES: After 11-month follow-up, the weakness of bilateral lower limbs worsens. LESSONS: We have presented a case of NHL involving peripheral polyneuropathy with IgM antibodies against GM1 and GD1b. Patients may initially present with peripheral nerve complications or develop them during the course of lymphoma, even when in remission. This could complicate the diagnosis of peripheral polyneuropathy secondary to NHL.
Asunto(s)
Inmunoglobulina M/sangre , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/inmunología , Polirradiculoneuropatía/etiología , Polirradiculoneuropatía/inmunología , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Gangliósido G(M1)/inmunología , Gangliósidos/inmunología , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/patología , Polirradiculoneuropatía/diagnóstico , Polirradiculoneuropatía/patologíaRESUMEN
Malignant lymphoma sometimes involves peripheral nerves due to paraneoplastic syndrome associated with anti-ganglioside antibodies. We report a very rare case of malignant lymphoma accompanied by an asymmetrical and isolated hypoglossal nerve palsy associated with a new subset of anti-ganglioside antibodies. Magnetic resonance imaging and 18F-2-deoxy-2-fluoro-D-glucose position emission tomography showed no abnormalities of the hypoglossal nerve nucleus; however, the patient' s serum was positive for anti-sulfated glucuronyl paragloboside IgM antibodies as well as anti-GM1 IgM and anti-GQ1b IgM antibodies. The present case might suggest a paraneoplastic asymmetrical and isolated hypoglossal nerve palsy associated with a new subset of anti-ganglioside antibodies.
Asunto(s)
Gangliósido G(M1)/inmunología , Globósidos/inmunología , Enfermedades del Nervio Hipogloso/etiología , Inmunoglobulina M/sangre , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/inmunología , Anciano , Fluorodesoxiglucosa F18 , Humanos , Enfermedades del Nervio Hipogloso/diagnóstico por imagen , Enfermedades del Nervio Hipogloso/inmunología , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND AND OBJECTIVES: Multifocal motor neuropathy (MMN) is a rare neuropathy and detailed descriptions of larger patient cohorts are scarce. The objective of this study was to evaluate epidemiological, clinical, and laboratory features of MMN patients and their response to treatment in Austria and to compare these data with those from the literature. METHODS: Anonymized demographic and clinical data about MMN patients until 31.12.2017 were collected from registered Austrian neurologists. Exploratory statistics on clinical and laboratory features as well as treatment regimens and responses were performed. RESULTS: 57 Patients with MMN were identified, resulting in a prevalence of 0.65/100.000. Mean age of onset was 44.1 ± 13.1 years, the diagnostic delay 5.5 ± 8.4 years. In 77% of patients, symptom onset was in the upper limbs, and in 92%, it occurred in distal muscles. Proximal onset was never observed in the lower limbs. At the final follow-up, the majority of patients had atrophy (88%) in affected regions. Definite motor conduction blocks (CB) were found in 54 patients. Anti-GM1-IgM antibodies were present in 43%. Treatment with intravenous immunoglobulins improved muscle strength and INCAT score initially, but at last follow-up, both scores deteriorated to values before treatment. DISCUSSION: The findings of the present study corroborate the previous findings in MMN. Onset typically occurs in the upper limbs and mostly distal, CBs are found in the majority of cases, while anti-GM1-IgM antibodies are detected in only approximately 40%. Our study underlines that the initial good response to treatment fades over time.
Asunto(s)
Enfermedad de la Neurona Motora/epidemiología , Enfermedad de la Neurona Motora/terapia , Adolescente , Adulto , Edad de Inicio , Anciano , Austria/epidemiología , Autoanticuerpos/metabolismo , Femenino , Estudios de Seguimiento , Gangliósido G(M1)/inmunología , Humanos , Inmunoglobulina M/metabolismo , Masculino , Persona de Mediana Edad , Enfermedad de la Neurona Motora/fisiopatología , Neurólogos , Prevalencia , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Antibodies to the ganglioside GD1b have been reported in various forms of immune-mediated neuropathy, but their clinical relevance for diagnosis and prognosis is unknown. We investigated the prevalence of anti-GD1b antibodies in acute and chronic immune-mediated neuropathies, and the clinical presentation and outcome in Guillain-Barré syndrome (GBS) and Miller Fisher-GBS overlap syndrome (MF-GBS). Anti-GD1b, anti-GM1 and anti-GQ1b antibodies were tested in serum of patients with GBS (N = 165), Miller Fisher syndrome (N = 10), MF-GBS (N = 28), monoclonal gammopathy of unknown significance neuropathy (MGUS; N = 101), chronic inflammatory demyelinating polyneuropathy (N = 29), paraneoplastic syndrome with anti-Hu-associated neuropathy (PNS; N = 11), other auto-immune diseases (AID; N = 60), and healthy controls (HC; N = 60). All samples were tested by enzyme-linked immunosorbent assay according to the Inflammatory Neuropathy Cause and Treatment protocol. IgM anti-GD1b antibodies were found in GBS (N = 4; 2.4%), MGUS (N = 3; 3.0%), and PNS patients (N = 1; 9.1%). IgG anti-GD1b antibodies were found in GBS (N = 20; 12.1%) and MF-GBS (N = 4; 14.3%) patients, but not in the AID and HC group. In the combined group of MF-GBS and GBS patients ((MF-)GBS), 14/36 (38.9%) patients with IgG anti-GD1b antibodies also had IgG anti-GM1 antibodies, and IgG anti-GD1b and IgG anti-GQ1b antibodies were found in 3/29 (10.3%) patients. Patients with (MF-)GBS and anti-GD1b without anti-GM1 antibodies did not differ regarding sensory disturbances or disease severity but recovered faster regarding the ability to walk independently compared with patients without anti-GD1b antibodies (P = 0.031) and with patients with both anti-GD1b and anti-GM1 antibodies (P = 0.034). In conclusion, testing for anti-GD1b antibodies may identify a specific group of immune-mediated neuropathies and (MF-)GBS patients with only anti-GD1b antibodies tend to recover faster.
Asunto(s)
Autoanticuerpos/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Gangliósidos/inmunología , Gammopatía Monoclonal de Relevancia Indeterminada/inmunología , Polineuropatía Paraneoplásica/inmunología , Adulto , Anciano , Autoanticuerpos/sangre , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Gangliósido G(M1)/inmunología , Síndrome de Guillain-Barré/sangre , Síndrome de Guillain-Barré/inmunología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Persona de Mediana Edad , Síndrome de Miller Fisher/sangre , Síndrome de Miller Fisher/inmunología , Gammopatía Monoclonal de Relevancia Indeterminada/sangre , Polineuropatía Paraneoplásica/sangre , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/sangre , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Síndrome de Sjögren/sangre , Síndrome de Sjögren/inmunologíaRESUMEN
We describe a twenty-year follow-up study of antiglycolipid antibodies and electrophysiological results in a 36-year-old man with Campylobacter jejuni-associated Guillain-Barré syndrome (GBS). The patient had a high titer of IgG antibodies to GM1 and GA1 20 years ago. Plasma exchange resulted in full recovery from a bedridden status to independent walking in three weeks, except for residual mild weakness of the bilateral extensor hallucis longus muscles and atrophy of the plantar muscles. Twenty years later, he is unable to run at full pace due to neurological sequelae, and IgG antibodies to GM1 and GA1 were still slightly positive. This case suggests that marked improvement in the acute phase does not necessarily guarantee a subsequent good quality of life (QOL). Optional treatment such as complement inhibitors in the acute phase may be required to achieve better QOL in subsets of patients with GBS.
Asunto(s)
Gangliósido G(M1)/inmunología , Síndrome de Guillain-Barré/inmunología , Inmunoglobulina G/sangre , Calidad de Vida , Adulto , Biomarcadores/sangre , Infecciones por Campylobacter , Campylobacter jejuni , Enteritis/complicaciones , Enteritis/microbiología , Estudios de Seguimiento , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/fisiopatología , Síndrome de Guillain-Barré/terapia , Humanos , Masculino , Conducción Nerviosa , Intercambio Plasmático , Pronóstico , Factores de TiempoRESUMEN
A 66-year-old man presented with subacute sensorimotor neuropathy in association with small cell lung cancer. Tests for the anti-ganglioside antibody GM1-IgM were positive. Chemotherapy and intravenous immunoglobulin treatment led to a slight improvement in neurological symptoms. Four additional cases of neuropathy accompanied by anti-ganglioside antibody and lung cancer have been reported. The most commonly reported pattern was subacute sensorimotor neuropathy. Patients died from cancer progression after 5 to 18 months. There is evidence that anti-ganglioside antibody inhibits tumor progression, prolonging the patient survival. However, severe neurological disturbance may offset the survival benefit of anti-ganglioside antibody in patients with paraneoplastic neurological syndrome.
Asunto(s)
Autoanticuerpos/inmunología , Gangliósido G(M1)/inmunología , Síndrome de Guillain-Barré/inmunología , Neoplasias Pulmonares/complicaciones , Carcinoma Pulmonar de Células Pequeñas/complicaciones , Anciano , Síndrome de Guillain-Barré/complicaciones , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Tomografía Computarizada por Rayos XRESUMEN
Purpose: The ganglioside fucosyl-GM1 (FucGM1) is a tumor-associated antigen expressed in a large percentage of human small cell lung cancer (SCLC) tumors, but absent in most normal adult tissues, making it a promising target in immuno-oncology. This study was undertaken to evaluate the preclinical efficacy of BMS-986012, a novel, nonfucosylated, fully human IgG1 antibody that binds specifically to FucGM1.Experimental Design: The antitumor activity of BMS-986012 was evaluated in in vitro assays using SCLC cells and in mouse xenograft and syngeneic tumor models, with and without chemotherapeutic agents and checkpoint inhibitors.Results: BMS-986012 showed a high binding affinity for FcγRIIIa (CD16), which resulted in enhanced antibody-dependent cellular cytotoxicity (ADCC) against FucGM1-expressing tumor cell lines. BMS-986012-mediated tumor cell killing was also observed in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) assays. In several mouse SCLC models, BMS-986012 demonstrated efficacy and was well tolerated. In the DMS79 xenograft model, tumor regression was achieved with BMS-986012 doses of 0.3 mg/kg and greater; antitumor activity was enhanced when BMS-986012 was combined with standard-of-care cisplatin or etoposide. In a syngeneic model, tumors derived from a genetically engineered model of SCLC were treated with BMS-986012 or anti-FucGM1 with a mouse IgG2a Fc and their responses evaluated; when BMS-986012 was combined with anti-PD-1 or anti-CD137 antibody, therapeutic responses significantly improved.Conclusions: Single-agent BMS-986012 demonstrated robust antitumor activity, with the addition of chemotherapeutic or immunomodulatory agents further inhibiting SCLC growth in the same models. These preclinical data supported evaluation of BMS-986012 in a phase I clinical trial of patients with relapsed, refractory SCLC. Clin Cancer Res; 24(20); 5178-89. ©2018 AACR.
Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Gangliósido G(M1)/análogos & derivados , Animales , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Antígenos de Neoplasias/inmunología , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Pequeñas/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Gangliósido G(M1)/antagonistas & inhibidores , Gangliósido G(M1)/inmunología , Gangliósido G(M1)/metabolismo , Humanos , Inmunohistoquímica , Inmunomodulación/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Unión Proteica , Receptores de IgG/metabolismo , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Previous studies have shown that patients with Guillain-Barré syndrome express autoantibodies against ganglioside GM1 (GM1), although its pathogenic significance for the development of the disease remains to be elucidated. nSMase2 is the best characterized neutral sphingomyelinase (nSMase) found in neuronal cells. Activation of this enzyme leads to ceramide production, which is a known second messenger of the cell-death program in neuronal cells. We have explored the effects of anti-GM1 antibodies on sphingomyelin metabolism of PC12 cells stably transfected with human trk cDNA (PCtrk cells) by determining their effects on nSMase2 activity. The data we present here strongly suggest that anti-GM1 caused a significant change in sphingomyelin content of the membrane fraction in PCtrk cells. Both nSMase2 activity and the level of nSMase2 protein were significantly decreased by anti-GM1 treatment of PCtrk cells, while acidic SMase activities remained unchanged. Our results indicate, for the first time, that anti-GM1 may produce profound impacts on lipid metabolism in neuronal cell membranes.
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Anticuerpos/farmacología , Gangliósido G(M1)/inmunología , Síndrome de Guillain-Barré/metabolismo , Esfingomielina Fosfodiesterasa/metabolismo , Esfingomielinas/metabolismo , Animales , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Humanos , Células PC12 , RatasRESUMEN
Guillain-Barré syndrome (GBS) is an autoimmune disorder of the peripheral nervous system triggered by molecular mimicry between pathogen lipopolysaccharides and host nerve gangliosides. Polymorphisms in the Fas receptor (FAS) and Fas ligand (FASL) genes may potentially alter the elimination of autoreactive immune cells and affect disease susceptibility or disease severity in GBS. We detected single nucleotide polymorphisms (SNPs) in FAS (-1377G/A and -670A/G) and FASL (-843C/T) in a prospective cohort of 300 patients with GBS and 300 healthy controls from the Bangladeshi population. Genotype distributions were not significantly different between patients with GBS and healthy controls. The FAS -670 AG heterozygous (P = 0.0005, OR = 2.5, 95% CI = 1.5-4.2) and GG homozygous (P = 0.0048, OR = 2.6, 95% CI = 1.3-5.0) genotypes were more common in patients with anti-GM1 antibodies than patients without anti-GM1 antibodies. The FAS -670 G allele was more prevalent in anti-GM1 antibody-positive than -negative patients (P = 0.0002, OR = 1.9, 95% CI = 1.4-2.7) and also in patients with the axonal subtype than demyelinating subtype (P < 0.0001, OR = 4.8, 95% CI = 2.3-10.1). The 1377G/-670G GG haplotype was significantly associated with the axonal subtype (P < 0.0001) and anti-ganglioside antibody-positivity (P = 0.0008) in GBS. Serum sFas (237.5 pg/mL vs. 159.5 pg/mL; P < 0.0001) and sFasL (225.1 pg/mL vs. 183.4 pg/mL; P = 0.0069) were elevated in patients with GBS compared to healthy controls, and among patients with high serum sFas was associated with severe GBS (P = 0.0406). In conclusion, this study indicates FAS-FASL promoter SNPs may promote the production of cross-reactive anti-ganglioside antibodies in GBS.
Asunto(s)
Proteína Ligando Fas/genética , Síndrome de Guillain-Barré/sangre , Sistema Nervioso Periférico/patología , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Receptor fas/genética , Adolescente , Adulto , Bangladesh , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Gangliósido G(M1)/inmunología , Síndrome de Guillain-Barré/patología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto Joven , Receptor fas/sangreRESUMEN
BACKGROUND AND PURPOSE: Many epidemiological studies of Guillain-Barré syndrome (GBS) and Fisher syndrome (FS) have been conducted in Europe and America. In contrast, epidemiological studies are rare in Asia where the GBS subtypes differ from those in Western countries. This study was undertaken to clarify the incidence of GBS and FS in a local area in Japan as well as their seasonal trends. METHOD: Seventy-one GBS and 37 FS patients were recorded from 2006 to 2015 in an area of approximately 1.5 million inhabitants in Japan. The incidence, seasonal trends and clinical features of GBS and FS were examined. RESULTS: The incidence rate of GBS was 0.42 cases per 100 000 person-years and that of FS was 0.22 cases per 100 000 person-years. The incidence of GBS increased with age and FS affected predominantly patients aged from 45 to 64 years old. There was some seasonal clustering of acute motor axonal neuropathy (AMAN) and FS in spring and summer, but it was not significant. AMAN and FS patients had a high frequency of preceding infection (AMAN, 68% gastrointestinal infection; FS, 65% upper respiratory infection). Antecedent respiratory infection was significantly associated with FS as an outcome. Serum antibodies to ganglioside GM1 were detected in 71% of AMAN patients and antibodies to GQ1b were detected in 81% of FS patients. CONCLUSIONS: Our study offers evidence of a lower incidence of GBS and a higher incidence of FS in a local area in Japan than in Western countries.