RESUMO
Under normal conditions, the blood-brain barrier effectively regulates the passage of immune cells into the central nervous system (CNS). However, under pathological conditions such as multiple sclerosis (MS), leukocytes, especially monocytes, infiltrate the CNS where they promote inflammatory demyelination, resulting in paralysis. Therapies targeting the immune cells directly and preventing leukocyte infiltration exist for MS but may compromise the immune system. Here, we explore how apolipoprotein E receptor 2 (ApoER2) regulates vascular adhesion and infiltration of monocytes during inflammation. We induced experimental autoimmune encephalitis in ApoER2 knockout mice and in mice carrying a loss-of-function mutation in the ApoER2 cytoplasmic domain. In both models, paralysis and neuroinflammation were largely abolished as a result of greatly diminished monocyte adherence due to reduced expression of adhesion molecules on the endothelial surface. Our findings expand our mechanistic understanding of the vascular barrier, the regulation of inflammation and vascular permeability, and the therapeutic potential of ApoER2-targeted therapies.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Endotélio Vascular/imunologia , Proteínas Relacionadas a Receptor de LDL/imunologia , Monócitos/imunologia , Animais , Adesão Celular/imunologia , Proteínas Relacionadas a Receptor de LDL/deficiência , Masculino , Camundongos , Camundongos KnockoutRESUMO
INTRODUCTION: The majority of patients with myasthenia gravis (MG) initially present with ocular symptoms, but it is difficult to predict which cases will remain as ocular MG (OMG) or will progress to generalized MG. Herein we evaluated the serologic profile of Japanese OMG and its relationship with clinical features. METHODS: Seventy-three patients with OMG from five Japanese myasthenia gravis (MG) centers were enrolled. Live cell-based assays (CBAs) were used to determine the presence of autoantibodies (Abs) to clustered adult (2α, ß, δ, ε) and fetal (2α, ß, δ, γ) acetylcholine receptor (AChR) isoforms, muscle-specific receptor tyrosine kinase (MuSK), and lipoprotein receptor-related protein-4 (LRP4). RESULTS: Thirty-four of 73 (46.5%) serum samples were positive for Abs against both the adult-type and fetal-type AChR, as expected, but 7 (9.6%) and 2 (2.7%) were positive only for fetal or adult AChR-Abs, respectively. Four (5.4%) samples were positive for MuSK-Abs, but two of these also contained antibodies to fetal AChR or LRP4. Twenty-six (35.6%) samples were seronegative. DISCUSSION: Abs against fetal-specific AChR, MuSK, and LRP4 are found in some patients with OMG. Future studies attempting to predict conversion from ocular symptoms to generalized MG may benefit from measurement of these antibodies.
Assuntos
Autoanticorpos/imunologia , Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/imunologia , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Blefaroptose/imunologia , Blefaroptose/fisiopatologia , Criança , Pré-Escolar , Diplopia/imunologia , Diplopia/fisiopatologia , Músculos Faciais/fisiopatologia , Feminino , Células HEK293 , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/fisiopatologia , Músculos Oculomotores/fisiopatologia , Isoformas de Proteínas , Adulto JovemAssuntos
Autoanticorpos/imunologia , Doença de Hodgkin/imunologia , Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/diagnóstico , Doença de Hodgkin/complicações , Doença de Hodgkin/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/complicações , Miastenia Gravis/imunologia , Receptores Colinérgicos/imunologiaAssuntos
Autoanticorpos/imunologia , Autoimunidade , Miastenia Gravis/imunologia , Receptores Colinérgicos/imunologia , Animais , Autoimunidade/efeitos dos fármacos , Humanos , Imunossupressores/uso terapêutico , Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/diagnóstico , Miastenia Gravis/tratamento farmacológico , Receptores Proteína Tirosina Quinases/imunologiaRESUMO
INTRODUCTION: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG). METHODS: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. RESULTS: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years. DISCUSSION: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.
Assuntos
Agrina/imunologia , Autoanticorpos , Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/diagnóstico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/epidemiologia , Miastenia Gravis/imunologia , Prevalência , Avaliação de Sintomas , Estados UnidosRESUMO
This article describes the first reported case of myasthenia gravis (MG) seropositive for both acetylcholine receptor antibody and low-density lipoprotein receptor-related protein 4 antibody, complicated by autoimmune polyglandular syndrome (APS) type 3. The patient exhibited myasthenic weakness restricted to the ocular muscles and ptosis. Severe clinical deterioration ensued with predominant bulbar symptoms. MG rapidly worsened, the patient was intubated, and agranulocytosis due to thiamazole was also present, so it was necessary to perform thyroidectomy with tracheostomy and thymectomy in two phases. Both the double-seropositive MG and the APS were involved in the patient's rapid deterioration.
Assuntos
Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/sangue , Miastenia Gravis/imunologia , Poliendocrinopatias Autoimunes/complicações , Poliendocrinopatias Autoimunes/imunologia , Receptores Colinérgicos/sangue , Receptores Colinérgicos/imunologia , Adolescente , Adulto , Idoso , Autoanticorpos/sangue , Feminino , Humanos , Lactente , Masculino , Adulto JovemRESUMO
We herein report the case of a 65-year-old woman diagnosed with myasthenia gravis (MG) after complaining of double vision. The patient had anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibody in her serum, although antibodies against the acetylcholine receptor and muscle-specific tyrosine kinase were not detected. Chest computed tomography showed an anterior mediastinal tumor with a high uptake on fluorodeoxyglucose-positron emission tomography. Endoscopic thymectomy successfully ameliorated her ocular symptoms and showed the lesion to be thymoma. The present case revealed that anti-LRP4 antibody-associated MG can be associated with thymoma, which has been regarded as a rare complication of this disease thus far.
Assuntos
Miastenia Gravis/diagnóstico , Timoma/diagnóstico , Neoplasias do Timo/diagnóstico , Idoso , Autoanticorpos/sangue , Diagnóstico Diferencial , Feminino , Humanos , Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/sangue , Miastenia Gravis/complicações , Tomografia por Emissão de Pósitrons , Timectomia , Timoma/complicações , Timoma/diagnóstico por imagem , Timoma/cirurgia , Neoplasias do Timo/complicações , Neoplasias do Timo/diagnóstico por imagem , Neoplasias do Timo/cirurgia , Tomografia Computadorizada por Raios X/efeitos adversosRESUMO
Myasthenia gravis (MG) is a disease caused by pathogenic autoantibodies against the neuromuscular junction and is characterized by muscle weakness. Most MG patients produce antibodies against the acetylcholine receptor (AChR), but a subset of patients have been found to produce autoantibodies against other components of the neuromuscular junction such as muscle specific tyrosine kinase (MuSK) and low-density lipoprotein receptor-related protein 4 (LRP4). The pathogenicity of these autoantibodies has been studied using polyclonal IgG or serum from MG patients; however, pathogenic B cells and monoclonal antibodies from these patients have rarely been investigated because of the difficulty in isolating them. Recently, isolation of pathogenic B cells from MuSK-MG patients and the subsequent generation of monoclonal pathogenic antibodies from these cells, was reported. These data revealed the existence of pathogenic IgG3 and IgG4 antibodies and identified a pathogenic mechanism alternative to the inhibition of MuSK phosphorylation. This review discusses research concerning pathogenic B cells in MG patients and rituximab therapy specifically depleting B cells. Accumulating studies show rituximab therapy is more effective in MuSK-MG patients than in AChR-MG patients. Advances in molecular biology may lead to greater understanding of pathogenic B cells in MG patients and thus potentially lead to the development of novel therapies for MG.
Assuntos
Linfócitos B/imunologia , Epitopos/imunologia , Miastenia Gravis/imunologia , Anticorpos Monoclonais/imunologia , Autoanticorpos/imunologia , Linfócitos B/efeitos dos fármacos , Humanos , Imunoglobulina G , Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/tratamento farmacológico , Junção Neuromuscular/imunologia , Fosforilação , Proteínas Tirosina Quinases/imunologia , Proteínas Tirosina Quinases/metabolismo , Receptores Colinérgicos/imunologia , Rituximab/farmacologia , Rituximab/uso terapêuticoRESUMO
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ). Autoantibodies target key molecules at the NMJ, such as the nicotinic acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (Lrp4), that lead by a range of different pathogenic mechanisms to altered tissue architecture and reduced densities or functionality of AChRs, reduced neuromuscular transmission, and therefore a severe fatigable skeletal muscle weakness. In this review, we give an overview of the history and clinical aspects of MG, with a focus on the structure and function of myasthenic autoantigens at the NMJ and how they are affected by the autoantibodies' pathogenic mechanisms. Furthermore, we give a short overview of the cells that are implicated in the production of the autoantibodies and briefly discuss diagnostic challenges and treatment strategies.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Músculo Esquelético/patologia , Miastenia Gravis/imunologia , Junção Neuromuscular/patologia , Agrina/imunologia , Agrina/metabolismo , Animais , Autoantígenos/metabolismo , Humanos , Proteínas Relacionadas a Receptor de LDL/imunologia , Proteínas Relacionadas a Receptor de LDL/metabolismo , Músculo Esquelético/imunologia , Músculo Esquelético/ultraestrutura , Miastenia Gravis/patologia , Junção Neuromuscular/imunologia , Junção Neuromuscular/ultraestrutura , Receptores Proteína Tirosina Quinases/imunologia , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Colinérgicos/imunologia , Receptores Colinérgicos/metabolismo , Receptores Nicotínicos/imunologia , Receptores Nicotínicos/metabolismoAssuntos
Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/metabolismo , Anticorpos/metabolismo , Proteínas Relacionadas a Receptor de LDL/antagonistas & inibidores , Junção Neuromuscular/imunologia , Junção Neuromuscular/metabolismo , Anticorpos/imunologia , Células HEK293 , Humanos , Proteínas Relacionadas a Receptor de LDL/imunologiaRESUMO
BACKGROUND AND PURPOSE: Low-density-lipoprotein-receptor-associated protein 4 (LRP4) autoantibodies have recently been detected in myasthenia gravis (MG), but little is known about the clinical characteristics associated with this serological type. In this study, the clinical features of Chinese patients with anti-LRP4 antibody-positive MG were characterized. METHODS: A total of 2172 MG serum samples were collected from patients in various parts of China. An enzyme-linked immunosorbent assay was used to detect acetylcholine receptor (AChR) antibody and titin antibody, and cell-based assays were used to detect muscle-specific kinase antibody and LRP4 antibody. Clinical data for patients with MG were collected from different provinces in China. RESULTS: In total, 16 (0.8%) patients with LRP4-MG were found amongst 2172 total patients, including three patients with AChR/LRP4-MG. Additionally, 13 (2.9%) patients with LRP4-MG were found amongst 455 patients with double seronegative MG. The ratio of males to females for these 13 patients was 1:1.6, and 53.8% patients were children. A total of 91.7% of cases exhibited initial ocular involvement, and 58.3% of cases exhibited simple eye muscle involvement. Responses to acetylcholinesterase inhibitors and prednisone were observed. CONCLUSION: The expanded sample confirmed that the positive rate of LRP4 antibodies in China is lower than that in western countries. Our results highlighted the differences between LRP4-MG and other antibody groups. Children and female patients with LRP4-MG have a higher prevalence, often involving the ocular muscles and limb muscles. The clinical symptoms are mild, and satisfactory responses to treatment are often achieved.
Assuntos
Autoanticorpos/análise , Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , China/epidemiologia , Inibidores da Colinesterase/uso terapêutico , Conectina/imunologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/epidemiologia , Miastenia Gravis/fisiopatologia , Músculos Oculomotores/fisiopatologia , Prednisona/uso terapêutico , Prognóstico , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/imunologia , Fatores Sexuais , Timoma/etiologia , Adulto JovemRESUMO
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction. Most patients have pathogenic autoantibodies against the acetylcholine receptor (AChR). In the last years a novel subpopulation of MG patients has been described that harbors antibodies against low-density lipoprotein receptor-related protein 4 (Lrp4), another postsynaptic neuromuscular antigen. In early-onset AChR MG (EOMG), the thymus plays an important role in immunopathogenesis, and early thymectomy is beneficial. It is still unknown if the thymus plays any role in Lrp4-MG. In this pilot study, we compared thymus samples from four patients with Lrp4-MG (one pre-treated with immunosuppressive drugs), four non-MG controls and five EOMG patients (not pretreated with immunosuppressive drugs). Immunohistochemistry of the Lrp4-MG thymi revealed normal architecture, with normal numbers and distribution of B-cells, lymphoid follicles and Hassall's corpuscles. Primary CD23+ lymphoid follicles were similarly infrequent in Lrp4-MG and control thymic sections. In none of the control or Lrp4-MG thymi did we find secondary follicles with CD10+ germinal centers. These were evident in 2 of the 5 EOMG thymi, where primary lymphoid follicles were also more frequent on average, thus showing considerable heterogeneity between patients. Even if characteristic pathological thymic changes were not observed in the Lrp4 subgroup, we cannot exclude a role for the thymus in Lrp4-MG pathogenesis, since one Lrp4-MG patient went into clinical remission after thymectomy alone (at one year follow-up) and one more improved after thymectomy in combination with immunosuppressive therapy.
Assuntos
Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/diagnóstico , Timo/patologia , Adulto , Feminino , Humanos , Masculino , Miastenia Gravis/imunologia , Miastenia Gravis/patologiaRESUMO
An 82-year-old woman developed neck weakness and dysarthria with antibodies against acetylcholine receptor (AChR) and low-density lipoprotein receptor-related protein 4 (LRP4). Myasthenia gravis (MG) was diagnosed by edrophonium and repetitive nerve stimulation tests. Her symptoms resolved completely by immunotherapy. One year later, she presented with muscle weakness and bulbar palsy accompanied by atrophy and fasciculation. Her tendon reflexes were brisk, and Babinski's sign was positive. She was diagnosed with probable amyotrophic lateral sclerosis (ALS). Immunotherapy did not improve her symptoms, and she ultimately died of respiratory failure. MG and ALS may share a pathophysiology, including anti-LRP4 antibodies at the neuromuscular junction.
Assuntos
Esclerose Lateral Amiotrófica/imunologia , Autoanticorpos/sangue , Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/imunologia , Receptores Colinérgicos/imunologia , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/terapia , Paralisia Bulbar Progressiva/imunologia , Disartria/imunologia , Feminino , Humanos , Imunoterapia/métodos , Debilidade Muscular/imunologia , Miastenia Gravis/complicações , Miastenia Gravis/terapia , Exame Neurológico , Reflexo de BabinskiAssuntos
Esclerose Lateral Amiotrófica , Autoanticorpos , Proteínas do Sistema Complemento , Imunoglobulina G , Proteínas Relacionadas a Receptor de LDL , Neurópilo , Idoso , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/patologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Feminino , Células HEK293 , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Proteínas Relacionadas a Receptor de LDL/imunologia , Proteínas Relacionadas a Receptor de LDL/metabolismo , Masculino , Pessoa de Meia-Idade , Neurópilo/imunologia , Neurópilo/metabolismo , Neurópilo/patologiaAssuntos
Doenças do Nervo Abducente/tratamento farmacológico , Doenças do Nervo Abducente/imunologia , Autoanticorpos/sangue , Proteínas Relacionadas a Receptor de LDL/imunologia , Prednisolona/uso terapêutico , Esteroides/uso terapêutico , Doenças do Nervo Abducente/diagnóstico , Diagnóstico Diferencial , Humanos , Masculino , Adulto JovemRESUMO
Acquired myasthenia gravis (MG) is a prototype autoimmune disease of the neuromuscular junction, caused in most patients by autoantibodies to the muscle nicotinic acetylcholine receptor (AChR). There seem to be ethnic and regional differences in the frequency and clinical features of MG seronegative for the AChR antibody. This study aimed to describe the autoantibody profiles and clinical features of Korean patients with generalized MG seronegative for the AChR antibody. A total of 62 patients with a high index of clinical suspicion of seronegative generalized MG were identified from 18 centers, and we examined their sera for antibodies to clustered AChR, muscle-specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (LRP4) by cell-based assays (CBA) and to MuSK by radioimmunoprecipitation assay (RIPA). We also included 8 patients with ocular MG, 3 with Lambert-Eaton myasthenic syndrome, 5 with motor neuron disease, and 9 with other diagnoses as comparators for the serological testing. Antibodies were identified in 25/62 (40.3%) patients: 7 had antibodies to clustered AChR, 17 to MuSK, and 2 to LRP4. Three patients were double seropositive: 1 for MuSK and LRP4, and 2 for MuSK and clustered AChR. The patients with MuSK antibodies were mostly female (88.2%) and characterized by predominantly bulbar involvement (70%) and frequent myasthenic crises (58.3%). The patients with antibodies to clustered AChR, including 2 with ocular MG, tended to have a mild phenotype and good prognosis.
Assuntos
Autoanticorpos/sangue , Miastenia Gravis/sangue , Miastenia Gravis/imunologia , Receptores Colinérgicos/imunologia , Adulto , Idoso , Estudos Transversais , Feminino , Seguimentos , Humanos , Proteínas Relacionadas a Receptor de LDL/imunologia , Síndrome Miastênica de Lambert-Eaton/sangue , Síndrome Miastênica de Lambert-Eaton/imunologia , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/sangue , Doença dos Neurônios Motores/imunologia , Ensaio de Radioimunoprecipitação , Receptores Proteína Tirosina Quinases/imunologia , República da Coreia , Estudos RetrospectivosRESUMO
BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction in which a clinical diagnosis may be confirmed with serological testing. The most common autoantibodies used to support a diagnosis of MG are anti-acetylcholine receptor antibodies and anti-muscle-specific tyrosine kinase antibodies. In cases in which both of these autoantibodies are negative (termed double-seronegative [dSNMG]), other autoantibodies such as low-density lipoprotein receptor-related protein 4 (LRP4) may be used to aid in diagnosis. METHODS: We have undertaken a systematic literature review to identify studies that have assessed the frequency of anti-LRP4 antibodies in dSNMG patients and the characteristics of anti-LRP4+ dSNMG patients (epidemiology, clinical features, electromyographic findings, or management). PubMed, EMBASE, Medline, and Scopus were searched on January 14, 2017, using the medical subject headings "myasthenia gravis" and "low-density lipoprotein receptor-related protein 4" or "LRP4." RESULTS: The initial search identified 367 articles. Fourteen publications met the inclusion criteria. There were ten cross-sectional research studies, three were case series, and one was a case report. The majority of studies were limited by small sample sizes of LRP4+ dSNMG. There has been a wide range of frequencies of anti-LRP4 antibodies detected in different MG patient populations, some involving different laboratory techniques. CONCLUSIONS: LRP4+ dSNMG is more likely than LRP4- dSNMG to have a younger onset of disease and occur in females. LRP4+ dSNMG most often is mild in severity and often involves isolated ocular weakness. It typically responds well to pyridostigmine or prednisone.
Assuntos
Autoanticorpos/sangue , Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/sangue , Bases de Dados Bibliográficas/estatística & dados numéricos , Humanos , Miastenia Gravis/diagnóstico , Miastenia Gravis/imunologiaRESUMO
Antibodies to the acetylcholine receptor (AChR) have been recognized for over 40 years and have been important in the diagnosis of myasthenia gravis (MG), and its recognition in patients of different ages and thymic pathologies. The 10-20% of patients who do not have AChR antibodies are now known to comprise different subgroups, the most commonly reported of which is patients with antibodies to muscle-specific kinase (MuSK). The use of cell-based assays has extended the repertoire of antibody tests to clustered AChRs, low-density lipoprotein receptor-related protein 4, and agrin. Autoantibodies against intracellular targets, namely cortactin, titin, and ryanodine receptor (the latter two being associated with the presence of thymoma), may also be helpful as biomarkers in some patients. IgG4 MuSK antibodies are clearly pathogenic, but the coexisting IgG1, IgG2, and IgG3 antibodies, collectively, have effects that question the dominance of IgG4 as the sole pathologic factor in MuSK MG. After a brief historical review, we define the different subgroups and summarize the antibody characteristics. Experiments to demonstrate the in vitro and in vivo pathogenic roles of MuSK antibodies are discussed.
Assuntos
Autoanticorpos/imunologia , Miastenia Gravis/imunologia , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/imunologia , Agrina/imunologia , Humanos , Imunoglobulina G/imunologia , Canal de Potássio Kv1.4/imunologia , Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/classificaçãoRESUMO
Myasthenia gravis (MG) is a common disorder that affects the neuromuscular junction. It is caused by antibodies against acetylcholine receptor and muscle-specific tyrosine kinase; however, some MG patients do not have antibodies against either of the proteins. Recent studies have revealed antibodies against agrin and its receptor LRP4-both critical for neuromuscular junction formation and maintenance-in MG patients from various populations. Results from experimental autoimmune MG animal models indicate that anti-LRP4 antibodies are causal to MG. Clinical studies have begun to reveal the significance of the new biomarkers. With their identification, MG appears to be a complex disease entity that can be classified into different subtypes with different etiology, each with unique symptoms. Future systematic studies of large cohorts of well-diagnosed MG patients are needed to determine whether each subtype of patients would respond to different therapeutic strategies. Results should contribute to the goal of precision medicine for MG patients. Anti-agrin and anti-LRP4 antibodies are also detectable in some patients with amyotrophic lateral sclerosis or Lou Gehrig's disease; however, whether they are a cause or response to the disorder remains unclear.