Practical issues in measuring autoantibodies to neuronal cell-surface antigens in autoimmune neurological disorders: 190 cases (original) (raw)
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Autoantibodies against Neurologic Antigens in Nonneurologic Autoimmunity
The Journal of Immunology, 2019
The aim of this study was to test whether autoantibodies against neurologic surface Ags are found in nonneurologic autoimmune diseases, indicating a broader loss of tolerance. Patient and matched healthy donor (HD) sera were derived from four large cohorts: 1) rheumatoid arthritis (RA) (n = 194, HD n = 64), 2) type 1 diabetes (T1D) (n = 200, HD n = 200), 3) systemic lupus erythematosus (SLE) (n = 200, HD n = 67; neuro-SLE n = 49, HD n = 33), and 4) a control cohort of neurologic autoimmunity (relapsing-remitting multiple sclerosis [MS] n = 110, HD n = 110; primary progressive MS n = 9; secondary progressive MS n = 10; neuromyelitis optica spectrum disorders n = 15; and other neurologic disorders n = 26). Screening of 1287 unique serum samples against four neurologic surface Ags (myelin oligodendrocyte glycoprotein, aquaporin 4, acetylcholine receptor, and muscle-specific kinase) was performed with live cell–based immunofluorescence assays using flow cytometry. Positive samples ident...
Frontiers in Neurology, 2021
Background: In our previous single-center study of autoimmune encephalitis (AE) related autoantibody test results we found positivity in 60 patients out of 1,034 with suspected AE from 2012 through 2018 as part of a Hungarian nationwide program. In our current multicenter retrospective study, we analyzed the clinical characteristics and outcome of AE patients with positive neuronal cell surface autoantibody test results.Methods: A standard online questionnaire was used to collect demographic and clinical characteristics, laboratory and imaging data, therapy and prognosis of 30 definitive AE patients in four major clinical centers of the region.Results: In our study, 19 patients were positive for anti-NMDAR (63%), 6 patients (20%) for anti-LGI1, 3 patients for anti-GABABR (10%) and 3 patients for anti-Caspr2 (10%) autoantibodies. Most common prodromal symptoms were fever or flu-like symptoms (10/30, 33%). Main clinical features included psychiatric symptoms (83%), epileptic seizures ...
autoimmune encephalitis (aiE) associated with neural autoantibodies is increasingly recognized as a cause of subacute onset amnesia, confusion, and seizures. in the past decade, several key antibody targets have been identified in aiE. These include the N-methyl d-aspartate (NMda) receptors, voltage-gated potassium channel complexes-in particular leucine-rich glioma inactivated 1 (lGi1) and glutamic acid decarboxylase (Gad). There is accumulating clinical and laboratory evidence that antibodies targeting the extracellular domains of cell-surface molecules are directly pathogenic. Each antibody target associates with a spectrum of clinical features and relative response to immunotherapies. These immunotherapies have been shown to improve short-and long-term clinical outcomes in affected patients. aiE is an important differential diagnosis to consider in patients presenting with symptoms of encephalitis as early diagnosis can lead to successful treatment.
Autoimmune encephalitis: Clinical diagnosis versus antibody confirmation
Annals of Indian Academy of Neurology, 2015
cases include the N-methyl D-aspartate receptor (NMDAR); [4] the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR); the γ-aminobutyric acid receptor-B (GABA B receptor); and proteins that associate with voltage-gated potassium channel (VGKCs)-leucine-rich glioma-inactivated protein 1(LGI1) and contactin-associated protein-like 2 (Caspr2). [5,6] It is often difficult to distinguish these from mimics like obscure central nervous system (CNS) infections, mitochondrial encephalopathy, and occult focal cortical dysplasia by clinical features alone. Failure to identify the etiology as autoimmune may deprive the patient of treatment for a potentially curable entity. Our objective was to screen a large number of patients admitted to neurology intensive care service with fulminant seizures that eluded specific diagnosis in order to identify and characterize those with autoimmune encephalitis.
Journal of Neurology, 2014
The field of neuronal surface-directed antibodymediated diseases of the central nervous system has dramatically expanded in the last few years and now forms an important cluster of treatable neurological conditions. In this review, we focus on three areas. First, we review the demographics, clinical features and treatment responses of these conditions. Second, we consider their pathophysiology and compare autoantibody mechanisms and their effects to genetic or pharmacological disruptions of the target antigens. Third, we discuss areas of controversy within the field, propose possible resolutions, and explore new directions for neuronal surface antibody-mediated diseases.
The spectrum of antineuronal autoantibodies in a series of neurological patients
Journal of the Neurological Sciences, 2004
The aim of the present study is to identify the range of neurological disorders expressing antineuronal antibodies, evaluate the number of different patterns of reactivity that can be detected, and analyse the contribution of these studies to the identification of subgroups of patients.
Journal of Neurology, 2018
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a common autoimmune encephalitis presenting with psychosis, dyskinesias, autonomic dysfunction and seizures. The underlying autoantibodies against the NR1 subunit are directly pathogenic by disrupting synaptic NMDAR currents. However, antibody titers correlate only partially with the clinical outcome, suggesting the relevance of other factors such as antibody affinity. We thus determined the binding curves of human monoclonal autoantibodies and patients' cerebrospinal fluid (CSF) against NR1-expressing HEK293 cells using flow cytometry. Antibody affinity was highly variable with binding constants (half-maximal concentration, c 50) ranging from 1 to 74 µg/ml for monoclonal antibodies. Comparing values of individual monoclonal antibodies with human CSF samples suggested that the CSF signal is predominantly represented by higher-affinity antibodies, potentially in a concentration range of NR1 antibodies between 0.1 and 5 µg/ml, roughly reflecting 1-10% of total CSF IgG in NMDAR encephalitis. Binding curves further depended on the CSF composition which must be considered when interpreting established clinical routine assays. Normalization of measurements using reference samples allowed high reproducibility. Accurate and reproducible measurement of NR1 antibody binding suggested that biophysical properties of the antibody might contribute to disease severity. Normalization of the data can be an elegant way to allow comparable inter-laboratory quantification of CSF NR1 antibody titers in autoimmune encephalitis patients, a prerequisite for use as surrogate markers in clinical trials. Based on our calculations, low-affinity antibodies can easily remain undetected in routine cell-based assays, indicating that their relation to clinical symptoms should be analyzed in future studies.
Seroprevalence of autoantibodies against brain antigens in health and disease
Annals of Neurology, 2014
Objective: We previously reported an unexpectedly high seroprevalence (10%) of N-methyl-D-aspartate-receptor subunit-NR1 (NMDAR1) autoantibodies (AB) in healthy and neuropsychiatrically ill subjects (N 5 2,817). This finding challenges an unambiguous causal relationship of serum AB with brain disease. To test whether similar results would be obtained for other brain antigen-directed AB previously connected with pathological conditions, we systematically screened serum samples of 4,236 individuals. Methods: Serum samples of healthy (n 5 1,703) versus neuropsychiatrically ill subjects (schizophrenia, affective disorders, stroke, Parkinson disease, amyotrophic lateral sclerosis, personality disorder; total n 5 2,533) were tested. For analysis based on indirect immunofluorescence, we used biochip mosaics of frozen brain sections (rat, monkey) and transfected HEK293 cells expressing respective recombinant target antigens. Results: Seroprevalence of all screened AB was comparable in healthy and ill individuals. None of them, however, reached the abundance of NMDAR1 AB (again 10%; immunoglobulin [Ig] G 1%). Appreciable frequency was noted for AB against amphiphysin (2.0%), ARHGAP26 (1.3%), CASPR2 (0.9%), MOG (0.8%), GAD65 (0.5%), Ma2 (0.5%), Yo (0.4%), and Ma1 (0.4%), with titers and Ig class distribution similar among groups. All other AB were found in 0.1% of individuals (anti-AMPAR-1/2, AQP4, CV2, Tr/DNER, DPPX-IF1, GABAR-B1/B2, GAD67, GLRA1b, GRM1, GRM5, Hu, LGl1, recoverin, Ri, ZIC4). The predominant Ig class depended on antigen location, with intracellular epitopes predisposing to IgG (chi-square 5 218.91, p 5 2.8 3 10 248 ). Interpretation: To conclude, the brain antigen-directed AB tested here are comparably detectable in healthy subjects and the disease groups studied here, thus questioning an upfront pathological role of these serum AB. ANN NEUROL 2014;76:82-94 T he occurrence in serum of autoantibodies (AB) directed against brain antigens has long been recognized in classical autoimmune diseases and in paraneoplastic syndromes (for review, see eg Diamond et al, 1 Sutton and Winer 2 ). Recent work reports the presence of AB directed against brain epitopes in serum of 90% of individuals, independent of any illness. 3 In this pivotal work, however, no antigen specificity of the braintargeting AB has been assessed. Some authors even propose the term immunculus for a normal network of constitutively expressed natural AB interacting with different extracellular, membrane, cytoplasmic, and nuclear self-View this article online at wileyonlinelibrary.com.