Evidence map›Paper›PMID 35473886›Full record

ArticleNeurology(R) neuroimmunology & neuroinflammation2022

Heterogeneity of Acetylcholine Receptor Autoantibody-Mediated Complement Activity in Patients With Myasthenia Gravis.

Abeer H Obaid, Chryssa Zografou, Douangsone D Vadysirisack, Bailey Munro-Sheldon, Miriam L Fichtner, Bhaskar Roy, William M Philbrick, Jeffrey L Bennett, Richard J Nowak, Kevin C O'Connor

Erratum issuedOpen access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neurology(R) neuroimmunology & neuroinflammation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 37 papers.

0numbers the graph read from it
0cells of the map it votes in
37citing papers in PubMed
6.5field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

37 citing papers in PubMed, 54 citations in OpenAlex.

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  20. Myasthenia gravis: the future is here.The Journal of clinical investigation · 2024
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors at 1 institution in 1 country.

Abeer H ObaidFrom the Department of Neurology (A.H.O., C.Z., B.M.-S., M.L.F., B.R., R.J.N., K.C.O'C.), Yale School of Medicine, New Haven, CT; Department of Immunobiology (A.H.O., C.Z., M.L.F., W.M.P., K.C.O'C.), Yale School of Medicine, New Haven, CT; Institute of Biomedical Studies (A.H.O.), Baylor University, Waco, TX; UCB Pharma (D.D.V.), Cambridge, MA; and Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, University of Colorado Anschutz Medical Campus, Aurora.ORCID 0000-0002-9846-1045
Chryssa ZografouFrom the Department of Neurology (A.H.O., C.Z., B.M.-S., M.L.F., B.R., R.J.N., K.C.O'C.), Yale School of Medicine, New Haven, CT; Department of Immunobiology (A.H.O., C.Z., M.L.F., W.M.P., K.C.O'C.), Yale School of Medicine, New Haven, CT; Institute of Biomedical Studies (A.H.O.), Baylor University, Waco, TX; UCB Pharma (D.D.V.), Cambridge, MA; and Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, University of Colorado Anschutz Medical Campus, Aurora.
Douangsone D VadysirisackFrom the Department of Neurology (A.H.O., C.Z., B.M.-S., M.L.F., B.R., R.J.N., K.C.O'C.), Yale School of Medicine, New Haven, CT; Department of Immunobiology (A.H.O., C.Z., M.L.F., W.M.P., K.C.O'C.), Yale School of Medicine, New Haven, CT; Institute of Biomedical Studies (A.H.O.), Baylor University, Waco, TX; UCB Pharma (D.D.V.), Cambridge, MA; and Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, University of Colorado Anschutz Medical Campus, Aurora.
Bailey Munro-SheldonFrom the Department of Neurology (A.H.O., C.Z., B.M.-S., M.L.F., B.R., R.J.N., K.C.O'C.), Yale School of Medicine, New Haven, CT; Department of Immunobiology (A.H.O., C.Z., M.L.F., W.M.P., K.C.O'C.), Yale School of Medicine, New Haven, CT; Institute of Biomedical Studies (A.H.O.), Baylor University, Waco, TX; UCB Pharma (D.D.V.), Cambridge, MA; and Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, University of Colorado Anschutz Medical Campus, Aurora.
Miriam L FichtnerFrom the Department of Neurology (A.H.O., C.Z., B.M.-S., M.L.F., B.R., R.J.N., K.C.O'C.), Yale School of Medicine, New Haven, CT; Department of Immunobiology (A.H.O., C.Z., M.L.F., W.M.P., K.C.O'C.), Yale School of Medicine, New Haven, CT; Institute of Biomedical Studies (A.H.O.), Baylor University, Waco, TX; UCB Pharma (D.D.V.), Cambridge, MA; and Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, University of Colorado Anschutz Medical Campus, Aurora.ORCID 0000-0002-0107-4103
Bhaskar RoyFrom the Department of Neurology (A.H.O., C.Z., B.M.-S., M.L.F., B.R., R.J.N., K.C.O'C.), Yale School of Medicine, New Haven, CT; Department of Immunobiology (A.H.O., C.Z., M.L.F., W.M.P., K.C.O'C.), Yale School of Medicine, New Haven, CT; Institute of Biomedical Studies (A.H.O.), Baylor University, Waco, TX; UCB Pharma (D.D.V.), Cambridge, MA; and Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, University of Colorado Anschutz Medical Campus, Aurora.ORCID 0000-0003-3604-6310
William M PhilbrickFrom the Department of Neurology (A.H.O., C.Z., B.M.-S., M.L.F., B.R., R.J.N., K.C.O'C.), Yale School of Medicine, New Haven, CT; Department of Immunobiology (A.H.O., C.Z., M.L.F., W.M.P., K.C.O'C.), Yale School of Medicine, New Haven, CT; Institute of Biomedical Studies (A.H.O.), Baylor University, Waco, TX; UCB Pharma (D.D.V.), Cambridge, MA; and Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, University of Colorado Anschutz Medical Campus, Aurora.
Jeffrey L BennettFrom the Department of Neurology (A.H.O., C.Z., B.M.-S., M.L.F., B.R., R.J.N., K.C.O'C.), Yale School of Medicine, New Haven, CT; Department of Immunobiology (A.H.O., C.Z., M.L.F., W.M.P., K.C.O'C.), Yale School of Medicine, New Haven, CT; Institute of Biomedical Studies (A.H.O.), Baylor University, Waco, TX; UCB Pharma (D.D.V.), Cambridge, MA; and Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, University of Colorado Anschutz Medical Campus, Aurora.
Richard J NowakFrom the Department of Neurology (A.H.O., C.Z., B.M.-S., M.L.F., B.R., R.J.N., K.C.O'C.), Yale School of Medicine, New Haven, CT; Department of Immunobiology (A.H.O., C.Z., M.L.F., W.M.P., K.C.O'C.), Yale School of Medicine, New Haven, CT; Institute of Biomedical Studies (A.H.O.), Baylor University, Waco, TX; UCB Pharma (D.D.V.), Cambridge, MA; and Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, University of Colorado Anschutz Medical Campus, Aurora.
Kevin C O'ConnorFrom the Department of Neurology (A.H.O., C.Z., B.M.-S., M.L.F., B.R., R.J.N., K.C.O'C.), Yale School of Medicine, New Haven, CT; Department of Immunobiology (A.H.O., C.Z., M.L.F., W.M.P., K.C.O'C.), Yale School of Medicine, New Haven, CT; Institute of Biomedical Studies (A.H.O.), Baylor University, Waco, TX; UCB Pharma (D.D.V.), Cambridge, MA; and Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, University of Colorado Anschutz Medical Campus, Aurora.ORCID 0000-0002-7056-419X
Baylor University · US

Funding

Yale Clinical and Translational Science Award (U Component)UL1TR001863 · NCATS · YALE UNIVERSITY · PI John H. Krystal, LUCILA OHNO-MACHADO · 2016 to 2026
$102.9M
Rare Disease Network for Myasthenia GravisU54NS115054 · NINDS · GEORGE WASHINGTON UNIVERSITY · PI HENRY J KAMINSKI · 2019 to 2026
$11.9M
Mechanisms of autoimmunity in myasthenia gravisR01AI114780 · NIAID · YALE UNIVERSITY · PI Kevin C O'Connor · 2016 to 2026
$4.7M
Humoral Immunity, Astrocyte Injury, and Demyelination in Neuromyelitis OpticaR01EY022936 · NEI · UNIVERSITY OF COLORADO DENVER · PI BENNETT, JEFFREY L · 2013 to 2022
$3.8M
Molecular determinants driving diverse mechanisms of antibody-mediated pathologyR21AI164590 · NIAID · YALE UNIVERSITY · PI O'CONNOR, KEVIN C · 2021 to 2022
$461k
NCATS NIH HHS UL1 TR001863NEI NIH HHS R01 EY022936NIAID NIH HHS R01 AI114780NIAID NIH HHS R21 AI164590NINDS NIH HHS U54 NS115054
6 · The paper itself

Abstract

BACKGROUND AND

objectivesAutoantibodies targeting the acetylcholine receptor (AChR), found in patients with myasthenia gravis (MG), mediate pathology through 3 mechanisms: complement-directed tissue damage, blocking of the acetylcholine binding site, and internalization of the AChR. Clinical assays, used to diagnose and monitor patients, measure only autoantibody binding. Consequently, they are limited in providing association with disease burden, understanding of mechanistic heterogeneity, and monitoring therapeutic response. The objective of this study was to develop a cell-based assay that measures AChR autoantibody-mediated complement membrane attack complex (MAC) formation.

methodsAn HEK293T cell line-modified using CRISPR/Cas9 genome editing to disrupt expression of the complement regulator genes (CD46, CD55, and CD59)-was used to measure AChR autoantibody-mediated MAC formation through flow cytometry.

resultsSerum samples (n = 155) from 96 clinically confirmed AChR MG patients, representing a wide range of disease burden and autoantibody titer, were tested along with 32 healthy donor (HD) samples. AChR autoantibodies were detected in 139 of the 155 (89.7%) MG samples through a cell-based assay. Of the 139 AChR-positive samples, autoantibody-mediated MAC formation was detected in 83 (59.7%), whereas MAC formation was undetectable in the HD group or AChR-positive samples with low autoantibody levels. MAC formation was positively associated with autoantibody binding in most patient samples; ratios (mean fluorescence intensity) of MAC formation to AChR autoantibody binding ranged between 0.27 and 48, with a median of 0.79 and an interquartile range of 0.43 (0.58-1.1). However, the distribution of ratios was asymmetric and included extreme values; 16 samples were beyond the 10-90 percentile, with high MAC to low AChR autoantibody binding ratio or the reverse. Correlation between MAC formation and clinical disease scores suggested a modest positive association (rho = 0.34, DISCUSSION: A novel assay for evaluating AChR autoantibody-mediated complement activity was developed. A subset of patients that lacks association between MAC formation and autoantibody binding or disease burden was identified. The assay may provide a better understanding of the heterogeneous autoantibody molecular pathology and identify patients expected to benefit from complement inhibitor therapy.

Indexed as

Myasthenia GravisAutoantibodiesComplement ActivationHEK293 CellsHumansReceptors, CholinergicAutoantibodiesReceptors, Cholinergic

Identifiers

PMID35473886
PMCPMC9128035
OpenAlexW4226521495

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.