Introduction
The prevalence and characteristics of Agrin and LRP4 antibody positive amyotrophic lateral sclerosis (ALS) patients were studied.
Methods
We tested 82 ALS patients and 59 controls for Agrin and LRP4 antibodies using ELISA.
Results
We found that 13.8% of ALS patients had Agrin antibodies, and 9.8% had LRP4 antibodies. Women ALS patients are twice as likely as men to have antibodies. Agrin-positive ALS patients are younger than Agrin-negative ALS patients.
Discussion
Antibodies to Agrin and LRP4 are found in ALS patients. It must be determined if these antibodies are pathogenic. Since antibody positive patients have upper as well as lower motor neuron findings, the antibodies’ effects cannot be explained solely by their actions at the neuromuscular junction. Perhaps a breakdown in inter-neuronal signaling might cause ALS. Further research is needed to resolve this question.
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.
Objective:To determine whether human anti-LRP4/agrin antibodies are pathogenic in mice and to investigate underpinning pathogenic mechanisms.Methods:Immunoglobulin (Ig) was purified from a MG patient with anti-LRP4/agrin antibodies and transferred to mice. Mice were characterized for body weight, muscle strength, twitch and tetanic force, NMJ functions including CMAP (compound muscle action potential) and endplate potentials, and NMJ structure. Effects of the antibodies on agrin-elicited MuSK activation and AChR clustering were studied and the epitopes of these antibodies were identified.Results:Patient Ig-injected mice suffered MG symptoms, including weight lost and muscle weakness. Decreased CMAPs, reduced twitch and tetanus force, compromised neuromuscular transmission, and NMJ fragmentation and distortion were detected in Patient Ig-injected mice. Patient Ig inhibited agrin-elicited MuSK activation and AChR clustering. The patient Ig recognized the β3 domain of LRP4 and the C-terminus of agrin and reduced agrin-enhanced LRP4-MuSK interaction.Conclusions:Anti-LRP4/agrin antibodies in the MG patient is pathogenic. It impairs the NMJ by interrupting agrin-dependent LRP4-MuSK interaction.
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