Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis

Bin Zhang, John S. Tzartos, Maria Belimezi, Samia Ragheb, Beverly Bealmear, Richard A. Lewis, Wencheng Xiong, Robert P. Lisak, Socrates J. Tzartos, Lin Mei

Research output: Contribution to journalArticle

197 Citations (Scopus)

Abstract

Objectives: To determine whether patients with myasthenia gravis (MG) have serum antibodies to lipopro-tein- related protein 4 (LRP4), a newly identified receptor for agrin that is essential for neuromuscular junction formation, and to establish whether such antibodies contribute to MG pathogenesis. Design: Serum samples from patients with MG with known status of serum antibodies to the acetylcholine receptor (AChR) and muscle-specific kinase (MuSK) and serum samples from control subjects (healthy individuals and individuals with other diseases) were tested for antibodies to LRP4. Serum samples with such antibodies were tested to determine whether they had the ability to inhibit 2 different functions of LRP4 at the neuromuscular junction. Setting: Serum samples were collected at the Hellenic Pasteur Institute and Wayne State University. Samples were tested for LRP4 autoantibodies at Georgia Health Sciences University. Other immunoreactivities of the samples were tested at the Hellenic Pasteur Institute, Athens, Greece, or processed through University Laboratories of the Detroit Medical Center, Michigan. Patients: The study included 217 patients with MG, 76 patients with other neurologic or psychiatric diseases, and 45 healthy control subjects. Results: Anti-LRP4 antibodies were detected in 11 of 120 patients with MG without detectable anti-AChR or anti-MuSK antibodies (double seronegative) and in 1 of 36 patients without anti-AChR antibodies but with anti-MuSK antibodies, but they were not detected in any of the 61 patients with anti-AChR antibodies. No healthy control subjects and only 2 of the 76 control patients with neurologic disease had anti-LRP4 antibodies. Serum samples from patients with MG with anti- LRP4 antibodies were able to inhibit the LRP4-agrin interaction and/or alter AChR clustering in muscle cells. Conclusions: Anti-LRP4 antibodies were detected in the serum of approximately 9.2% of patients with double-seronegative MG. This frequency is intermediate compared with 2 recent studies showing anti-LRP4 antibodies in 2% and 50% of patients with double-seronegative MG from different geographic locations. Together, these observations indicate that LRP4 is another autoantigen in patients with MG, and anti-LRP4 autoantibodies may be pathogenic through different immunopathogenic processes.

Original languageEnglish (US)
Pages (from-to)445-451
Number of pages7
JournalArchives of Neurology
Volume69
Issue number4
DOIs
StatePublished - Apr 1 2012

Fingerprint

Myasthenia Gravis
Autoantibodies
Lipoproteins
Antibodies
Cholinergic Receptors
Proteins
Serum
Healthy Volunteers
Phosphotransferases
Neuromuscular Junction
Muscles
Protein
Agrin
Geographic Locations
Greece
Autoantigens
Nervous System Diseases
Muscle Cells
Nervous System
Cluster Analysis

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

Zhang, B., Tzartos, J. S., Belimezi, M., Ragheb, S., Bealmear, B., Lewis, R. A., ... Mei, L. (2012). Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Archives of Neurology, 69(4), 445-451. https://doi.org/10.1001/archneurol.2011.2393

Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. / Zhang, Bin; Tzartos, John S.; Belimezi, Maria; Ragheb, Samia; Bealmear, Beverly; Lewis, Richard A.; Xiong, Wencheng; Lisak, Robert P.; Tzartos, Socrates J.; Mei, Lin.

In: Archives of Neurology, Vol. 69, No. 4, 01.04.2012, p. 445-451.

Research output: Contribution to journalArticle

Zhang, B, Tzartos, JS, Belimezi, M, Ragheb, S, Bealmear, B, Lewis, RA, Xiong, W, Lisak, RP, Tzartos, SJ & Mei, L 2012, 'Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis', Archives of Neurology, vol. 69, no. 4, pp. 445-451. https://doi.org/10.1001/archneurol.2011.2393
Zhang, Bin ; Tzartos, John S. ; Belimezi, Maria ; Ragheb, Samia ; Bealmear, Beverly ; Lewis, Richard A. ; Xiong, Wencheng ; Lisak, Robert P. ; Tzartos, Socrates J. ; Mei, Lin. / Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. In: Archives of Neurology. 2012 ; Vol. 69, No. 4. pp. 445-451.
@article{fe5550b014784fafadb1c5de7e21119b,
title = "Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis",
abstract = "Objectives: To determine whether patients with myasthenia gravis (MG) have serum antibodies to lipopro-tein- related protein 4 (LRP4), a newly identified receptor for agrin that is essential for neuromuscular junction formation, and to establish whether such antibodies contribute to MG pathogenesis. Design: Serum samples from patients with MG with known status of serum antibodies to the acetylcholine receptor (AChR) and muscle-specific kinase (MuSK) and serum samples from control subjects (healthy individuals and individuals with other diseases) were tested for antibodies to LRP4. Serum samples with such antibodies were tested to determine whether they had the ability to inhibit 2 different functions of LRP4 at the neuromuscular junction. Setting: Serum samples were collected at the Hellenic Pasteur Institute and Wayne State University. Samples were tested for LRP4 autoantibodies at Georgia Health Sciences University. Other immunoreactivities of the samples were tested at the Hellenic Pasteur Institute, Athens, Greece, or processed through University Laboratories of the Detroit Medical Center, Michigan. Patients: The study included 217 patients with MG, 76 patients with other neurologic or psychiatric diseases, and 45 healthy control subjects. Results: Anti-LRP4 antibodies were detected in 11 of 120 patients with MG without detectable anti-AChR or anti-MuSK antibodies (double seronegative) and in 1 of 36 patients without anti-AChR antibodies but with anti-MuSK antibodies, but they were not detected in any of the 61 patients with anti-AChR antibodies. No healthy control subjects and only 2 of the 76 control patients with neurologic disease had anti-LRP4 antibodies. Serum samples from patients with MG with anti- LRP4 antibodies were able to inhibit the LRP4-agrin interaction and/or alter AChR clustering in muscle cells. Conclusions: Anti-LRP4 antibodies were detected in the serum of approximately 9.2{\%} of patients with double-seronegative MG. This frequency is intermediate compared with 2 recent studies showing anti-LRP4 antibodies in 2{\%} and 50{\%} of patients with double-seronegative MG from different geographic locations. Together, these observations indicate that LRP4 is another autoantigen in patients with MG, and anti-LRP4 autoantibodies may be pathogenic through different immunopathogenic processes.",
author = "Bin Zhang and Tzartos, {John S.} and Maria Belimezi and Samia Ragheb and Beverly Bealmear and Lewis, {Richard A.} and Wencheng Xiong and Lisak, {Robert P.} and Tzartos, {Socrates J.} and Lin Mei",
year = "2012",
month = "4",
day = "1",
doi = "10.1001/archneurol.2011.2393",
language = "English (US)",
volume = "69",
pages = "445--451",
journal = "Archives of Neurology",
issn = "0003-9942",
publisher = "American Medical Association",
number = "4",

}

TY - JOUR

T1 - Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis

AU - Zhang, Bin

AU - Tzartos, John S.

AU - Belimezi, Maria

AU - Ragheb, Samia

AU - Bealmear, Beverly

AU - Lewis, Richard A.

AU - Xiong, Wencheng

AU - Lisak, Robert P.

AU - Tzartos, Socrates J.

AU - Mei, Lin

PY - 2012/4/1

Y1 - 2012/4/1

N2 - Objectives: To determine whether patients with myasthenia gravis (MG) have serum antibodies to lipopro-tein- related protein 4 (LRP4), a newly identified receptor for agrin that is essential for neuromuscular junction formation, and to establish whether such antibodies contribute to MG pathogenesis. Design: Serum samples from patients with MG with known status of serum antibodies to the acetylcholine receptor (AChR) and muscle-specific kinase (MuSK) and serum samples from control subjects (healthy individuals and individuals with other diseases) were tested for antibodies to LRP4. Serum samples with such antibodies were tested to determine whether they had the ability to inhibit 2 different functions of LRP4 at the neuromuscular junction. Setting: Serum samples were collected at the Hellenic Pasteur Institute and Wayne State University. Samples were tested for LRP4 autoantibodies at Georgia Health Sciences University. Other immunoreactivities of the samples were tested at the Hellenic Pasteur Institute, Athens, Greece, or processed through University Laboratories of the Detroit Medical Center, Michigan. Patients: The study included 217 patients with MG, 76 patients with other neurologic or psychiatric diseases, and 45 healthy control subjects. Results: Anti-LRP4 antibodies were detected in 11 of 120 patients with MG without detectable anti-AChR or anti-MuSK antibodies (double seronegative) and in 1 of 36 patients without anti-AChR antibodies but with anti-MuSK antibodies, but they were not detected in any of the 61 patients with anti-AChR antibodies. No healthy control subjects and only 2 of the 76 control patients with neurologic disease had anti-LRP4 antibodies. Serum samples from patients with MG with anti- LRP4 antibodies were able to inhibit the LRP4-agrin interaction and/or alter AChR clustering in muscle cells. Conclusions: Anti-LRP4 antibodies were detected in the serum of approximately 9.2% of patients with double-seronegative MG. This frequency is intermediate compared with 2 recent studies showing anti-LRP4 antibodies in 2% and 50% of patients with double-seronegative MG from different geographic locations. Together, these observations indicate that LRP4 is another autoantigen in patients with MG, and anti-LRP4 autoantibodies may be pathogenic through different immunopathogenic processes.

AB - Objectives: To determine whether patients with myasthenia gravis (MG) have serum antibodies to lipopro-tein- related protein 4 (LRP4), a newly identified receptor for agrin that is essential for neuromuscular junction formation, and to establish whether such antibodies contribute to MG pathogenesis. Design: Serum samples from patients with MG with known status of serum antibodies to the acetylcholine receptor (AChR) and muscle-specific kinase (MuSK) and serum samples from control subjects (healthy individuals and individuals with other diseases) were tested for antibodies to LRP4. Serum samples with such antibodies were tested to determine whether they had the ability to inhibit 2 different functions of LRP4 at the neuromuscular junction. Setting: Serum samples were collected at the Hellenic Pasteur Institute and Wayne State University. Samples were tested for LRP4 autoantibodies at Georgia Health Sciences University. Other immunoreactivities of the samples were tested at the Hellenic Pasteur Institute, Athens, Greece, or processed through University Laboratories of the Detroit Medical Center, Michigan. Patients: The study included 217 patients with MG, 76 patients with other neurologic or psychiatric diseases, and 45 healthy control subjects. Results: Anti-LRP4 antibodies were detected in 11 of 120 patients with MG without detectable anti-AChR or anti-MuSK antibodies (double seronegative) and in 1 of 36 patients without anti-AChR antibodies but with anti-MuSK antibodies, but they were not detected in any of the 61 patients with anti-AChR antibodies. No healthy control subjects and only 2 of the 76 control patients with neurologic disease had anti-LRP4 antibodies. Serum samples from patients with MG with anti- LRP4 antibodies were able to inhibit the LRP4-agrin interaction and/or alter AChR clustering in muscle cells. Conclusions: Anti-LRP4 antibodies were detected in the serum of approximately 9.2% of patients with double-seronegative MG. This frequency is intermediate compared with 2 recent studies showing anti-LRP4 antibodies in 2% and 50% of patients with double-seronegative MG from different geographic locations. Together, these observations indicate that LRP4 is another autoantigen in patients with MG, and anti-LRP4 autoantibodies may be pathogenic through different immunopathogenic processes.

UR - http://www.scopus.com/inward/record.url?scp=84859939384&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859939384&partnerID=8YFLogxK

U2 - 10.1001/archneurol.2011.2393

DO - 10.1001/archneurol.2011.2393

M3 - Article

C2 - 22158716

AN - SCOPUS:84859939384

VL - 69

SP - 445

EP - 451

JO - Archives of Neurology

JF - Archives of Neurology

SN - 0003-9942

IS - 4

ER -