Pathomechanisms of anti-cytosolic 5'-nucleotidase 1A autoantibodies in sporadic inclusion body myositis.
OBJECTIVE
Sporadic inclusion body myositis (sIBM), an intractable progressive muscle disease, frequently occurs in older persons. sIBM pathogenesis may involve protein degradation dysfunction and immune abnormalities. Autoantibodies recognizing cytosolic 5'-nucleotidase 1A (cN1A) were found in plasma and serum from sIBM patients. However, whether anti-cN1A autoantibodies play a pathogenic role in sIBM is controversial. This study investigated the pathogenic properties of anti-cN1A autoantibodies in sIBM pathogenesis.


METHODS
We developed a cell-based assay to detect anti-cN1A autoantibodies, which we found in serum from patients with neuromuscular diseases including sIBM. We also investigated the clinicopathological differences between sIBM patients with and without the autoantibodies. We used passive in vitro and in vivo immunization models to evaluate the pathogenic role of the autoantibodies.


RESULTS
Of 67 patients with sIBM, 24 (35.8%) possessed anti-cN1A autoantibodies as determined via our cell-based assay. In the anti-cN1A-positive group, the percentage of patients with hepatitis C virus antibodies was significantly lower and the mean area of type 2 myofibers was significantly smaller compared with the autoantibody-negative group. In the in vitro passive immunization model, p62/SQSTM1 significantly increased in anti-cN1A-positive sIBM immunoglobulin G (IgG)-supplemented cells. In the in vivo passive immunization model, anti-cN1A-positive sIBM IgG-injected mice demonstrated p62/SQSTM1-positive sarcoplasmic aggregates in myofibers, associated with macrophage infiltration.


CONCLUSIONS
Our cell-based assay is useful for anti-cN1A autoantibodies detection. Patients with anti-cN1A autoantibodies demonstrated unique clinicopathological features. In vitro and in vivo passive immunization model results suggest that anti-cN1A autoantibodies may affect protein degradation in myofibers. Ann Neurol 2017;81:512-525.
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto.
Nozomu
N
Tawara
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto.
Satoshi
S
Yamashita
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto.
Xiao
X
Zhang
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto.
Mai
M
Korogi
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto.
Ziwei
Z
Zhang
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto.
Tsukasa
T
Doki
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto.
Yoshimasa
Y
Matsuo
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto.|Department of Molecular Neurology and Therapeutics, Kumamoto University Hospital, Kumamoto.
Shunya
S
Nakane
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto.
Yasushi
Y
Maeda
Department of Neurology, Nara Medical University School of Medicine, Nara.
Kazuma
K
Sugie
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Naoki
N
Suzuki
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Masashi
M
Aoki
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto.
Yukio
Y
Ando
D015720:5'-Nucleotidase / Q000276:immunology*; D000328:Adult; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D001681:Biological Assay / Q000379:methods*; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007116:Immunization, Passive / Q000706:statistics & numerical data; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018979:Myositis, Inclusion Body / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
D001323:Autoantibodies; D015720:5'-Nucleotidase