TY - JOUR
T1 - Anti-centromere antibodies target centromere-kinetochore macrocomplex
T2 - A comprehensive autoantigen profiling
AU - Kajio, Nobuhiko
AU - Takeshita, Masaru
AU - Suzuki, Katsuya
AU - Kaneda, Yukari
AU - Yamane, Humitsugu
AU - Ikeura, Kazuhiro
AU - Sato, Hidekazu
AU - Kato, Shin
AU - Shimizu, Hiroyuki
AU - Tsunoda, Kazuyuki
AU - Takeuchi, Tsutomu
N1 - Funding Information:
Acknowledgements We thank Ms. Harumi Kondo and Ms. Mayumi Ota for collecting clinical samples. This study was supported by the Collaborative Research Resources, Keio University School of Medicine, which provided technical assistance. The pEFs vector was kindly gifted from Dr. A. Yamashita, Yokohama City University School of Medicine, Japan.
Funding Information:
Funding This work was supported by JSPS KAKENHI, Grant numbers JP 16K19609 and JP 17H04216.
Publisher Copyright:
© 2021 Author(s) (or their employer(s)). Re-usepermitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - Objectives Anti-centromere antibodies (ACAs) are detected in patients with various autoimmune diseases such as Sjögren's syndrome (SS), systemic sclerosis (SSc) and primary biliary cholangitis (PBC). However, the targeted antigens of ACAs are not fully elucidated despite the accumulating understanding of the molecular structure of the centromere. The aim of this study was to comprehensively reveal the autoantigenicity of centromere proteins. Methods A centromere antigen library including 16 principal subcomplexes composed of 41 centromere proteins was constructed. Centromere protein/complex binding beads were used to detect serum ACAs in patients with SS, SSc and PBC. ACA-secreting cells in salivary glands obtained from patients with SS were detected with green fluorescent protein-fusion centromere antigens and semiquantified with confocal microscopy. Results A total of 241 individuals with SS, SSc or PBC and healthy controls were recruited for serum ACA profiling. A broad spectrum of serum autoantibodies was observed, and some of them had comparative frequency as anti-CENP-B antibody, which is the known major ACA. The prevalence of each antibody was shared across the three diseases. Immunostaining of SS salivary glands showed the accumulation of antibody-secreting cells (ASCs) specific for kinetochore, which is a part of the centromere, whereas little reactivity against CENP-B was seen. Conclusions We demonstrated that serum autoantibodies target the centromere-kinetochore macrocomplex in patients with SS, SSc and PBC. The specificity of ASCs in SS salivary glands suggests kinetochore complex-driven autoantibody selection, providing insight into the underlying mechanism of ACA acquisition.
AB - Objectives Anti-centromere antibodies (ACAs) are detected in patients with various autoimmune diseases such as Sjögren's syndrome (SS), systemic sclerosis (SSc) and primary biliary cholangitis (PBC). However, the targeted antigens of ACAs are not fully elucidated despite the accumulating understanding of the molecular structure of the centromere. The aim of this study was to comprehensively reveal the autoantigenicity of centromere proteins. Methods A centromere antigen library including 16 principal subcomplexes composed of 41 centromere proteins was constructed. Centromere protein/complex binding beads were used to detect serum ACAs in patients with SS, SSc and PBC. ACA-secreting cells in salivary glands obtained from patients with SS were detected with green fluorescent protein-fusion centromere antigens and semiquantified with confocal microscopy. Results A total of 241 individuals with SS, SSc or PBC and healthy controls were recruited for serum ACA profiling. A broad spectrum of serum autoantibodies was observed, and some of them had comparative frequency as anti-CENP-B antibody, which is the known major ACA. The prevalence of each antibody was shared across the three diseases. Immunostaining of SS salivary glands showed the accumulation of antibody-secreting cells (ASCs) specific for kinetochore, which is a part of the centromere, whereas little reactivity against CENP-B was seen. Conclusions We demonstrated that serum autoantibodies target the centromere-kinetochore macrocomplex in patients with SS, SSc and PBC. The specificity of ASCs in SS salivary glands suggests kinetochore complex-driven autoantibody selection, providing insight into the underlying mechanism of ACA acquisition.
KW - Sjogren's syndrome
KW - autoantibodies
KW - autoimmunity
KW - scleroderma
KW - systemic
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U2 - 10.1136/annrheumdis-2020-218881
DO - 10.1136/annrheumdis-2020-218881
M3 - Article
C2 - 33208344
AN - SCOPUS:85096448200
SN - 0003-4967
VL - 80
SP - 651
EP - 659
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
IS - 5
ER -