Anti-centromere antibodies target centromere-kinetochore macrocomplex: a comprehensive autoantigen profiling

Area of Science:

• Immunology
• Autoimmunity
• Molecular Biology

Background:

• Anti-centromere antibodies (ACAs) are biomarkers in autoimmune diseases like Sjögren's syndrome (SS), systemic sclerosis (SSc), and primary biliary cholangitis (PBC).
• The precise autoantigens targeted by ACAs within the centromere structure remain incompletely understood.
• Understanding ACA targets is crucial for elucidating autoimmune disease pathogenesis.

Purpose of the Study:

• To comprehensively identify the autoantigens targeted by ACAs in patients with SS, SSc, and PBC.
• To investigate the role of specific centromere proteins and complexes in driving autoantibody production.
• To explore the relationship between ACA targets and disease-specific immune cell activity.

Main Methods:

• Construction of a comprehensive centromere antigen library comprising 16 subcomplexes and 41 proteins.
• Utilizing protein/complex binding beads for serum ACA detection in patient cohorts (SS, SSc, PBC) and healthy controls.
• Employing confocal microscopy to visualize and quantify ACA-secreting cells (ASCs) in SS salivary glands using fluorescently labeled antigens.

Main Results:

• A wide array of serum autoantibodies targeting centromere components were identified across the three diseases.
• The prevalence of various ACA specificities was similar across SS, SSc, and PBC patient groups.
• Immunostaining revealed ASCs in SS salivary glands primarily targeting kinetochore components, with minimal reactivity against CENP-B.

Conclusions:

• Serum autoantibodies in SS, SSc, and PBC patients predominantly target the centromere-kinetochore macrocomplex.
• The observed specificity of ASCs in SS suggests that the kinetochore complex is a key driver of autoantibody selection in this disease.
• These findings provide critical insights into the mechanisms underlying ACA acquisition in autoimmune conditions.