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

Abstract

ObjectivesAnti-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.MethodsA 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.ResultsA 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.ConclusionsWe 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.

Is the anti-centromere antibody a marker for a distinct subset of polyautoimmunity in Sjögren’s syndrome?

“…Several studies of epitope specificity have demonstrated that anti-CBX5 and anti-CENP-C are more common in SS than SSc patients [ 5 ]. However, a recent study of autoantigen profiling of ACA showed similar reactivities against centromere antigens in SS and SSc, unlike previous reports, and ACA-positive SS, SSc, and PBC patients had common clinical characteristics [ 13 ]. A further study should investigate if Korean SS patients with ACA have distinct epitopes from SSc and PBC patients with ACA.…”

“…A retrospective Japanese study reported that 81 (37.9%) of 309 ACA-positive patients were ultimately diagnosed with SSc, and 50 (23.4%) with SS [ 12 ]. Furthermore, it was recently reported that ACA-secreting cells accumulate in the salivary glands of SS patients [ 13 ]. Therefore, researchers have been examining the clinical characteristics of ACA-positive SS.…”

“…ACA-positive SS patients have more severe symptoms and signs of exocrine dysfunction, and higher prevalences of Raynaud’s phenomenon and sclerodactyly [ 13 ]. Autoimmune responses with autoantibodies occur in genetically susceptible individuals, and the associated diseases evolve progressively in a multi-hit fashion.…”

The Meta-Analysis About The Expression and Prognosis of Anti-Ro-52, Anti-CENP-B and AMA in Sjogren's Syndrome and Systemic Sclerosis

“…(Figure 3 As a popular antinuclear antibody to detect autoimmune diseases, the expression of anti-CENP-B in SS patients also has certain characteristics. In this group, we included 9 studies with corresponding data, recorded the number of SS patients with positive expression of anti-CENP-B, the total number of patients studied, the number of patients with positive expression of anti-SSB in the control group, and the total number of patients in the control group, and input the data into Revman for forest map analysis [13]. As shown in Figure 3-4, the results of four studies intersect with the invalid line, three of which are in favor of the side against SSB, and only one study is slightly in favor of the side of anti-CENP-B.…”

Uncovering potential new biomarkers and immune infiltration characteristics in primary Sojgren's syndrome by integrated bioinformatics analysis

“…It was suggested that neonates after exposure to anti-RO/La autoantibodies demonstrate innate immune activation, which was mainly related to IFN-γ producted by NK cells, CD4 + T cells and CD8 + T cells [48]. Additional study indicated that anti-centromere antibodies (ACAs) in the cytoplasm were detected in pSS and were associated with the accumulation of SGs centromere antibody secreting cells (ASCs) [49]. However, one study proposed that GO analysis was signi cantly different in salivary and lacrimal glands in time series [45].…”