The peptide link between pathogens and human centromere proteins

Abstract

Anti-centromere antibodies (ACA) were firstly detected in 1980 via indirect immunofluorescence (IIF) after incubation of human epithelial cell line 2 (HEp-2) cell substrates with serum samples from individuals with CREST (calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly and telangiectasias) syndrome. 1 Then, ACA were shown to be useful molecular markers for diagnosing systemic sclerosis (SSc), with a positive rate approximating 20%-40%. 2 However, ACA are not specific to SSc. Although with reduced frequency, ACA are detected in multiple additional autoimmune pathologies and malignancies, including primary Sjögren syndrome, 3 systemic lupus erythematosus, 4 rheumatoid arthritis, 5 type 1 diabetes mellitus 6 and breast cancer without symptoms of rheumatologic disease. 7 Subsequent reports identified ACA autoantigens. Currently, many centromere proteins (CENPs) are considered ACA autoantigens, with CENP-A, CENP-B and CENP-C being major centromere proteins. 8 The above three autoantigens with similar structures represent the best-described centromere constituents in humans.Centromere proteins are considered intracellular, nuclear proteins contributing to the assembly of kinetochores that are critical to mitosis progression and chromosome segregation. CENP-A represents a 17-kDa protein found at centromeric sites with high sequence similarity to histone H3. 9 Meanwhile, CENP-B (80 kDa) interacts with αsatellite DNA sequences 10 at the heterochromatic centromere. CENP-C represents a 140-kD protein found in the kinetochore's inner plate. 11 ACA detection in serum samples from individuals with SSc or other pathologies suggests CENPs may cause the immune system to induce autoimmune reactions. However, multiple unanswered questions and data gaps remain. First, how antibodies are primed to CENPs is unclear. As nuclear proteins, CENPs are theoretically inaccessible to the immune system.