Systemic sclerosis and primary biliary cholangitis share an antibody population with identical specificity.

SYSTEMIC scleroderma; PYRUVATE dehydrogenase complex; CHOLANGITIS; NUCLEAR proteins; IMMUNOGLOBULINS

Anti-centromere (ACA) and antimitochondrial antibodies (AMA) are specific for limited-cutaneous systemic sclerosis (lcSSc) and primary biliary cholangitis (PBC), respectively, and can coexist in up to 25 and 30% of SSc and PBC patients. Here, we evaluated whether anti-centromeric protein A (CENP-A) antibodies cross-react with mitochondrial antigens. To this end, sera from two lcSSc patients (pt1 and pt4), one of them (pt4) also affected by PBC, were used as the source of ACA, previously shown to recognize different groups of amino acids (motifs) in the CENP-A region spanning amino acids 1–17 (Ap1–17). Pt1 and pt4 Ap1–17-specific IgG were purified by affinity-chromatography on insolubilized Ap1–17-peptide column and tested by western blotting with nuclear and cytoplasmic protein extract from HeLa cells. Immunoreactive proteins were identified by mass spectrometry and validated by immunodot. The results showed that affinity-purified SSc/PBC pt4 anti-Ap1–17 and not SSc pt1 anti-Ap1–17 Ab, specifically cross-reacted with the E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial autoantigen in PBC. Sequence homology analysis indicated that the motif A-x-x-P-x-A-P recognized by pt4 anti-Ap1–17 IgG and shared by CENP-A and PDC-E2, is also expressed by some members of the Human Herpesvirus family, suggesting that they may trigger the production of these cross-reacting antibodies. A novel anti-CENP-A Ab-specific epitope, shared with the major primary biliary cholangitis autoantigen PDC-E2, has been identified. The definition at a molecular level of this shared epitope sheds light on the origin of this subgroup of antibodies and discloses novel opportunities for investigation of their pathogenic significance. Sequence homology analysis indicates this motif is also expressed on exogenous antigens which may trigger the production of anti-CENP-A/ PDC-E2 cross-reacting antibodies. Graphical Abstract [ABSTRACT FROM AUTHOR]