Novel Biomarker for Antimitochondrial Antibodies in Systemic Sclerosis Patients

We previously identified, using a synthetic peptide, namely peptide 4.33 (p4.33), a subgroup of anti-CENP-A antibodies (Abs) recognizing an epitope shared between the CENP-A region spanning amino acids 1-17 (Ap1-17) and the E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial target autoantigen in primary biliary cholangitis (PBC). Here, we evaluated whether anti-p4.33 Ab positivity may be associates with a higher prevalence of antimitochondrial Ab (AMA) in systemic sclerosis (SSc) patients.

Serum samples from 145 anti-CENP^pos SSc patients were tested for anti-CENP-A, -Ap1-17, and -p4.33 Abs by ELISA. Subsequently, 32 anti-Ap1-17^pos/p4.33^pos and 32 anti-Ap1-17^pos/p4.33^neg were randomly selected and tested for AMA by immunoblotting.

Of 145 anti-CENP^pos patients, 128 (88.2%) were anti-CENP-A^pos patients, of which 103 (80.5%) were positive for anti-Ap1-17 Abs and 66 (51.6%) were positive for anti-p4.33 Abs. Of 32 selected anti-Ap1-17^pos/p4.33^pos patients, 15 (46.9%) were also positive for AMA targeting PDC-E2 and/or the branched chain 2-oxo acid dehydrogenase complex (BCOADC-E2). In the Ap1-17^pos/p4.33^neg group, AMA were detected in only two patients (6.25%). AMA positivity was statistically different between groups. Anti-p4.33 Ab levels were directly associated more than anti-Ap1-17 Ab levels with AMA levels. Sequence homology analyses demonstrated that anti-p4.33 Abs recognize an epitope (kPsaP) strongly overlapping with those of Ap1-17, PDC-E2, and BCOADC-E2, also expressed by viral and bacterial proteins.

Anti-p4.33 Abs may be a useful biomarker to define a subset of SSc patients with a higher prevalence of AMA. Our findings also support the hypothesis that pathogens can trigger autoimmunity.