Anti-mitochondrial antibodies in systemic sclerosis target enteric neurons and are associated with GI dysmotility.

BACKGROUND: Most patients with systemic sclerosis (SSc) experience gastrointestinal (GI) dysmotility. The enteric nervous system (ENS) regulates GI motility, and its dysfunction causes dysmotility. A subset of SSc patients harbor autoantibodies against the M2 mitochondrial antigen (AM(2)A). Here, we investigate whether M2 is expressed by specific ENS cells, and if AM(2)A associate with GI dysmotility in SSc patients. METHODS: Sera from 154 well-characterized patients with SSc were screened for AM(2)A by ELISA. Clinical features and GI transit data were compared between AM(2)A-positive and negative patients. HepG2 cells were cultured with these sera and co-stained with AM(2)A. RESULTS: Nineteen of 147 patients (12.9%) were AM(2)A positive. AM(2)A positivity was significantly associated with slower transit in the esophagus (β -14.4, 95%CI -26.2, -2.6) and stomach (β -7.9, 95% CI -14.1, -1.6). Immunostaining demonstrated pan-mitochondrial antigens TOM-20 and M2 enrichment in human ENS neurons, specifically in mesoderm-derived enteric neurons (MENS). HepG2 cells cultured with SSc sera showed that SSc autoantibodies penetrate live cells and that AM(2)A and other SSc autoantibodies are localized to subcellular compartments containing target antigens. CONCLUSION: AM(2)A in SSc patients associate with slower GI transit. MENs are enriched in mitochondria, suggesting enhanced susceptibility to mitochondrial dysfunction and associated GI dysmotility in SSc. Our finding that SSc autoantibodies penetrate live cells in vitro suggests that SSc-AM(2)A may penetrate MENs in vivo, driving ENS and GI dysfunction. Further studies are warranted to understand whether AM(2)As contribute to mitochondrial dysfunction, and whether mitochondrial dysfunction contributes to GI dysmotility in SSc.