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

BackgroundMost 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 (AM2A). Here, we investigate whether M2 is expressed by specific ENS cells, and if AM2A associate with GI dysmotility in SSc patients. MethodsSera from 154 well-characterized patients with SSc were screened for AM2A by ELISA. Clinical features and GI transit data were compared between AM2A-positive and negative patients. HepG2 cells were cultured with these sera and co-stained with AM2A. ResultsNineteen of 147 patients (12.9%) were AM2A positive. AM2A positivity was significantly associated with slower transit in the esophagus ({beta} -14.4, 95%CI -26.2, -2.6) and stomach ({beta} -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 AM2A and other SSc autoantibodies are localized to subcellular compartments containing target antigens. ConclusionAM2A 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-AM2A may penetrate MENs in vivo, driving ENS and GI dysfunction. Further studies are warranted to understand whether AM2As contribute to mitochondrial dysfunction, and whether mitochondrial dysfunction contributes to GI dysmotility in SSc. Key messagesO_LIWhat is already known on this topic O_LIsubset of SSc patients have autoantibodies against the M2 mitochondrial antigen (AM2A). Whether AM2A antibodies inform the presence or severity of GI dysfunction in SSc is unknown. C_LI C_LI O_LIWhat this study adds: O_LIAM2A antibodies in SSc patients associate with slower upper GI transit. C_LIO_LIMitochondria are enriched in a recently identified mesoderm-derived lineage of enteric neurons (MENs), which play a major role in GI motility. This suggests that MENS may be more mitochondrial-dependent than other cell types, and thus more susceptible to mitochondrial dysfunction. This may contribute to dysmotility in AM2A-positive SSc patients. C_LIO_LISSc autoantibodies penetrate live cells in vitro and bind to their target antigens intracellularly. C_LI C_LI O_LIHow this study might affect research, practice or policy O_LIAM2A antibodies in SSc patients may penetrate MENs in vivo, driving ENS dysfunction and subsequent GI dysmotility C_LIO_LIThis potentially novel mechanism in SSc GI disease could inform our current approach to diagnosing and managing these patients. C_LI C_LI