Autoantibodies against the immunodominant sCha epitope discriminate the risk of sudden death in chronic Chagas cardiomyopathy

In Chagas disease (ChD) caused by Trypanosoma cruzi, new biomarkers to predict chronic cardiac pathology are urgently needed. Previous studies in chagasic patients with mild symptomatology showed that antibodies against the immunodominant R3 epitope of sCha, a fragment of the human basic helix‐loop‐helix transcription factor like 5, correlated with cardiac pathology. To validate sCha as a biomarker and to understand the origin of anti‐sCha antibodies, we conducted a multicenter study with several cohorts of chagasic patients with severe cardiac symptomatology. We found that levels of antibodies against sCha discriminated the high risk of sudden death, indicating they could be useful for ChD prognosis. We investigated the origin of the antibodies and performed an alanine scan of the R3 epitope. We identified a minimal epitope MRQLD, and a BLAST search retrieved several T. cruzi antigens. Five of the hits had known or putative functions, of which phosphonopyruvate decarboxylase showed the highest cross‐reactivity with sCha, confirming the role of molecular mimicry in the development of anti‐sCha antibodies. Altogether, we demonstrate that the development of antibodies against sCha, which originated by molecular mimicry with T. cruzi antigens, could discriminate electrocardiographic alterations associated with a high risk of sudden death. To validate sCha as a biomarker and to understand the origin of anti‐sCha antibodies, we conducted a multicenter study with several severe cardiac cohorts of patients. Our results allowed us to identify the origin of autoantibodies against sCha by a molecular mimicry mechanism between the immunodominant R3H5 epitope and the PPDC peptide, and even though their pathological role was not evaluated, they are without doubt good discriminating biomarkers of ECG alterations associated with a high risk of sudden death.