Introduction: Recent advances in synthetic biology tools enable massively multiplexed serologic antibody profiling by phage display immunoprecipitation (PhIP-Seq) and protein microarray. We apply these tools toward unbiased investigation of antibody repertoires in APS-1 patients (autoimmune polyendocrine syndrome type 1). These patients bear widespread autoantibodies due to a genetic defect in the thymic transcription factor AIRE.
Methods: To determine antibody repertoires in APS-1, we analyzed single or multi-timepoint serum samples (N=96) from over 70 unique APS-1 patients. Patients with diverse comorbidities were analyzed using human proteome microarrays (HuProt, >21,000 proteins), human proteome PhIP-Seq (HuScan, >700,000 49-mer peptides), and pan-viral PhIP-Seq (VirScan, >480,000 62-mer peptides). Patients negative for HSV-1 were additionally investigated using virion display arrays (VirD, >400 GPCRs and other membrane receptors).
Results: In addition to previously reported autoantibodies against type I interferons, we observed numerous potentially novel autoantibodies associated with comorbidities such as diabetes mellitus, Sjögren's-like syndrome, enamel hypoplasia, and many others. Non-disease factors such as patient sex imparted additional features across the serologic profiles. In some patients, we detected autoantibodies against untagged membrane-embedded receptors on the virion display arrays.
Conclusion: Many chronic conditions associated with APS-1 syndrome are found throughout the general population. This comprehensive autoantibody survey reveals potentially pathogenic mechanisms that, once validated, could inform therapeutic strategies for both APS-1 patients and the broader population affected by these conditions.
