Daugherty, Patrick S.

Widely employed diagnostic antibody serology for Lyme disease, known as standard two-tier testing (STTT), exhibits insufficient sensitivity in early Lyme disease, yielding many thousands of false-negative test results each year. Given this problem, we applied serum antibody repertoire analysis (SERA), or next-generation sequencing (NGS)-based serology, to discover IgG and IgM antibody epitope motifs capable of detecting Lyme disease-specific antibodies with high sensitivity and specificity. Iterative motif discovery and bioinformatic analysis of epitope repertoires from subjects with Lyme disease ( n = 264) and controls ( n = 391) yielded a set of 28 epitope motifs representing 20 distinct IgG antibody epitopes and a set of 38 epitope motifs representing 21 distinct IgM epitopes, which performed equivalently in a large validation cohort of STTT-positive samples.

Significance The diagnosis of many diseases is dependent upon accurate detection of particular antibodies present in blood. However, the development of biochemical reagents that can reliably detect these antibodies has proved remarkably challenging. This study describes a process to create biochemical reagents that can accurately and reliably detect disease-associated antibodies, without requiring knowledge of the cause or mechanisms of disease. Simultaneously, this process enabled identification of a critical environmental agent involved in celiac disease. Thus, the process presented here may enable the development of effective diagnostic tests for other medical conditions where such tests are lacking and the identification of environmental factors involved in disease.