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Antibodies undergo rigorous selection to achieve this high affinity, yet some maintain an additional basal level of low affinity, broad reactivity to diverse epitopes, a phenomenon termed \u2018polyreactivity\u2019. While polyreactivity has been observed in antibodies isolated from various immunological niches, the biophysical properties that allow for promiscuity in a protein selected for high-affinity binding to a single target remain unclear. Using a database of over 1000 polyreactive and non-polyreactive antibody sequences, we created a bioinformatic pipeline to isolate key determinants of polyreactivity. These determinants, which include an increase in inter-loop crosstalk and a propensity for a neutral binding surface, are sufficient to generate a classifier able to identify polyreactive antibodies with over 75% accuracy. The framework from which this classifier was built is generalizable, and represents a powerful, automated pipeline for future immune repertoire analysis.<\/jats:p>","DOI":"10.7554\/elife.61393","type":"journal-article","created":{"date-parts":[[2020,11,10]],"date-time":"2020-11-10T08:04:43Z","timestamp":1604995483000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.61393","source":"Crossref","is-referenced-by-count":57,"title":["Biochemical patterns of antibody polyreactivity revealed through a bioinformatics-based analysis of CDR loops"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7106-4699","authenticated-orcid":true,"given":"Christopher T","family":"Boughter","sequence":"first","affiliation":[{"name":"Graduate Program in Biophysical Sciences, University of Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta T","family":"Borowska","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna J","family":"Guthmiller","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Bendelac","sequence":"additional","affiliation":[{"name":"Committee on Immunology, University of Chicago, Chicago, United States"},{"name":"Department of Pathology, University of Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick C","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, United States"},{"name":"Committee on Immunology, University of Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5254-2712","authenticated-orcid":true,"given":"Benoit","family":"Roux","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6271-8574","authenticated-orcid":true,"given":"Erin J","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United States"},{"name":"Committee on Immunology, University of Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2020,11,10]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.coi.2013.09.005","article-title":"Lipid presentation by human CD1 molecules and the diverse T cell populations that respond to them","volume":"26","author":"Adams","year":"2014","journal-title":"Current Opinion in Immunology"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1034\/j.1600-065x.2001.1830104.x","article-title":"Species-specific evolution of MHC class I genes in the higher primates","volume":"183","author":"Adams","year":"2001","journal-title":"Immunological Reviews"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"892","DOI":"10.4049\/jimmunol.1901025","article-title":"An ancient, MHC-Linked, nonclassical class I lineage in cartilaginous fish","volume":"204","author":"Almeida","year":"2020","journal-title":"The Journal of Immunology"},{"key":"bib4","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad0522","article-title":"Immune history profoundly affects broadly protective B cell responses to influenza","volume":"7","author":"Andrews","year":"2015","journal-title":"Science Translational Medicine"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1002\/cem.785","article-title":"Partial least squares for discrimination","volume":"17","author":"Barker","year":"2003","journal-title":"Journal of Chemometrics"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"1518","DOI":"10.1016\/j.jmb.2008.01.093","article-title":"The intrinsic contributions of tyrosine, serine, glycine and arginine to the affinity and specificity of antibodies","volume":"377","author":"Birtalan","year":"2008","journal-title":"Journal of Molecular Biology"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nature05907","article-title":"CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor","volume":"448","author":"Borg","year":"2007","journal-title":"Nature"},{"key":"bib8","article-title":"AIMS - An Automated Immune Molecule Separator","volume-title":"GitHub","author":"Boughter","year":"2020","unstructured":"Boughter CT. 2020. 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