Abstract Clinical diagnoses rely on a wide variety of laboratory tests and imaging studies, interpreted alongside physical examination findings and the patient’s history and symptoms. Currently, the tools of diagnosis make limited use of the immune system’s internal record of specific disease exposures encoded by the antigen-specific receptors of memory B cells and T cells, and there has been little integration of the combined information from B cell and T cell receptor sequences. Here, we analyze extensive receptor sequence datasets with three different machine learning representations of immune receptor repertoires to develop an interpretive framework, MAchine Learning for Immunological Diagnosis (Mal-ID) , that screens for multiple illnesses simultaneously. This approach is effective in identifying a variety of disease states, including acute and chronic infections and autoimmune disorders. It is able to do so even when there are other differences present in the immune repertoires, such as between pediatric or adult patient groups. Importantly, many features of the model of immune receptor sequences are human-interpretable. They independently recapitulate known biology of the responses to infection by SARS-CoV-2 and HIV, provide evidence of receptor antigen specificity, and reveal common features of autoreactive immune receptor repertoires, indicating that machine learning on immune repertoires can yield new immunological knowledge. This framework could be useful in identifying immune responses to new infectious diseases as they emerge.

Disease diagnostics using machine learning of immune receptors