![]() Based on these and other sequence features, and with the help of computational techniques, a classifier is developed that reliably separates the two groups. Robust statistical and mathematical techniques are used to identify patterns in the form of specific sequences, motifs (e.g., the IGH CDR3 shown in red), and clusters, as well as changes in overall sequence diversity, that are characteristic of the cases but not the controls. (B) To develop a test for a specific condition, immunomes are sequenced from a set of cases positive for the condition and an appropriately matched set of controls. The recombined immunoglobulin (B cell receptor) and TR (T cell receptor) rearranged genes are sequenced, leading to a list of the hundreds of thousands of different sequences present in the sample: i.e., the patient’s immunome. (A) Testing begins with a standard clinical blood draw. Because of their intimate association with many different diseases, B- and T-cell immunomes will feature prominently in the future of clinical lab testing ( 7) ( Figure 1).įigure 1 Immunome-based diagnostic testing. NGS-based testing has also advanced the field of immunogenomics, providing a more streamlined means of identifying and cataloguing novel human leukocyte antigen (HLA) genes and associating allelic variants and haplotypes with diseases and immune perturbations (see below). In situations where there are many variants that may be diagnostically or prognostically useful, as is the case for cancer and in genetic disorders such as cystic fibrosis, sequencing has been shown to be more sensitive than tests that target a limited set of variants, for example using PCR ( 5, 6). The main appeal of sequencing as a diagnostic modality is its potential to detect all of the possible variants of a given gene or genes in a single test. Examples of high-throughput sequencing applications that have begun to enter the clinic in recent years include cancer-gene sequencing to identify clinically actionable mutations and whole-genome and metagenomic sequencing to resolve medical mysteries ( 1– 4). The convergence of high-throughput sequencing technologies with advances in computation and data science has given sequencing a growing role in clinical diagnosis. We conclude with a call to clinicians, researchers, and others to join efforts with the Adaptive Immune Receptor Repertoire Community (AIRR-C) to realize the diagnostic potential of the immunome. Here we discuss some of these opportunities, the current state of immunome-based diagnostics, and highlight some of the challenges involved. Because of its diversity and complexity, the immunome provides singular opportunities for advancing personalized medicine by serving as the substrate for a highly multiplexed, near-universal blood test. It is increasingly clear that an extraordinarily diverse range of clinically important conditions-including infections, vaccinations, autoimmune diseases, transplants, transfusion reactions, aging, and cancers-leave telltale signatures in the millions of V(D)J-rearranged antibody and T cell receptor genes collectively expressed by a person’s B cells (antibodies) and T cells. 5Roche Sequencing Solutions, Pleasanton, CA, United States.4Department of Neurology and Institute of Translational Neurology, University of Muenster, Muenster, Germany.3Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.2Department of Pathology, Harvard Medical School, Boston, MA, United States.1Department of Pathology and Division of Clinical Informatics, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States.Luning Prak 3, Nicholas Schwab 4*‡, Florian Rubelt 5*‡ and the Adaptive Immune Receptor Repertoire Community †
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