Interpretable Inflammation Landscape of Circulating Immune cells

Inflammation is a biological phenomenon involved in a wide variety of physiological and pathological processes. Although a controlled inflammatory response is beneficial for restoring homeostasis, it can become unfavorable if dysregulated. In recent years, major progress has been made in characterizing acute and chronic inflammation in specific diseases. However, a global, holistic understanding of inflammation is still elusive. This is particularly intriguing, considering the crucial function of inflammation for human health and its potential for modern medicine if fully deciphered. Here, we leverage advances in the field of single-cell genomics to delineate the full spectrum of circulating immune cell activation underlying inflammatory processes during infection, immune-mediated inflammatory diseases and cancer. Our single-cell atlas of >2 million peripheral blood mononuclear cells from 356 patients and 18 diseases allowed us to learn a foundation model of inflammation in circulating immune cells. The atlas expanded our current knowledge of the biology of inflammation of acute (e.g. inflammatory bowel disease, sepsis) and chronic (e.g. cirrhosis, asthma, and chronic obstructive pulmonary disease) disease processes and laid the foundation to develop a precision medicine framework using unsupervised as well as explainable machine learning. Beyond a disease-centered classification, we charted altered activity of inflammatory molecules in peripheral blood cells, depicting functional biomarkers to further understand mechanisms of inflammation. Finally, we have laid the groundwork for developing precision medicine diagnostic tools for patients experiencing severe acute or chronic inflammation by learning a classifier for inflammatory diseases, presenting cells in circulation as a powerful resource for patient stratification. ### Competing Interest Statement H.H. is co-founder and shareholder of Omniscope, scientific advisory board member of Nanostring and MiRXES and consultant to Moderna and Singularity. J.C.N. is scientific consultant to Omniscope. V.S. has received research grants from AstraZeneca and honoraria from GSK unrelated to this study. M.v.d.B has received research grants (unrestricted) from AstraZeneca, Novartis, GlaxoSmithKline, Roche, Genentech, Chiesi and Sanofi. M.N. has been awarded with research grants (unrestricted) from AstraZeneca and GSK. A.S. is the recipient of research grants from Roche-Genentech, Abbvie, GSK, Scipher Medicine, Pfizer, Alimentiv, Inc, Boehringer Ingelheim and Agomab; receives consulting fees from Genentech, GSK, Pfizer, HotSpot Therapeutics, Alimentiv, Origo Biopharma, Deep Track Capital, Great Point Partners and Boxer Capital; and is on the advisory boards of BioMAdvanced Diagnostics, Goodgut and Orikine. A.A. is a computational biologist at IMIDomics, Inc. A.J. is the chief data scientist at IMIDomics, Inc. S.M. is the co-founder and CMO at IMIDomics, Inc.