AutoCore: A network-based definition of the core module of human autoimmunity and autoinflammation

Abstract

Although research on rare autoimmune and autoinflammatory diseases has enabled definition of nonredundant regulators of homeostasis in human immunity, because of the single gene-single disease nature of many of these diseases, contributing factors were mostly unveiled in sequential and noncoordinated individual studies. We used a network-based approach for integrating a set of 186 inborn errors of immunity with predominant autoimmunity/autoinflammation into a comprehensive map of human immune dysregulation, which we termed “AutoCore.” The AutoCore is located centrally within the interactome of all protein-protein interactions, connecting and pinpointing multidisease markers for a range of common, polygenic autoimmune/autoinflammatory diseases. The AutoCore can be subdivided into 19 endotypes that correspond to molecularly and phenotypically cohesive disease subgroups, providing a molecular mechanism–based disease classification and rationale toward systematic targeting for therapeutic purposes. Our study provides a proof of concept for using network-based methods to systematically investigate the molecular relationships between individual rare diseases and address a range of conceptual, diagnostic, and therapeutic challenges.