Although research on rare autoimmune and autoinflammatory diseases has enabled definition of non-redundant regulators of homeostasis in human immunity, due to the single gene-single disease nature of many of these diseases, contributing factors were mostly unveiled in sequential and non-coordinated individual studies. Here, 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 multi-disease 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 towards 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.