A second area of discovery involves granulomatous inflammation. Granulomas are organized immune aggregates composed of macrophages, T cells, B cells, and other immune populations, yet the signals that initiate and sustain this architecture remain poorly understood. We identified osteopontin as a signal uniquely enriched in granulomatous inflammation across a broad spectrum of human inflammatory skin diseases. We demonstrated that thrombin-cleaved osteopontin, rather than its full-length form, functions as a key signaling ligand in granuloma formation and maintenance, revealing a conserved biochemical pathway for inflammatory tissue organization. We also showed that granulomas from distinct diseases contain disease-specific immune architectures, including enrichment of B cells and innate lymphoid cells in sarcoidosis. This work provides a molecular framework for mechanistically understanding how these classic histopathological structures are formed and sustained.