It is largely unknown how invading autoreactive T cells initiate the pathogenic process inside the diseased organ in organ-specific autoimmune disease. In this study, we used a chronic uveitis disease model in mice, experimental autoimmune uveitis (EAU), induced by adoptive transfer of uveitogenic, interphotoreceptor retinoid binding protein (IRBP)-specific T cells and showed that high mobility group box chromosomal protein 1 (HMGB1), an important endogenous molecule that serves as a danger signal, is rapidly released from retinal tissue cells into the extracellular matrix and intra-ocular fluid in response to IRBP-specific T cell transfer. HMGB1 levels in the intra-ocular fluid correlated with disease severity. The HMGB1-releasing tissue cells remained intact, showing that this molecule was not released by necrotic/apoptotic cells. HMGB1 release required direct cell-cell contact between retinal tissue cells and IRBP-specific T cells. Administration of HMGB1 antagonists markedly suppressed development of EAU via mechanisms including inhibition of migration of granulocytes/monocytes and Th1 cytokine production. Our study demonstrates that HMGB1 is an early and critical mediator of ocular inflammation initiated by autoreactive T cell invasion.
- Copyright © 2013 by The American Association of Immunologists, Inc.