Abstract
Purpose: :
To determine the role of HMGB1 (high mobility group box protein-1), a major damage associated molecular pattern (DAMP), in ocular autoimmunity.
Methods: :
EAU was induced in C57BL/6 (B6) mice by adoptive transfer of interphotoreceptor retinoid-binding protein (IRBP)1-20 peptide-specific T cells. HMGB1 was then serially identified in the retina by immunohistology and in the aqueous humor (AqH) by ELISA. Mice receiving IRBP-specific T cells were treated with HMGB1 antagonists and intraocular inflammation documented by funduscopy and histology. Proliferation, cytokine production and the disease inducing ability of antigen-responder T cells from treated or non-treated mice were compared.
Results: :
After adoptive transfer of IRBP-specific T cells, intracellular HMGB1 in the inner ganglion cell layer was dramatically reduced within 24h and almost completely undetectable in the retina by day 7. By contrast, HMGB1 was significantly increased in the AqH compared to the control eye. Ocular inflammation induced by IRBP-specific T cells was ameliorated by treatment with ethyl pyruvate (EP), an antioxidant that suppressesHMGB1 release, or a neutralizing antibody to HMGB1. The level of HMGB1 in the AqH of treated mice was dramatically reduced compared to untreated mice, although proliferation of uveitogenic T cells was the same in both mice.
Conclusions: :
The pathogenicity of autoreactive T cells is dependent on the rapid release of HMGB1 from viable retinal tissue cells. Inhibition of HMGB1 will suppress the development of adoptively transferred EAU.
Keywords: autoimmune disease • inflammation • chorioretinitis