Lymphopenia and local antigen presentation combine to induce colitis in a transgenic mouse model of uveitis

Undifferentiated uveitis (intraocular inflammation, IOI) is an idiopathic sight-threatening, presumed autoimmune disease, accountable for ~ 10% of all blindness in the developed world. We have investigated the association of uveitis with inflammatory bowel disease (IBD) using a mouse model of spontaneous experimental autoimmune uveoretinitis (EAU). Mice expressing the transgene (Tg) hen egg lysozyme (HEL) in the retina were crossed with 3A9 mice expressing a transgenic HEL-specific TCR. Double transgenic (dTg TCR/HEL) mice with EAU also spontaneously develop clinical signs of colitis at ~ P30 (post-partum day) with diarrhoea, bowel shortening, oedema and lamina propria (LP) inflammatory cell infiltration. Single (s)Tg TCR (3A9) mice also show histological LP cell infiltration but no clinical signs. dTg TCR/HEL mice are profoundly lymphopenic at weaning. In addition, dTg TCR/HEL mice contain myeloid cells which express MHC Class II-HEL peptide (MHCII-HEL) complexes, not only in the inflamed retina but also in the colon. In this model the lymphopenia and reduction in the absolute Treg numbers in dTg TCR/HEL mice is sufficient to initiate eye disease. We suggest that cell-associated antigen released from the inflamed eye, activates colonic HEL-specific T cells which, in a microbial micro-environment, not only cause colitis but feed-back to amplify IOI.