Typical EAU induced with IRBP in the B10.RIII mouse. (a and b) Healthy retina by fundus examination (a) and by histology (b). Note ordered retinal layers V: vitreous; G: ganglion cell layer; P: photoreceptor cell layer; R: retinal pigment epithelium; C: choroid; S: sclera. (c and d) Uveitic retina. Note detached retina around optic nerve head, perivascular cuffing and semicircular lesions (c). The retinal architecture is disorganized (d) showing vasculitis, retinal folds, subretinal exudate, loss of nuclei in the ganglion and the photoreceptor cell layers, disruption of the retinal pigment epithelium and inflammation of the choroid. Adapted from [13]

Conditions of initial exposure to Ag that may determine effector dominance are the quality/quantity of TLR and other innate receptor signals and the type/variety of cells participating as APC. Not depicted is the duration of exposure to the stimulus. Adapted and expanded from [23]

Shown is a schematic representation of the checkpoints and regulatory events in the process of ocular autoimmunity. Incomplete elimination of retina-specific effector precursor T cells in the thymus, combined with deficient peripheral tolerance, leads to a circulating pool of non-tolerized T cells that can be triggered by exposure to a retina-derived or crossreactive Ag presented in the context of inflammatory danger signals. This leads to a differentiation of the activated T cells to an autoaggressive Th1 or Th17 phenotype. “Natural” Treg cells are exported from the thymus along with the effector precursors and inhibit their activation and clonal expansion in an Ag-specific as well as in a bystander fashion. Activated effector T cells migrate and extravasate at random, and some reach the eye. Recognition of the cognate Ag in the tissue is followed by downstream events culminating in a breakdown of the blood–retinal barrier, recruitment of inflammatory leukocytes, further amplification of the inflammatory process and uveitis. Retina-derived Ags released from the damaged tissue induce generation of Ag specific Tregs in a process requiring the spleen, which help establish a new type of balance and maintain functional tolerance. Previously published in [14]