Editors' ChoiceUveitis

The "Eyes" Have It

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Science Translational Medicine  03 Aug 2011:
Vol. 3, Issue 94, pp. 94ec123
DOI: 10.1126/scitranslmed.3002966

In some tissues, the immune system can do more harm than good. This is especially true in the eye, where immune activation and inflammation may impede vision. The eye has a more tightly controlled inflammatory response than other tissues; however, inflammation may still occur. Uveitis, or inflammation of the middle layer of the eye, can result from either infection or systemic inflammation and is a major cause of blindness worldwide. One potential cause of uveitis is the presence of an underlying systemic autoimmune disease. The intraocular inflammation in this setting is thought to result from a loss of tolerance to self-antigens in the eye. Indeed, there is substantial evidence for autoimmune-mediated uveitis directed against two candidate retinal proteins, soluble antigen (S-Ag) and interphotoreceptor retinoid-binding protein (IRBP). However, as with all studies of human autoimmunity, the pathogenic role of these antigens in uveitis remains unproven. A recent paper by Mattapallil et al. makes important progress toward establishing a causative role for S-Ag in human uveitis, as well as supports a future role for S-Ag as a diagnostic biomarker for patients with autoimmune eye disease.

In this study, the authors examined available strains of transgenic mice that expressed human class II HLA alleles known to be associated with intraocular inflammation. They identified in vivo the S-Ag peptides that were processed by these diverse HLA molecules and then presented to T cells implicated in autoimmune uveitis pathogenesis. First, they established which HLA alleles conferred susceptibility to uveitis in their system by identifying which mouse lines develop disease when immunized with the S-Ag protein. They next pinpointed the immunodominant amino acid sequences in human S-Ag by identifying peptides that induced the greatest lymphocyte proliferation in cells from affected mice. Tetramers loaded with immunodominant peptides were then used to identify antigen-specific T cells in the peripheral blood of animals. Importantly, the authors demonstrated an autoimmune basis for eye disease by showing that these T cells elicited uveitis when transferred into unaffected mice. Lastly, in an exciting translation to human disease Matipallil et al. showed that their tetramer could identify S-Ag–specific T cells in a subject with known autoimmune uveitis. Through their work, the authors have established a mouse system that can be used to develop and validate biomarkers for autoimmune uveitis and provide further insight into the pathogenesis of this potentially debilitating disease.

M. J. Mattapallil et al., Uveitis-associated epitopes of retinal antigens are pathogenic in the humanized mouse model of uveitis and identify autoaggressive T cells. J. Immunol. 15 July 2011 (10.4049/jimmunol.1101247). [Abstract]

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