Thursday 13 February 2014
Novel insights into the pathogenesis of Birdshot Chorioretinopathy
Promotor: Prof. dr. A. Rothova
Defence: 13 February 2014
Birdshot chorioretinopathy (BSCR) is a rare and poorly understood form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele and defines the strongest documented HLA association for a human disease. To better understand the underlying pathophysiology we investigated the role of T cell subsets, ocular microenvironment in disease outcome, and sought additional genetic markers associated with BSCR. Patients showed elevated intraocular levels of pro-inflammatory cytokines (TNF-alpha, IL-1-beta, IL-6,…,) and IL-17. Interestingly, IL-17-specific cytokine responses and the induction of T helper 17 cells are observed in peripheral blood mononuclear cells stimulated with human ocular antigens. Also, intraocular T cells (derived from vitreous fluid during pars plana vitrectomy) are directed against retinal and choroid antigens. This substantiates the emerging concept of autoreactive eye-specific T cells in the pathophysiology of BSCR. Finally, in the first genome-wide association study of this extremely rare eye disease, we demonstrated that the MHC association is conferred by HLA-A*29:02 with unusually large effect size. More importantly, we identified an ERAP2 polymorphism that increases mRNA and protein expression levels of ERAP2. The dual association between a specific HLA-A allele and ERAP2 implicates a role for peptide processing and antigen presentation in the disease mechanism.