Inhibition of Spontaneous Lymphocyte Apoptosis Contributes to the Breakdown of Immune Privilege in Uveitis

Abstract

Abstract: : Purpose: Active induction of apoptosis of inflammatory cells has been shown to be central to ocular immune privilege. We investigated whether inhibition of apoptosis by the ocular microenvironment in uveitis contributes to the intraocular accumulation of leukocytes. Methods: Aqueous humour (AqH) lymphocytes from patients with untreated active uveitis were analysed for apoptosis by morphology and caspase-3 activation. An in vitro culture system was used to study the effect of control and uveitis AqH on both Fas-mediated and spontaneous apoptosis. Short-term CD4₊ T cell lines were cultured for 4h with sFasL or overnight in the absence of growth factors. Apoptosis was measured by the loss of mitochondrial polarisation, activation of caspase-3 and nuclear fragmentation. Results: There was an absence of significant apoptotic lymphocytes in AqH from recent-onset uveitis. Spontaneous apoptosis of CD4₊ T cells in vitro was profoundly inhibited by uveitis but not control AqH. By contrast, no effect was seen on Fas-mediated apoptosis. Furthermore, inhibition of spontaneous apoptosis correlated with the degree of inflammation in the eye and was present in both self-limiting and persistent uveitis. Conclusion: Our results suggest that immune privilege is circumvented in uveitis due to inhibition of spontaneous apoptosis, leading to the accumulation of inflammatory cells and subsequent damage to ocular tissues. The mechanism of inhibition is currently under investigation.

Keywords: 323 apoptosis/cell death • 437 inflammation • 612 uveitis-clinical/animal model