Immunoregulatory mechanisms in the eye

National Eye Institute

Investigators

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Abstract

Following the discovery that suppressor of cytokine signaling 3 (SOCS3) is predominantly expressed in Th2 but not Th1 cells (J Immunol. 168:3181-7, 2002), it was revealed that expression of SOCS3 by peripheral blood mononuclear cells (PBMC) of patients with asthma or atopic dermatitis is elevated compared with healthy people. In addition, it was also shown that the severity of these Th2-mediated diseases correlated with the level of SOCS3 mRNA in PBMC (Nat Med 9, 1047-54, 2003). This has led to the suggestion that SOCS3 is a potential new target for anti-allergy drugs. Thereafter, it was established that SOCS5 is preferentially expressed in Th1 but not Th2 cells, leading to the notion that whereas SOCS3 is a molecular marker of Th2 cells, SOCS5 is a Th1 cell marker. Uveitis is a Th1-mediated disease and our studies have established the potential use of SOCS mRNA levels as surrogate markers for monitoring the intensity of uveitis and response of patients to anti-uveitis therapy. To further understanding of the role of SOCS proteins in immuno-pathogenesis of uveitis, we examined the temporal expression of inflammatory cytokines and SOCS genes in the retina, blood and lymph nodes of mice with experimental autoimmune uveitis (EAU), a T cell-mediated disease that serves as model of human uveitis. Because destruction of the neural retina in this disease results from secretion of proinflammatory cytokines by EAU-inducing Th1 lymphocytes (uveitogenic T cells), EAU is ideally suited to examine whether the pattern of SOCS expression correlates with severity of uveitis or host protective mechanisms. Our results indicate that SOCS expression in retina is temporarily correlated with progression of uveitis as peak of EAU correlates with significant increases in SOCS1, SOCS3 and CIS genes expression while disease resolution coincides with their down-regulation. Surprisingly, we found that SOCS5 is constitutively expressed in retina. Furthermore, the level of SOCS5 expression increases significantly during EAU and remains elevated even after disease resolution. Our data thus provides evidence suggesting that cytokine-inducible SOCS members (SOCS1, SOCS3, CIS) negatively regulate inflammatory cytokines activities during EAU while SOCS5, a SOCS member that is constitutively expressed in many tissues, may have protective functions in the neuroretina