Inhibition of T Cell Apoptosis in the Aqueous Humor of Patients with Uveitis by IL-6/Soluble IL-6 Receptor trans-Signaling

Abstract

A fundamental mechanism of immune privilege in the eye is the induction of T lymphocyte apoptosis. Intraocular inflammation in uveitis implies compromise of immune privilege. This study sought to determine whether apoptosis of T cells is actively inhibited in patients with uveitis and by what pathways this may occur. Apoptotic lymphocytes were found to be absent from aqueous humor (AqH) of virtually all patients with recent-onset uveitis. However, T cells removed from the eye were highly susceptible to both spontaneous and Fas ligand-induced apoptosis in vitro. AqH from patients with uveitis had no modulatory effect on Fas ligand-induced apoptosis, but strongly suppressed survival factor deprivation-induced apoptosis. In contrast, noninflammatory AqH from patients undergoing cataract surgery had no modulatory effects on apoptosis at all. These data suggest that triggering of the Fas pathway is diminished in uveitis, and also that homeostatic resolution through survival factor deprivation-induced apoptosis is inhibited by factors present in AqH. The most widely recognized pathways, common γ-chain cytokines and type I IFNs, did not contribute to AqH-mediated T cell survival. High levels of both IL-6 and soluble IL-6R were found in AqH. IL-6 alone did not induce T cell survival, because IL-6R expression on T cells in AqH was too low to facilitate signaling. However, combinations of IL-6 and soluble IL-6R were highly effective inhibitors of T cell apoptosis, suggesting that the trans-signaling pathway is likely to be a key mediator of T cell apoptosis inhibition mediated by uveitis AqH.

Therapeutic Targeting of IL-6 Trans Signaling Counteracts STAT3 Control of Experimental Inflammatory Arthritis

“…Structural cells of the joint typically lack IL-6R expression, and cells including synoviocytes may only respond to IL-6 through trans signaling (27,30). More recent advances, however, suggest that IL-6 trans signaling may directly affect T cell activation and apoptotic clearance (21,(47)(48)(49)(50). In this respect, T cell IL-6R expression is closely associated with surface markers typically associated with naive or central memory T cell subsets, suggesting that effector and effector memory T cells at sites of inflammation lack IL-6R expression (47,51,52).…”

“…Roles for IL-6 trans signaling have been linked with the control of infection, inflammation, vascular tone, and immunological responses associated with tumor progression (18,21,22,27,(47)(48)(49)(50)(51)53). The assignment of these activities to IL-6 trans signaling has been best illustrated in vivo when sIL-6R-mediated signaling via membrane-bound gp130 has been selectively antagonized with sgp130.…”

Cytokines and Chemokines in Uveitis - Is there a Correlation with Clinical Phenotype?

“…It is, therefore, proposed that combinations of IL-6 and IL-6 receptors are highly effective inhibitors of T cell apoptosis mediated by uveitis aqueous humor. 94 In addition to being found in the aqueous humor of patients with anterior uveitis, increased serum IL-8 levels have been associated with increased disease activity in idiopathic intermediate uveitis. 79,95 In humans, IL-4 has only been detected in low levels and at levels not significantly different from controls in the aqueous humor and serum of patients with idiopathic uveitis.…”

Noncarrier naked antigen-specific DNA vaccine generates potent antigen-specific immunologic responses and antitumor effects

“…Pilling et al reported that gold particle-coated DNA bombardment with the gene gun system induced local skin reactions two days post-dosing in mini-pigs. 47 By 28 days, the skin lesions had regressed apart from a low grade peri-vascular mononuclear cell infiltration in the upper dermis, which persisted up to 141 days, together with a small number of phagocytosed gold particles. 47 We also observed that gold particle-coated DNA vaccine bombardment by a gene gun has definite local skin damage as compared to noncarrier naked DNA vaccine ( Figure 6).…”

“…47 By 28 days, the skin lesions had regressed apart from a low grade peri-vascular mononuclear cell infiltration in the upper dermis, which persisted up to 141 days, together with a small number of phagocytosed gold particles. 47 We also observed that gold particle-coated DNA vaccine bombardment by a gene gun has definite local skin damage as compared to noncarrier naked DNA vaccine ( Figure 6). In addition, the most severe local skin damage of the mice was seen three days after bombardment with gold particle-coated DNA vaccine.…”