The nature of antigen in the eye has a profound effect on the cytokine milieu and resultant immune response

Abstract

The eye is endowed with a number of mechanisms that protect it from immune-mediated injury. One such mechanism, termed anterior chamber-associated immune deviation (ACAID), evokes the antigen-specific, systemic down-regulation of Th1 responses to antigen inoculated into the anterior chamber of the eye. ACAID has been correlated with the selective production of IL-10 by the antigen-presenting cells (APC) and the development of a cross-regulatory Th2-like response. A small subset of antigens do not induce ACAID, but instead provoke IL-12 and normal Th1 immunity. Remarkably, all soluble antigens tested are capable of inducing ACAID; only cell-associated antigens do not induce ACAID. We hypothesized that the nature of antigen plays a decisive role in the resultant immune response. This hypothesis was tested with two well-characterized antigens, ovalbumin (OVA) and SV40 large T antigen (SV40 Lg T Ag). The soluble forms of OVA and SV40 Lg T Ag induced ACAID in both in vivo and in vitro models of the eye. In contrast, the particulate forms of these antigens, i.e. OVA passively absorbed onto inert latex beads (OVA-latex) and SV40 Lg T Ag expressed in two different cell lines, 99E1 and SV-T2, did not induce ACAID in either in vivo or in vitro models of the eye. In addition, the cytokine profiles of ocular APC pulsed with OVA or OVA-latex showed that soluble OVA induced the production of IL-10, whereas OVA-latex induced the production of IL-12. These data suggest that the nature of the antigen in the eye, whether soluble or particulate, is a crucial determinant in the resultant immune response. Moreover, they suggest a mechanism in which soluble antigens preferentially induce the release of ACAID-inducing IL-10 whereas particulate antigens preferentially induce the release of Th1-inducing IL-12 by responding APC.

Goodpasture Autoantibodies Unmask Cryptic Epitopes by Selectively Dissociating Autoantigen Complexes Lacking Structural Reinforcement

“…The nature of the molecular interactions underpinning the formation of NC1 dimers has been extensively studied in the homologous (␣1␣2␣1) 2 hexamers, but the detailed mechanism remains unknown. A subset of M-␣1␣2␣1 hexamers composed of ␣1 and ␣2 NC1 monomers exists in the bovine lens capsule basement membrane, and dimer-rich D-␣1␣2␣1 hexamers are predominant in the placenta basement membrane (24).…”

“…Privilege originally implied a location anatomically protected from attack by the immune system, such as the eye, brain, or testes (1). It is now recognized that the pathophysiology of protectiveness involves multiple mechanisms, including cytokines that inhibit innate or adaptive immunity (2), systemic regulatory T cells (3), and local cytotoxic mechanisms producing apoptosis of effector T cells induced by local FasL-Fas interactions (4). What has not been widely appreciated is that the molecular sequestration of self-antigen in complex structures can be a critical mechanism of immunologic privilege.…”

Ocular Immune Privilege Promoted by the Presentation of Peptide on Tolerogenic B Cells in the Spleen. II. Evidence for Presentation by Qa-1

“…However, the suppression of IgG and IgM Ab responses in that study was due to IFN-␥ produced by Qa-1-restricted CD8 ϩ regulatory T cells (10). By contrast, ACAID involves the down-regulation of IFN-␥ and a concomitant induction of IL-10 production (31)(32)(33). In other systems, Qa-1-restricted CD8 ϩ regulatory T cells have been shown to down-regulate Th1 immune responses and mitigate Th1-mediated autoimmune diseases, such as experimental allergic encephalomyelitis (34,35).…”

Immune response following intraocular delivery of recombinant viral vectors

“…31 However, particulate or cell-associated antigens may also induce IL-12 and Th1 responses after anterior chamber injection. 32 The posterior part of the eye also appears to have immune deviant features. Streilein et al 30,33,34 reported an immune-deviant response against soluble and cell-bound antigens in the subretinal space.…”