Inflammatory processes triggered by TCR engagement or by local cytokine expression: differences in profiles of gene expression and infiltrating cell populations

Abstract

Immune cell-mediated inflammatory responses are triggered by TCR engagement with the target antigen, the initial event that brings about the complex sequence of events of the inflammatory process. Another form of inflammation is induced by local expression of certain cytokines. Unlike the former form of inflammation, little is known about the basic features of the cytokine-induced responses. Here, we analyzed tissue morphology, the infiltrating cells, and up-regulated, inflammation-related genes in mouse eyes in which inflammation is triggered by local transgenic (Tg) expression of cytokines and compared these features with those in eyes with experimental autoimmune uveitis (EAU), in which inflammation is initiated by engagement of TCR on sensitized T cells with their target antigen, followed by the well-defined, subsequent cytokine production. Eyes of IFN-gamma Tg mice exhibited severe, morphological changes but essentially no inflammation, and intense inflammation was found in eyes of interleukin (IL)-1 or IL-7 Tg mice. The cellular infiltration in eyes of these latter two lines of Tg mice resembled that in eyes with EAU by including many CD4 cells, but unlike in EAU, the infiltration in Tg eyes contained large proportions of B cells and only small numbers of macrophages. Real-time PCR analysis of eye RNA revealed differences among the disease models in the expression profiles of various inflammation-related genes. It is interesting that a bias toward T helper cell type 1 immunity (high IFN-gamma, RANTES/CCL5, MIG/CXCL9, and T-bet but low IL-4, IL-5, and GATA-3 transcripts) was found in EAU eyes but not in eyes of IL-1 and IL-7 Tg mice. The results thus show that similar to TCR engagement, local expression of certain cytokines triggers a complex, subsequent production of numerous inflammation-related molecules, but features of the ensued inflammatory process are determined by the triggering mechanism.

Complement Deposits on Ocular Tissues Adjacent to Sites of Inflammation

“…In older Tg mice the inflammatory process may distort the ocular tissues and all layers. 12 Unlike the anticipated deposition of complement on damaged tissues, it was unexpected to observe complement localization in the cornea or lens capsule, where no inflammation developed (Figs. 2B and 2E).…”

“…11 Eyes of interleukin (IL)-1 transgenic (Tg) mice, where IL-1 is expressed under control of the αA-crystallin promoter, include changes seen in all eye tissues and dense infiltrate of inflammatory cells. 12 IL-1 Tg animals could serve as models for rare diseases in humans in which inflammation develops due to excessive expression of cytokines, especially IL-1. 12 These conditions, named "auto-inflammatory diseases," respond to IL-1 inhibition.…”

“…12 IL-1 Tg animals could serve as models for rare diseases in humans in which inflammation develops due to excessive expression of cytokines, especially IL-1. 12 These conditions, named "auto-inflammatory diseases," respond to IL-1 inhibition. 13 IL-7 Tg mice expressing IL-7 under control of the αA-crystallin promoter develop cellular inflammatory infiltration and proteinaceous exudate in the anterior chamber and vitreous.…”

“…Also characteristic of IL-7 Tg eyes are aggregates of lymphocytes in the limbus and the optic nerve pia and dura sheath. 12 Also included in our study was damage by exposure to light. This type of damage is of interest since a key feature of retinal dystrophies, and AMD is loss of visual cells by apoptosis, which can be studied through photoreceptor apoptosis induced by excessive exposure to light.…”

Association of T-Bet, GATA-3, RORC, and FOXP3 Copy Number Variations With Acute Anterior Uveitis With or Without Ankylosing Spondylitis in Chinese Han

“…[10][11][12] Expression of GATA- 3 has not yet been studied in clinical uveitis, but was shown to be increased during experimental autoimmune uveitis in mice. 13 Expression of RORC has been studied in Behçet disease but was not shown to be different compared with healthy controls 14 Expression of FOXP3 has been shown to be associated with the control of both experimental as well as clinical uveitis. 7,15,16 Genetic polymorphisms of the transcription factors delineated above may alter their expression and function and an association between certain genetic variants of these factors iovs.arvojournals.org j ISSN: 1552-5783 and immune-related disorders have been reported.…”