Anterior Chamber-Associated Immune Deviation (ACAID): An Acute Response to Ocular Insult Protects from Future Immune-Mediated Damage?

Abstract

The "immune privilege" that inhibits immune defense mechanisms that could lead to damage to sensitive ocular tissue is based on the expression of immunosuppressive factors on ocular tissue and in ocular fluids. In addition to this environmental protection, the injection of antigen into the anterior chamber or infection in the anterior chamber induces a systemic suppression of potentially damaging cell-mediated and humoral responses to the antigen. Here we discuss evidence that suggests that Anterior Chamber-Associated Immune Deviation (ACAID)(a) is initiated by an ocular response to moderate inflammation that leads to a systemic immunoregulatory response. Injection into the anterior chamber induces a rise in TNF-α and MCP-1 in aqueous humor and an infiltration of circulating F4/80(+) monocytes that home to the iris. The induction of ACAID is dependent on this infiltration of circulating monocytes that eventually emigrate to the thymus and spleen where they induce regulatory T cells that inhibit the inductive or effector phases of a cell-mediated immune response. ACAID therefore protects the eye from the collateral damage of an immune response to infection by suppressing a future potentially damaging response to infection.

Keywords: ACAID; immune privilege; inflammation.

Figure 1

The intracameral injection of antigen elevates TNF-a and MCP-1 in aqueous humor. Three–6 hr after 6–8 week-old naïve female BALB/c mice received iv 5 × 10⁶ − 1 × 10⁷ CFSE-labeled PBMC the mice were anesthetized with an ip injection of ketamine/xylazine and received an intracameral injection of PBS, PBS + 50 μg OVA or a needle stick only with a 24 g needle. Six hr after naïve mice received an intracameral injection, aqueous humor was recovered from the euthanized mice and 10 μl assayed by ELISA for TNF-α and MCP-1. Data represent the average +/− S.E.M. pg detected from 4–6 replicates/group in 2–3 experiments.

Figure 2

Migration of PBMC after intracameral injection. Anesthetized BALB/c mice received an intracameral injection of trinitrophenylated bovine albumin six hr after the mice received iv 5 × 10⁶ −1 × 10⁷ CFSE-labeled PBMC. Twenty-four hrs after the intracameral injection the mice were euthanized by CO₂ inhalation and irides, spleens and thymi removed, pooled and single cell suspensions prepared. The cells were then labeled with phycocyanin-anti-F4/80 and analyzed by flow cytometry. The percent increase in CFSE, F480⁺ cells was computed by: $\frac{\%\text{CFSE},\text{F}480+\hspace{0.17em}\text{cells\hspace{0.17em}in\hspace{0.17em}iv},\text{AC}\hspace{0.17em}\text{group}}{\%\text{CFSE},\text{F}480+\hspace{0.17em}\text{cells\hspace{0.17em}in}\hspace{0.17em}\text{iv\hspace{0.17em}only\hspace{0.17em}group}}\times 100$

Figure 3

Hypothetical model for events in the anterior chamber following the intracameral injection of antigen. The trauma of injection induces damage associated molecular pattern (DAMP) molecules that induce the production of MCP-1 and TNF-α. TNF-a is also induced and/or maintained by TGF-β in aqueous humor. TNF-a increases the production of MCP-1. MCP-1 attracts circulating F4/80⁺ cells that enter the anterior chamber and obtain antigen from resident iris/ciliary body F4/80⁺, CD11c⁺ cells. The infiltrated monocytes are influenced by TGF-β and exit the anterior chamber via Schlemms canal. These cells recirculate to the thymus and spleen where they participate in the induction of regulatory thymocytes and splenic T cells.