Anterior Chamber-Associated Immune Deviation (ACAID) is an active immunosuppressive and immune tolerance phenomenon that confers immune privilege to the anterior chamber of the eye. It is a mechanism that integrates multiple organ systems and cell populations.
The eye has several mechanisms to protect itself from unnecessary intraocular inflammation. These include:
The combination of these three mechanisms maintains the immunological privilege of the eye. Immune and inflammatory reactions eliminate harmful foreign substances but also induce tissue destruction and scar formation, which can impair ocular transparency. The suppression of inflammatory responses through immune privilege is essential for preserving ocular transparency.
In the mid-1900s, it was thought that the eye and brain had natural barriers against circulating antibodies and leukocytes, and that they lacked a lymphatic drainage system. This formed the basis for the concept of “immune-privileged sites.”
This idea was overturned in the 1970s when immune-privileged tissues that defy transplantation rules were discovered. Subsequently, research by Streilein and Niederkorn revealed that ocular immune privilege is not merely “immunological ignorance” but derives from active immune suppression (Active Immune Privilege) [¹⁻²].
“Immune privilege” refers to a state in which certain tissues or spaces (such as the anterior chamber of the eye, brain, and testes) are protected from normal immune responses. It is not simply a lack of immune reaction but involves active immunosuppressive mechanisms (such as anterior chamber-associated immune deviation). The cornea’s lack of lymphatics and blood vessels is also an important factor contributing to immune privilege.
Anterior chamber-associated immune deviation has the following characteristics:
Any antigen placed in the anterior chamber can induce anterior chamber-associated immune deviation, but not all encounters evoke permanent anterior chamber-associated immune deviation.
Antigen Capture and Transport
Antigen capture in the anterior chamber: Antigens that enter the anterior chamber are captured by F4/80-positive CD11b-positive antigen-presenting cells (APCs).
Role of TGF-β₂: TGF-β₂ assists APCs in capturing antigens and transporting them through the trabecular meshwork into the bloodstream.
Transport route: They are transported hematogenously to the thymus and spleen [⁴⁻⁶].
Induction of Immune Deviation in the Spleen
Activation of CD8⁺ T cells: In the spleen, antigens are cleaved into peptide fragments on class I molecules, activating CD8⁺ T cells.
Suppression of CD4⁺ T cells: APCs secrete TGF-β, which suppresses CD4⁺ T cells.
Interaction with regulatory cells: In the splenic marginal zone, they interact with MZ regulatory B cells, γδ Tregs, iNKT cells, and NKT regulatory cells. These immunoregulatory cells migrate via the bloodstream and induce antigen-specific immune deviation.
Humoral factors that make the anterior chamber an immune-privileged site are also important:
The best-known clinical application of anterior chamber-associated immune deviation is corneal transplantation (keratoplasty).
Normal organ transplantation: MHC incompatibility results in 100% rejection.
Characteristics of corneal transplantation: Even with MHC incompatibility, the rejection rate is only about 20%. This low rejection rate reflects that the immune privilege of the anterior chamber suppresses the late cellular immune and Th1 responses against new antigens presented by the donor graft [⁵].
Allo-MHC antigens are expressed on the epithelium and endothelium of the donor cornea, which should normally be targets for rejection. However, the actual resistance to rejection is due to immune-suppressive mechanisms including anterior chamber-associated immune deviation.
Anterior chamber-associated immune deviation is an immune mechanism that, unlike solid organ transplantation which requires lifelong immunosuppression, may allow corneal transplantation to be managed with only temporary immunosuppression.
Anterior chamber-associated immune deviation is thought to be involved in the pathogenesis of viral uveitis, such as acute retinal necrosis and herpetic iridocyclitis.
When a virus invades the eye, anterior chamber-associated immune deviation (ACAID) against the virus is established, suppressing the immune response to the virus. While this may reduce inflammation and tissue destruction, it may also promote viral proliferation, potentially leading to the progression and persistence of intraocular infection.
Studies have shown that ACAID can be clinically utilized against antigens such as interphotoreceptor retinoid-binding protein (IRBP). Through ACAID and regulatory T cells (Tregs), IRBP-specific T cells are suppressed, leading to protection from IRBP-induced autoimmune uveitis. However, this is still a research-stage finding[²⁻³].
Human cultured endothelial cells (hCEC) therapy is a new treatment alternative to conventional corneal transplantation. Studies have shown that cultured corneal endothelial cells suppress immune responses by blocking the production of IL-2 and IL-4, thereby inhibiting T cell activation. Human cultured corneal endothelial cell transplantation is made possible in part by the immunosuppressive environment provided by ACAID.
Anterior chamber-associated immune deviation (ACAID) is a mechanism induced by antigen inoculation into the anterior chamber, but it has recently become clear that a similar mechanism also operates in the vitreous cavity and subretinal space.
This has led to the need for a broader understanding of the maintenance mechanism of immune privilege throughout the entire eye.
To maintain ocular transparency, excessive inflammatory responses are harmful. The transparency of the cornea, lens, and vitreous is irreversibly damaged if opacity or scarring occurs due to inflammation.
Anterior chamber-associated immune deviation can be interpreted as a mechanism that evolved to protect ocular transparency. Rather than completely blocking immune responses, it induces a “deviated” immune response that selectively suppresses tissue-destructive cell-mediated immunity (DTH) while maintaining antibody production (humoral immunity).
Studies of an experimental uveitis model (experimental autoimmune uveoretinitis, EAU) induced in rats and mice immunized with retinal antigens also suggest the involvement of anterior chamber-associated immune deviation in the pathology. The T cells that trigger experimental autoimmune uveoretinitis are CD4⁺ Th1 cells, but it has recently become clear that Th17 cells also contribute to pathogenesis. The efficacy of the anti-TNF-α antibody infliximab for Behçet’s disease is a finding derived from this research.
Reduced inflammatory response may allow intraocular tumor growth by suppressing immune pathways. There is concern that immune privilege mechanisms, including anterior chamber-associated immune deviation, may work to weaken immune surveillance of intraocular tumors.
Inducing anterior chamber-associated immune deviation (ACAID) has been shown to protect against autoimmune uveitis (experimentally induced by IRBP). In the future, artificially inducing ACAID may be applied to treat immune-mediated ocular diseases.
hCEC therapy is being developed as an alternative to conventional corneal transplantation. It has been shown that corneal endothelial cell cultures suppress T cell activation, and the immune-privileged environment of ACAID is thought to support the success of this therapy.
Further elucidation of the role of Treg cells in anterior chamber-associated immune deviation is underway, and their application in developing novel immunotherapies utilizing the immune privilege of the eye is expected. Since Treg cells also suppress immune responses against tumors, research is also progressing on their relationship with intraocular tumors.
