Anterior Chamber-Associated Immune Deviation (ACAID)
Anterior chamber-associated immune deviation (ACAID) is a phenomenon of active immune suppression (tolerance) that grants immune privilege to the eye's anterior chamber (AC). ACAID integrates multiple organ systems and cell populations. (1) The eye has several mechanisms to shell itself from unwarranted ocular inflammation, including the blood-ocular barrier ((hemato-aqueous and hemato-retinal), soluble or membrane-bound immune inhibitors, targeting and killing an invading microorganism or cell that may be inducing inflammation, and lastly, a methods by which a state of immune tolerance is induced based on anatomo-histologic characteristics and microambience properties of certain tissues and spaces in the eye mainly, the anterior chamber and the subretinal space. (2,3) ACAID is a means to the latter.
History and background
In the mid-1900s, it was described that both the eye and brain have a natural barrier for circulating antibodies and leukocytes. It was also thought that the eye and brain lacked a lymphatic drainage system. These two ideas were the basis of the proposition of “immune privileged sites”, in which a blood-tissue barrier and a lack of a lymphatic system together prevented the immune system from acting on these sites. (4)
It was not until the 70s that this was challenged by the discovery of immune-privileged tissues which broke the rules of transplantation. Grafts of these tissues survived, even in the absence of exogenous immunosuppression. The passive “immune privilege” was later replaced by a more relevant explanation, as the blood-ocular barrier is neither absolute nor a passive process; and the uveoscleral pathway carries fluid to the cervical lymph nodes.
The cornea is an immunologically privileged site partly because it lacks lymphatics and blood vessels (5). Research pioneered by Streilen (6) and Niederkorn (7) elucidated the understanding that the immune privilege that confers corneal transplantation´s capacity to survive for long periods under ideal conditions without being immunologically rejected is not only derived from immunological ignorance. Other important immunoregulatory microenvironmental features of the anterior chamber-associated immune deviation (ACAID) phenomenon play a crucial role by conferring active immune privilege to the cornea (8-10) . What is also known as the active immune privilege.
By exploring local and systemic graft-versus-host responses, it was discovered that splenomegaly developed in mice that received ocular injections of allogenic parental lymphocytes into the anterior chamber of the eye. These studies confirmed that an antigen introduced into the anterior chamber of the eye (an immune-privileged site) can be detected by the systemic immune system; a deviation from the expected immune response.
Mechanism of ACAID
As shown in animal models, an antigen in the AC is processed by antigen-presenting cells (APCs) that migrate via the blood to the thymus and the spleen. (11) Any antigen can induce ACAID when placed in the AC, however, not all antigenic encounters evoke a permanent state of ACAID. These include major and minor histocompatibility gene-encoded antigens, TNP-derivatized spleen cells, tumor-specific transplantation antigens, antigens encoded by pathogens (herpes simplex virus) and molecules (such as retinal S antigen and serum albumin). (12)
The ACAID response involves the inhibition of systemic delayed-type hypersensitivity and the complement-fixing antibody response, the maintenance of the normal humoral and T-cell cytotoxic suppressive response, and the capacity to adoptively transfer ACAID through splenic suppressor T cells to immunologically naive recipients. (13)
Primarily, TGFb-2 aids antigen-presenting cells (APC) containing F4/80 and CD11b molecules to capture antigens and pass through the trabecular meshwork onto the bloodstream and into the thymus and spleen where they cleave into peptide fragments on class l molecules and therefore activate CD8+ T cells. These APCs secrete TGFb as well, which inhibits CD4+ T cells. (11) In addition, in the marginal zone of the spleen, APCs interact with other cells and molecules such as MZ regulatory B cells, γδ Tregs, iNKT, and NKT regulatory cells. These immunomodulatory cells migrate through the bloodstream and induce antigen-specific immune deviation.
Clinical relevance of ACAID
As previously stated, ACAID provides a distinct immunological privilege to the eye. The regulation of inflammatory processes by ACAID cells leads to clinical protection from potentially blinding inflammatory processes. (14) ACAID suppresses CD4, Th1/2, and B cells. Recent studies have demonstrated the clinical use of ACAID to stimulate immunization when exposed to antigens such as interphotoreceptor retinoid-binding protein (IRBP). Via ACAID and Tregs cells, IRBP T cells are inhibited leading to protection from IRBP autoimmune uveitis. (14)
While ACAID can help regulate intraocular inflammation, such mechanisms can also limit the immune response to certain other less-frequent pathologies. Impaired ocular inflammation can limit the response to microorganisms that invade the cornea such as the herpes simplex virus. One example of this is corneal infectious keratitis. Upon corneal damage, the cascade of inflammatory and healing responses is triggered. Treg cells previously described can inhibit the response to these conditions worsening visual outcomes. (15) Similarly, the reduced inflammatory response would allow for the proliferation of intraocular tumors by inhibiting immunological pathways. (15)
Corneal transplantation is another example of the clinical application of ACAID. Corneal keratoplasty is usually exempt from HLA-matching because of ACAID. Major histocompatibility complex (MHC) mismatch results in a 100% allogenic graft rejection in bodily tissues, while it has been proved that because of immune privilege, MHC mismatch only results in around 20% of corneal graft rejection. The low percentage of graft rejection is a reflection of anterior segment immune privilege abolishing the late cellular and TH1 response when induced to the new antigens presented by the donor graft. (16) ACAID abolishes inflammatory response in exemption of trauma, infection, and neovascularization. Hence, ACAID is an immune mechanism through which corneal transplantation may require temporary immunosuppression in comparison to lifetime requirements in solid organ transplantation. (17)
Human cultured endothelial cells therapy (hCEC) is an emerging alternative to conventional corneal transplantation. Studies have shown that cultures of corneal endothelium (CE) cells inhibit the immune response by blocking IL-2 and IL-4 production. (18) Similarly, in vitro studies have shown a capacity of blocking T-cell activation by providing a strong inhibitor response. (19) hCEC transplantation is partially possible due to the immunological suppression of ACAID and the unique environment it provides. (20)
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