This term was initially coined by Peter Medawar in the middle of the 20th century, essentially to describe his observation that tissue grafts from non—genetically identical animals placed in the eye were not rejected It was subsequently found by many groups to be a highly complex phenomenon, resulting from the combined effects of efficient separation of the eye from the immune system by a blood-retinal barrier, local inhibition of immune responses by the unique intraocular microenvironment, and systemic induction of immunosuppressive regulatory T cells by eye-specific mechanisms.
However, while it is generally accepted that immune privilege protects the eye from day-to-day inflammatory insults and contributes to the extraordinary success of corneal grafts, its role in protection from ocular autoimmunity has been contentious.
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It has been convincingly demonstrated that elimination in the thymus of self-reactive T cells, a process known as central tolerance, applies to retinal antigens The mechanisms underlying central tolerance rely on an immature T cell interacting with its cognate tissue antigen through its specific TCR. Tissue antigens, including the retinal antigens IRBP and arrestin, are ectopically expressed in the thymus under the control of the gene-regulatory protein autoimmune regulator AIRE 12 , Mice made deficient for the Aire gene and humans with AIRE mutations have absent or reduced expression of tissue antigens in the thymus, fail to eliminate autoreactive T cells, and develop multiorgan autoimmunity in humans, this condition is known as autoimmune polyendocrinopathy—candidiasis—ectodermal dystrophy [APECED] However, thymic expression of retinal antigens among individual humans and mouse strains is variable 15 , 16 , and levels of expression insufficiently high to induce the elimination of T cells bearing cognate TCRs may permit the escape of retinal antigen—specific T cells into the periphery.
Indeed, T cells specific for retinal arrestin can be detected in healthy humans by their proliferation in culture in the presence of retinal arrestin with a frequency of up to 4 per 10 million peripheral blood lymphocytes This is likely to be a gross underestimation of their numbers, as methods that do not rely on proliferation but quantitate the frequency of antigen-reactive T cells directly through the use of MHC-peptide tetramers typically detect fold-higher retinal antigen—specific T cell frequencies Additionally, arrestin is only one of at least 10 retinal antigens known to be uveitogenic in animals 8.
T cells reactive to tissue antigens that escape control in the thymus are normally subject to regulation by peripheral tolerance mechanisms, which induce T cells to become nonresponsive tolerant to their specific antigen when they encounter that antigen in healthy tissues, but retinal antigens residing in the eye are relatively inaccessible. Indeed, it has been demonstrated that forced expression of a retinal antigen in the periphery as a transgene, by retroviral delivery, or by vaccination with naked DNA results in tolerance and in resistance to the subsequent induction of autoimmunity 20 — Therefore, by sequestering retinal antigens within the eye and hindering peripheral tolerance, immune privilege may actually predispose to ocular autoimmunity Understanding of uveitis has advanced tremendously as a result of the development of animal models of the disease.
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Experimental autoimmune uveitis EAU is induced by immunization of animals with the retinal antigens known to elicit responses in lymphocytes isolated from patients with uveitis. In fact, stimulation of the innate immune response can by itself result in ocular inflammation in animal models 25 , 26 and possibly in humans Table 1. The major models of uveitis and their salient points are summarized in Table 2. In general, EAU models can be divided into induced by immunization and spontaneous although the mice have been genetically manipulated.
By combining the use of specific immunological reagents and genetically manipulated strains of mice, this model has provided most of the insights into the pathogenesis of uveitis reviewed in refs.
Clinical and histological appearance of uveitis: human and mouse. Lower-right panels of A and B reproduced with permission from Immunological Reviews Arrestin is the ocular antigen to which uveitis patients most frequently respond, but it is not effective at inducing uveitis in wild-type mice. In HLA-DR3 transgenic mice, the region of arrestin responsible for pathology was identified to be the same as that recognized by T cells from patients with uveitis ref. Mattapallil and R.
A look at autoimmunity and inflammation in the eye
Caspi, unpublished observations. Because in mice transgenic for human HLA class II alleles the autoantigen is presented by a human MHC molecule, these animals may help to identify the antigenic regions functionally involved in human disease, which is a prerequisite for defining antigen-specific biomarkers and therapies for human uveitis. The second category of EAU models comprises those in which disease arises spontaneously. Arguably, in this regard, they are more similar to human disease than the induced EAU models; however, they develop in hosts that have been genetically manipulated and therefore are immunologically very different from normal.
Nevertheless, these models can teach us about some of the variables that might bring about susceptibility to disease. One example is mice lacking the transcriptional regulator AIRE, in which deficient thymic expression of tissue antigens such as IRBP and arrestin results in failure to eliminate retina-antigen—specific T cells.
Another example is double-transgenic mice expressing both a foreign protein as a neo-self antigen in the eye and a TCR specific for that protein on most T cells Table 2. However, data obtained with neoantigen models should be interpreted with some caution, due to uncertainty about whether the location and level of expression of the neoantigen truly mimic those of a native retinal antigen. Furthermore, TCRs specific for neoantigens typically have a much higher affinity for their cognate antigen than those specific for native antigen that escape the thymic process of central tolerance; they are thus not representative of typical autoreactive T cells.
An intriguing model is spontaneous uveitis that develops between 8 and 12 months of age in HLA-A29 transgenic mice 33 , HLA-A29 is highly associated with birdshot retinochoroidopathy in humans Table 1. No information is available as to the antigen s targeted in HLA-A29 uveitis in humans, and the etiological mechanisms remain obscure.
This model may provide a much-needed tool to approach these questions. The most widely used model of autoinflammatory uveitis driven largely by innate immune mechanisms is endotoxin-induced uveitis EIU , which can be elicited in rats and in mice by systemic injection of bacterial LPS. The response is acute anterior uveitis of short duration 25 , 26 Table 2. While EIU has been useful for dissecting mechanisms of innate inflammation and examining therapeutic modalities, it is not quite clear which human disease the model represents.
In that regard, the recently developed uveitis model induced by intraocular injection of muramyl dipeptide MDP , a ligand of nucleotide-binding oligomerization domain 2 NOD2; also known as CARD15 , is arguably a better representation of autoinflammatory uveitic diseases such as Blau syndrome, which is associated with mutations in NOD2 Uveitis in humans has thus far been associated primarily with HLA genes. Because HLA molecules are involved in antigen presentation, HLA associations are thought to reflect recognition of particular antigen s and epitopes.
Immune responses in sympathetic ophthalmia as well as VKH disease target melanin-related antigens 4 , BR mice , and H-2 r which is found in B RIII mice. Clearly, however, MHC accounts for only a part of the genetic influences predisposing to uveitis. The availability of H-2 congenic mouse strains, which share the same genetic background but have a different H-2 haplotype or share the same H-2 haplotype but differ in genetic background, has allowed researchers to demonstrate that background genes have a major effect on penetrance and severity of disease 38 , The effects of these genes are complex and involve all aspects of the immune response, including hormonal responses to stress; levels of ectopic tissue antigen expression in the thymus which translate to efficiency of central tolerance ; and innate responses to environmental stimuli acting as adjuvants, which in turn affect the outcome of adaptive immunity.
Integration of these diverse genetic effects with those provided by the environment shapes disease pathogenesis. Critical checkpoints in the disease process: lessons from animal models. Animal models of uveitis have helped to identify critical checkpoints in the pathogenesis of the disease Figure 3.
Activated T cells specific for retinal antigens mediate EAU in animals. These cells can transfer disease from immunized donors to genetically compatible naive recipients and orchestrate the entire process of uveitis. It is believed that T cells are also central to the pathogenesis of human uveitis. Strong support for this notion comes from the clinical success of approaches that directly target T cells, including macrolide antibiotics such as cyclosporine, FK, and mycophenolic acid, which inhibit signaling through the IL-2 receptor pathway that is needed to sustain T cell activation and function, and antibodies specific for the IL-2 receptor 40 , The role of antibodies to ocular antigens in disease pathogenesis is less clear.
In animals, antibodies in the form of hyperimmune serum are, by themselves, unable to transfer disease to naive recipients, probably because they are too large in molecular size to penetrate the blood-retinal barrier.
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However, if uveitogenic T cells disrupt the blood-retinal barrier, serum antibodies exacerbate EAU Here, I attempt to systematically present what we have learned about the stages of the disease process using animal models, following the order presented in Figure 3. Critical checkpoints in uveitis, as defined from studies with animal models.
These undergo clonal expansion, migrate to the eye, break down the blood-retinal barrier, and recruit inflammatory leukocytes from the circulation. The resulting inflammation results in damage to the tissue and release of ocular antigens, which triggers eye-specific regulatory mechanisms that terminate the disease and limit pathology. Modified with permission from Immunological Reviews As mentioned above, deficiencies in central and peripheral tolerance lead to the presence in healthy individuals of nontolerant retinal antigen—specific T cells that can be activated to acquire effector function.
The number of these T cells and the affinity of their TCR for cognate antigen, both of which are determined by the effectiveness of autoreactive T cell elimination in the thymus, can be a predisposing factor to uveitis. T cells from IRBP-deficient mice are more uveitogenic in normal hosts than are T cells from wild-type mice These cells are thought to arise from maturing T cells whose TCRs have an affinity that is relatively high, but not quite high enough to trigger deletion.
They are naturally present in all normal individuals hence their name and have been shown to control various manifestations of autoimmunity Using IRBP-deficient mice, my laboratory has demonstrated that although generation of nTregs specific to IRBP is dependent on endogenous expression of IRBP, nTregs of other specificities activated during the process of immunization by as-yet-unidentified signals may also participate in controlling EAU Furthermore, despite extensive evidence that peripheral tolerance to sequestered retinal antigens is minimal, it may not be entirely absent.
This suggests that some low level of preexisting peripheral tolerance to antigens within the eye may exist Nevertheless, it remains to be confirmed whether this also applies to native retinal antigens. In individuals who develop uveitis in any one of its various manifestations Table 1 , the threshold of susceptibility set by nTregs has evidently been passed.
The triggers responsible for activating retinal antigen—specific cells so that they escape from nTreg control are largely unknown in humans. One possible exception is sympathetic ophthalmia.
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It is thought that antigens released from the traumatized eye find their way into the draining lymph node and elicit systemic immunity. An accompanying infection may provide an adjuvant effect although severe endophthalmitis, which quickly destroys the injured eye and eliminates the source of antigen, may actually lessen chances of developing the disease 3.
In uveitic disease that cannot be linked to a trauma, it is believed that T cells capable of recognizing retinal antigens are primed in the periphery by microbial stimuli that may be immunologically similar in structure to their cognate retinal antigen antigenic mimicry 48 — Following exposure to a uveitogenic stimulus, circulating retinal antigen—specific cells become activated and acquire effector function.
Experiments with adoptive transfer of retinal antigen—specific effector T cells versus nonspecific T cells, activated ex vivo and fluorescently labeled, have led to the conclusion that a very small number of infused cells infiltrate the eye within hours after transfer, reaching the eye entirely by chance 51 , They recognize their specific antigen there and cause changes within the eye that bring about development of disease several days later. The APCs within the retina have still not been positively identified. Although there are resident dendritic cells in the retina that could serve as APCs, their expression of MHC class II molecules is low, at least until inflammation is underway It can be calculated by infusing labeled retina-antigen—specific T cells that fewer than ten such T cells must reach the eye to trigger the early changes leading to EAU In the meantime, the bulk of the transferred cells take up residence in the spleen, where they proliferate and undergo a maturation process that includes upregulation of the chemokine receptor CXCR3 On day four, the retinal antigen—specific T cells leave the spleen and migrate to the eye, where they reactivate and drive the inflammatory process started by the initial infiltrating cells, by secreting cytokines and chemokines, activating the retinal vasculature, and promoting massive recruitment of inflammatory leukocytes from the circulation.
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Each of the recruited cell types apparently provides an essential function, as depletion of any one of them reduces the severity of EAU 53 , 56 , Monocytic cells, in addition to functioning as inflammatory cells, can also differentiate to a regulatory phenotype, known as myeloid-derived suppressor cells, which inhibit autoaggressive T cells Because these agents are used to manage autoimmune disorders, diagnosing DILE can be challenging. The challenge is being able to differentiate a true drug-induced lupus from an exacerbation of preexisting lupus or the unmasking of a second autoimmune disease.
In addition, research efforts need to focus on identifying susceptible genes to stand as biomarkers to help identify patients at risk for developing DILE.
Garza received her doctor of pharmacy degree from the University of Texas at Austin. She is currently working as the director of the Life Sciences Library at RxWiki, where she continues to build her practice on the fundamental belief that providing patients with medication information and medical knowledge contributes significantly to the quality of care they receive and improves quality of life and health outcomes. Her work focuses on educating patients and providing them with the resources needed to navigate the overwhelming and complex health system. Drug-induced lupus erythematosus: incidence, management and prevention.
Drug Saf. Vasoo Sheila. Drug-induced lupus: an update. Drug-induced lupus: Including anti-tumor necrosis factor and interferon induced. Pharmacotherapy: A Pathophysiologic Approach.