Immune Privilege

Immune privilege is a term used to describe certain sites in the body which are able to tolerate the introduction of antigen without eliciting an inflammatory immune response. Tissue grafts are normally recognised as foreign antigen by the body and attacked by the immune system. However, in immune privileged sites tissue grafts can survive for extended periods of time without rejection occurring [3]. Known immunologically privileged sites include:

• the brain
• the eyes
• the uterus when carrying a fetus
• the testicles

Immune privilege is thought to be an evolutionary adaptation to protect vital structures from the potentially damaging effects of an inflammatory immune response. Inflammation in the brain or eye can lead to loss of organ function, while immune responses directed against a fetus can lead to the loss of the child.

The existence of immune privileged regions of the eye was recognised as early as the late 19th century and investigated by Medawar.The original explantion of this phenonoma was that physical barriers around the immune privileged sites enabled it to avoid detection from the immune system altogether, preventing the immune system from 'seeing' any antigens present. More recent investigations have revealed a number of different mechanisms by which immune privileged sites interact with the immune system. Antigens from immune privileged regions have been found to interact with T cells in an unusual way inducing tolerance as opposed to a destructive response [9]. Immune privilege has emerged as an active rather than a passive process.

Physical structures surrounding privileged sites cause a lack of lymphatic drainage, limiting the immune systems' ability to enter the site. Other factors that contribute to the maintenance of immune privilege include:

• low expression of MHC molecules
• increased expression of surface molecules that inhibit complement activation
• local production of immunosuppressive cytokines such as TGF-β
• presence of neuropeptides
• constitutive expression of Fas ligand that controls the entry of Fas-expressing lymphoid cells [3].

The nature of isolation of immunologically privileged sites from the rest of the body's immune system can lead to them becoming targets of autoimmune diseases or conditions including sympathetic opthalmia in the eye.

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Eye

AS well as the mechanisms that limit immune cell entry and induce immune suppression (see table1 and table 2) the eye also contains active immune cells that act upon the detection of foreign antigen. These cells interact with the immune system to induce unusual suppression of the systemic immune system response to an antigen introduced into the eye. This is known as Anterior Chamber Associated Immune Deviation (ACAID) [4,7].

Sympathetic ophthalmia is a rare diease which results from the isolation of the eye from the systemic immune system. Usually, trauma to one eye induces the release of eye antigens which are recognised and picked up by local antigen presenting cells (APC) such as neutrophils and dedritic cells. These APC carry the antigen to local lymph nodes to be sampled by T cells and B cells. . Entering the systemic immune system, these antigens are recognised as foreign and an immune response is mounted against them. The result is the sensitisation of immune cells against a self-protein, causing an autoimmune attack of both the damaged eye and the non-damaged eye [9].

In this manner, the Immune privileged property has served to work against the eye instead. T cells normally encounter self-antigens during their development, when they move to the tissue draining lymph nodes. Anergy is induced in T cells which bind to self-antigens, deactivating them and preventing an autoimmune response in the future. However, the physical isolation of eye antigens results in the body's T cells never having encountered them at any time during development. Studies in mice have shown that the lack of presentation of eye self-antigens to specific T cells will fail to induce a sufficient amount of anergy to the self-antigens. While the lack of antigen presentation (due to the physical barriers) is sufficient to prevent the activation of autoreactive immune cells to the eye, the failure to induce sufficient anergy to T cells has detrimental results as well. In the case of damage or chance presentation to the immune system, the antigen presentation and immune response will occur at elevated rates [8] .

Pregnant uterus

A mother’s uterus is able to provide protection from microbial infections without mounting an immune response against fetal tissues expressing paternally inherited alloantigens. A better understanding of the immunology of pregnancy may lead to the discovery of reasons for miscarriage.

Regulatory T-cells (Tregs) appear to be important in the maintenance of tolerance to fetal antigen. Increased numbers of Tregs are found during normal pregnancy. In both mouse models and humans diminished numbers of Tregs were associated with immunological rejection of the fetus and miscarriage. Experiments in mice involving the transfer of CD4+/CD25+ Treg cells from normal pregnant mice into abortion-prone animals resulted in the prevention of abortion [12]. This confirmed the importance of these cells in maintaining immune privilege in the womb.

A number of theories exist as to the exact mechanism by which fetal tolerance is maintained. It has been proposed in recent literature by Zenclussen et al [13] that a tolerant microenvironment is created at the interface between the mother and fetus by regulatory T-cells producing ‘tolerant molecules’. These molecules including heme oxygenase 1 (HO-1), leukaemia inhibitory factor (LIF), transforming growth factor β (TGF-β) and interleukin 10 (IL-10) have all been implicated in the induction of immune tolerance.This hypothesis is illustrated in the figure below. Foxp3 and neuropillin are markers expressed by the regulatory T-cells by which they are identified.

[Figure from Zenclussen AC, Schumacher A, Zencluseen ML, Wafula P, Volk HD. (2007). Immunology of pregnancy: cellular mechanisms allowing fetal survival within the maternal uterus. Expert Reviews in Molecular Medicine. 9 (10):1-14]

Brain

The brain is a sensitive organ with a limited capacity for regeneration. This makes immune privilege in the brain essential for the limitation of inflammation and maintenance of function. The blood-brain barrier is important in maintaining the brains separation from the systemic immune system but it is not on its own responsible for the maintenance of immune privilege [1]. Immune privilege of the brain varies throughout different compartments being most pronounced in the parenchyma tissue or ‘white matter’ [1].

[Figure from Galea I, Beckmann I, Perry V.H. (2007). What is Immune Privilege (not)?. Trends in Immunology. 28(1): 12-18]

The brain is limited in its capacity to deliver antigen to local lymph nodes and cause T-cell activation [10] . In normal tissues antigen is taken up by antigen presenting cells (dendritic cells), which migrate to the lymph nodes, or soluble antigen can drain by itself into the lymph node. Dendritic cells have not been found in normal parenchyma tissue or perivascular space although they are present in the meninges and choroids plexus [1].

Although there is no conventional lymphatic system in the brain the drainage of antigen from the brain to cervical lymph nodes has been demonstrated. The response elicited in the lymph nodes to brain antigen is skewed towards B-cells. Dendritic cells from cerebrospinal fluid have been found to migrate to B-cell follicles of cervical lymph nodes [2] . The skewing of the response to antigen from the brain towards a humoral response means that a more dangerous inflammatory T-cell response can be avoided.

The induction of systemic tolerance to an antigen introduced into the brain has been proven [11] . This was seen in the absence of the T-cell mediated inflammatory ‘delayed type hypersensitivity reaction’ (DTH) when the antigen was reintroduced in another part of the body. This response is analogous to ACAID in the eye.

References

1. Galea I, Beckmann I, Perry V.H. (2007). What is Immune Privilege (not)?. Trends in Immunology. 28(1): 12-18

2. Hatterer, E. et al. (2006). How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes. Blood. 107: 806–812

3. Hong, Seokmann, Van Kaer, Luc (1999). Immune Privilege: Keeping an Eye on Natural Killer T Cells. The Journal of Experimental Medicine. 190 (9): 1197-1200

4. Keino, H, Takeuchi, M, Kezuka, T, Hattori, T, Usui, M, Taguchi, O, Streilein, JW, Stein-Streilein, J. (2006). Induction of Eye-Derived Tolerance Does Not Depend on Naturally Occurring CD4+CD25+ T Regulatory Cells. Investigative Ophthalmology and Visual Science.47:1047-1055

5. Niederkorn, JY. (1990). Immune privilege and immune regulation in the eye. Advances in Immunology. 48:191-226

6. Niederkorn, JY. (2006). See no evil, hear no evil, do no evil: the lessons of immune privilege. Nature Immunology. 7:354 – 359

7. Streilein, JW, Stein-Streilein, J. (2002). Anterior chamber associated immune deviation (ACAID): regulation, biological relevance, and implications for therapy. International Reviews of Immunology. 21(2-3):123-52

8. Lambe, T., J. C. H. Leung, H. Ferry, T. Bouriez-Jones, K. Makinen, T. L. Crockford, H. R. Jiang, J. M. Nickerson, L. Peltonen, J. V. Forrester, and R. J. Cornall. (2007). Limited Peripheral T Cell Anergy Predisposes to Retinal Autoimmunity. The Journal of Immunology 178:4276-4283.

9. Janeway, C. A.Jr., Travers, P., Walport, M., Shlomchik. M.J. (2005). ImmunoBiology, the immune system in health and disease 6th Edition. Garland Science.

10. Mendez-Fernandez, Y.V. et al. (2005) Anatomical and cellular requirements for the activation and migration of virus-specific CD8+ T cells to the brain during Theiler’s virus infection. Journal of Virology. 79: 3063– 3070

11. Wenkel, H. et al. (2000). Systemic immune deviation in the brain that does not depend on the integrity of the blood–brain barrier. Journal of Immunology. 164: 5125–5131

12. Zenclussen A,C. (2006). Regulatory T cells in pregnancy. Springer Seminars in Immunopathology. 28(1): 31-39

13. Zenclussen AC, Schumacher A, Zencluseen ML, Wafula P, Volk HD. (2007). Immunology of pregnancy: cellular mechanisms allowing fetal survival within the maternal uterus. Expert Reviews in Molecular Medicine. 9 (10):1-14.