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Transcript of Immune Privilege
1. Separation or Sequestration: The posterior chamber of the eye becomes separated from the immune system by an efficient blood-retinal barrier that is very selective and excludes molecules even as small as 376 Da.
2. Inhibition: Although the blood-retinal barrier effectively excludes protein molecules, including antibodies and complement components, it is not effective against activated lymphocytes. An infiltrating lymphocyte that enters the eye encounters a profoundly hostile environment, which is not favorable to supporting their activation and function:
1.The posterior part of the eye has a small number of major histocompatibility complex (MHC) class-II-positive cells that might act as APCs.
2.Ocular resident cells are able to inhibit activated lymphocytes by contact-mediated mechanisms, such as:
• Membrane-bound transforming growth factor-b (TGF-b), Fas ligand (FasL), B7_CTLA4 interaction, galectin-1 and thrombospondin .
3.The ocular fluids contain a number of immunoinhibitory molecules, such as:
•TGF-b, immunosuppressive neuropeptides, including a-melanocyte-stimulating hormone (a-MSH), calcitonin-gene-related peptide, vasoactive intestinal peptide, somatostatin, and migration inhibitory factor (MIF).
4.Inhibitors of complement activation are constitutively expressed within the eye and are functionally active.
3. Regulation: Eye immune privilege is maintained if blood-retinal barrier is breached via processes that deliver antigens from the anterior chamber of the eye to the spleen in murine models. The first discovered and the best studied (though certainly not the only) model of eye-derived tolerance is the phenomenon known as “anterior chamber-associated immune deviation” (ACAID). ACAID is the active, systemic component of immune privilege. A foreign protein injected into the anterior chamber of the eye is not ignored by the immune system; instead, it elicits a deviant immune response characterized by a dampened delayed-type hypersensitivity (DTH) response, elicitation of non-complement binding antibodies, and production of antigen-specific regulatory T cells (Tregs). It involves exit of antigen-bearing APCs from the anterior chamber and their obligate migration to the spleen. There they recruit natural killer T cells and Marginal zone B cells, which culminates in the induction of CD4þ and CD8þ Tregs. The former inhibit acquisition of immunity (afferent acting) and the latter suppress expression of immunity (efferent acting) (See Figure 1.)
Eye: Brain: In the brain, the blood brain barrier and absence of lymphatic drainage isolate the CNS from the immune system. Nevertheless, the immune system is aware of CNS antigens, but the cellular immune responses are supressed to CNS antigens under normal circumstances. For example:
•Triggering receptor expressed on myeloid cells (TREM), expressed by microglia, is essential for the phagocytosis of apoptotic neurons without eliciting inflammation.
However, the window of susceptibility to acute inflammation in juveniles is still unexplained, as is the activated phenotype of microglia in the aged brain. Several molecular interactions accounting for the inhospitality of the CNS to inflammation have recently been discovered, although we do not yet possess a thorough understanding of the molecular mechanisms underlying the induction and maintenance of CNS immune privilege.
Check out this article! Placenta: During pregnancy, the fetus is in indirect contact with the uterine and cells of the mother. The mechanisms involved in placent and fetus immune privile are:
1.The fetus is separated from the mother by membranes as well as the presence of layers of cells between two circulations in placenta.
2.Decrease of MHC molecules in the fetus.
3.Different cytokines are produced by the placenta that have anti-inflammatory properties, i.e transforming growth factor (TGF)-b2, interleukin (IL)-4 and IL-10, interferon (INF)-y and tumor necrosis factor (TNF)- a.
4.Trophoblasts express Fas ligand which contributes to apoptosis of the target cells, the activated Fas-expressing lymphocytes, providing a powerful mechanism to down-regulate a deleterious immune response.
These characteristics of the uterus as an immune-privileged site have been suggested to play a vital role in the survival of fetal allograft to term.
http://www.sciencedaily.com/releases/2009/10/091029102430.htm Testis: In the testis the expression of cytokines by immune and somatic cells provides local immunosuppression in addition to the blood-testis barrier and a reduced capability to build up an inflammatory response. The mechanisms are:
1.A high testosterone concentration in the testis mediates anti-inflammatory functions on testicular leukocytes.
2.Testicular macrophages have an immunoregulatory role in maintaining immune privilege.
3.TGF- and activin A play a role in maintaining immune privilege by inhibiting specific immune responses,minimizing the risk of autoimmune reactions to testicular self-antigens
4.On the developing germ cells, MHC antigens are reduced or absent, indicating that spermatogenic cells avoid recognition by CD4+ and CD8+ T cells, which is important for reducing the potential for antigen-specific immune responses elicited by dendritic cells or macrophages in the seminiferous epithelium.
The mechanisms responsible for the testis’s immune privilege aren’t well understood, but it is noticeable that the identified elements involved are multiple.
Take home messages Want to learn more? Did you know?? Sir Peter Brian Medawar, 1960 Nobel prize winner was one
of the the first researchers to demonstrate this immune privilege phenomenon in 1948. What are the mechanisms involved? Privileged sites lack lymphatic vessels, limiting the ability of immune cells to enter these tissues.
Systemic immune deviation, which is the activation of a humoral response and the suppresion of T CD4+ cells, through the work of T reg cells.
Low expression of MHC class Ia molecules.
Expression of immunoregulatory class Ib MHC molecules.
Increased expression of surface molecules that inhibit complement activation.
Local production of immunosuppressive cytokines (i.e Transforming Growth Factor beta, TGF-b).
Production of neuropeptides.
Expression of Fas ligand that induces apoptosis in infiltrating immune cells, although the relevance of this has been recently debated. Is TGF-beta important in immune priviledged sites? 1. TGF-beta induces systemic deviation.
2. Suppresses Mitogen and antigen-driven T cells.
3. Suppresses mediators released by neutrophils.
4. Suppresses nitric oxide produced by macrophages.
5. Blocks the actions of Natural killer cells. Check out this article! http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633103/ Maria Clavijo and Nubia Macedo Visit our blog! http://immunonews.blogspot.com/ Fig 2. Role of TGF-beta in the induction and maintenance of skin graft tolerance Figure 1. Anterior chamber-associated immune deviation. 1. Immune privilege is an experimental defined phenomenon, where certain tissue do not follow the rules of transplantation immunology.
2. Systemic immmune deviation is one of the most well unterstood processes that occur in immune privileged sites.
3. Parenchymal cells of the privileged sites secrete TGF-beta which suppresses both local expression of innante and adaptative immune response.
4. Currently, a main theme that is being studied is the therapeutic implications of natural immunoregulatory mechanisms that contribute to immune privilege. In tissue transplantation and treatment of autoimmune diseases the aim is to create an artificial immuneprivileged state that protects a target organ under autoimmune attack. The same principle should be suitable to chronic infections that exhibit features of immune suppression and privilege. http://www.nature.com/cdd/journal/v8/n7/full/4400891a.html Check this out! References 1. Streilein JW, Regional immunity and ocular immune privilege. In: Immune responses and the eye, Streilein JW, ed, Chemical Immuno- logy 73, Karger AG, Basel pp. 11, 1999.
2. Streilein J.W. 2OO3. Ocular immune privilege: the eye takes a dim but practical view of immunity and inflammation. Journal of Leukocyte Biology. 2003;74:179-185
3. Uckan, D. et al. 2003. Trophoblasts express Fas ligand: a proposed mechanism for immune privilege in placenta and maternal invasion. Molecular Human Reproduction vol.3 no.8 pp. 655662, 1997
4. Mellor and Munn, Immune privilege: a recurrent theme in immunoregulation?, Immunological Reviews, 2006.
5. Streilein JW et al. Human Immunol 63, 435,2002.
6. Taylor AW, Ocular immunosuppressive microenvironment. In: Immune responses and the eye, Streilein JW, ed, Chemical Immunology 73, Karger AG, Basel, pp. 72, 1999
7. Katagiri K et al. J Immunol 169, 84, 2002. THANK YOU! And.........