Immune privilege
Encyclopedia
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. Immunologically privileged sites were thought to include:
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 fetus.
Medically, a cornea transplant
is currently the only procedure that takes advantage of this.
s in an unusual way inducing tolerance as opposed to a destructive response. Immune privilege has emerged as an active rather than a passive process.
Physical structures surrounding privileged sites cause a lack of lymph
atic drainage, limiting the immune system's ability to enter the site. Other factors that contribute to the maintenance of immune privilege include:
The nature of isolation of immunologically privileged sites from the rest of the body's immune system can cause them to become targets of autoimmune diseases or conditions, including sympathetic ophthalmia
in the eye.
Sympathetic ophthalmia
is a rare disease 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 recognized and picked up by local antigen presenting cells (APC) such as macrophages and dendritic cells. These APC carry the antigen to local lymph nodes to be sampled by T cell
s and B cell
s. Entering the systemic immune system, these antigens are recognized as foreign and an immune response is mounted against them. The result is the sensitization of immune cells against a self-protein, causing an autoimmune attack on both the damaged eye and the non-damaged eye.
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 node
s. 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. In the case of damage or chance presentation to the immune system, the antigen presentation and immune response will occur at elevated rates.
.
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. 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 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. Foxp3 and neuropillin are markers expressed by the regulatory T-cells by which they are identified.
is established, therefore the body recognizes them as foreign and mounts an immune reaction against them. Therefore, mechanisms for their protection must exist in this organ to prevent any autoimmune reaction. The blood-testis barrier
is likely to contribute to the survival of sperm. However, it is believed in the field of testicular immunology that the blood-testis barrier cannot account for all immune suppression in the testis, due to (1) its incompleteness at a region called the rete testis
and (2) the presence of immunogenic molecules outside the blood-testis barrier, on the surface of spermatogonia. Another mechanism which is likely to protect sperm is the suppression of immune responses in the testis.
. In that regard, the concept of "immune privilege" within the CNS was once thought to be critical in limiting inflammation. The blood-brain barrier
plays an important role in maintaining the separation of CNS from the systemic immune system but the presence of the blood-brain barrier, does not, on its own, provide immune privilege. It is thought that immune privilege within the CNS varies throughout the different compartments of the system, being most pronounced in the parenchyma
tissue or "white matter".
The concept of CNS as an "immune-privileged" organ system, however, has been overwhelmingly challenged and re-evaluated over the last two decades. Current data do not only indicate the presence of resident CNS macrophages (known as microglia
) within the CNS, but there is also a wide body of evidence suggesting the active interaction of the CNS with peripheral immune cells.
Generally, in normal (uninjured) tissue, antigens are taken up by antigen presenting cells (dendritic cells), and subsequently transported to the lymph nodes. Alternatively, soluble antigens can drain into the lymph nodes. In contrast, in the CNS, dendritic cells are not thought to be present in normal parenchymal tissue or perivascular space
although they are present in the meninges
and choroids plexus. Thus, the CNS is thought to be limited in its capacity to deliver antigens to local lymph nodes and cause T-cell activation.
Although there is no conventional lymphatic system in the CNS, the drainage of antigens from CNS tissue into the cervical lymph nodes has been demonstrated. The response elicited in the lymph nodes to CNS antigens is skewed towards B-cells. Dendritic cells from cerebrospinal fluid
have been found to migrate to B-cell follicles of cervical lymph nodes. The skewing of the response to antigen from the CNS 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 CNS has been previously shown. 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.
. The original explanation of this phenomenon was that physical barriers around the immune privileged site enabled it to avoid detection from the immune system altogether, preventing the immune system from responding to any antigens present. More recent investigations have revealed a number of different mechanisms by which immune privileged sites interact with the immune system.
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
without eliciting an inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
immune response. Tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
grafts
Medical grafting
Grafting refers to a surgical procedure to move tissue from one site to another on the body, or from another person, without bringing its own blood supply with it. Instead, a new blood supply grows in after it is placed. A similar technique where tissue is transferred with the blood supply intact...
are normally recognised as foreign antigen by the body and attacked by the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. However in immune privileged sites, tissue grafts can survive for extended periods of time without rejection
Transplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
occurring. Immunologically privileged sites were thought to include:
- the brainHuman brainThe human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
, but this is now known to be incorrect and indeed immune cells of the CNS contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood - the eyeHuman eyeThe human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
s - the placentaPlacentaThe placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
and the fetusFetusA fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The... - the testicleTesticleThe testicle is the male gonad in animals. Like the ovaries to which they are homologous, testes are components of both the reproductive system and the endocrine system...
s
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 fetus.
Medically, a cornea transplant
Cornea transplant
Corneal transplantation, also known as corneal grafting, is a surgical procedure where a damaged or diseased cornea is replaced by donated corneal tissue in its entirety or in part...
is currently the only procedure that takes advantage of this.
Mechanisms
Antigens from immune privileged regions have been found to interact with T cellT cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s in an unusual way inducing tolerance as opposed to a destructive response. Immune privilege has emerged as an active rather than a passive process.
Physical structures surrounding privileged sites cause a lack of lymph
Lymph
Lymph is considered a part of the interstitial fluid, the fluid which lies in the interstices of all body tissues. Interstitial fluid becomes lymph when it enters a lymph capillary...
atic drainage, limiting the immune system's ability to enter the site. Other factors that contribute to the maintenance of immune privilege include:
- low expression of classical MHC class IaMajor histocompatibility complexMajor histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
molecules - expression of immunoregulatory nonclassical, low polymorphic class Ib MHCMajor histocompatibility complexMajor histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
molecules - increased expression of surface molecules that inhibit complementComplement systemThe complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
activation - local production of immunosuppressiveImmunosuppressionImmunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
cytokineCytokineCytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s such as TGF-β - presence of neuropeptideNeuropeptideNeuropeptides are small protein-like molecules used by neurons to communicate with each other. They are neuronal signaling molecules, influence the activity of the brain in specific ways and are thus involved in particular brain functions, like analgesia, reward, food intake, learning and...
s - constitutive expression of FasFas receptorThe FAS receptor also known as apoptosis antigen 1 , cluster of differentiation 95 or tumor necrosis factor receptor superfamily member 6 is a protein that in humans is encoded by the TNFRSF6 gene....
ligandLigandIn coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
that controls the entry of Fas-expressing lymphoid cells.
The nature of isolation of immunologically privileged sites from the rest of the body's immune system can cause them to become targets of autoimmune diseases or conditions, including sympathetic ophthalmia
Sympathetic ophthalmia
Sympathetic ophthalmia is a granulomatous uveitis of both eyes following trauma to one eye. It can leave the patient completely blind. Symptoms may develop from days to several years after a penetrating eye injury. See also the reviews by Damico et al. , Chu and Foster , and Friedlaender et al...
in the eye.
Eye
As well as the mechanisms that limit immune cell entry and induce immune suppression, the eye also contains active immune cells that act upon the detection of foreign antigens. 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).Sympathetic ophthalmia
Sympathetic ophthalmia
Sympathetic ophthalmia is a granulomatous uveitis of both eyes following trauma to one eye. It can leave the patient completely blind. Symptoms may develop from days to several years after a penetrating eye injury. See also the reviews by Damico et al. , Chu and Foster , and Friedlaender et al...
is a rare disease 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 recognized and picked up by local antigen presenting cells (APC) such as macrophages and dendritic cells. These APC carry the antigen to local lymph nodes to be sampled by T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s and B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s. Entering the systemic immune system, these antigens are recognized as foreign and an immune response is mounted against them. The result is the sensitization of immune cells against a self-protein, causing an autoimmune attack on both the damaged eye and the non-damaged eye.
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 node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
s. Anergy
Anergy
Anergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system is unable to mount a normal...
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. In the case of damage or chance presentation to the immune system, the antigen presentation and immune response will occur at elevated rates.
Placenta and Fetus
The mother’s immune system 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 miscarriageMiscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
.
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. 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 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. Foxp3 and neuropillin are markers expressed by the regulatory T-cells by which they are identified.
Testes
Sperm are immunogenic - that is they will cause an autoimmune reaction if transplanted from the testis into a different part of the body. This has been demonstrated in experiments using rats by Lansteiner (1899) and Metchinikoff (1900), mice and guinea pigs. The likely reason for this is that sperm first mature at puberty, after immune toleranceImmune tolerance
Immune tolerance or immunological tolerance is the process by which the immune system does not attack an antigen. It can be either 'natural' or 'self tolerance', in which the body does not mount an immune response to self antigens, or 'induced tolerance', in which tolerance to external antigens can...
is established, therefore the body recognizes them as foreign and mounts an immune reaction against them. Therefore, mechanisms for their protection must exist in this organ to prevent any autoimmune reaction. The blood-testis barrier
Blood-testis barrier
The blood–testis barrier is a physical barrier between the blood vessels and the seminiferous tubules of the animal testes...
is likely to contribute to the survival of sperm. However, it is believed in the field of testicular immunology that the blood-testis barrier cannot account for all immune suppression in the testis, due to (1) its incompleteness at a region called the rete testis
Rete testis
Rete testis is an anastomosing network of delicate tubules located in the hilum of the testicle that carries sperm from the seminiferous tubules to the vasa efferentia....
and (2) the presence of immunogenic molecules outside the blood-testis barrier, on the surface of spermatogonia. Another mechanism which is likely to protect sperm is the suppression of immune responses in the testis.
Central Nervous System
The Central Nervous System (CNS), which includes the brain and spinal cord, is a sensitive system with limited capacity for regenerationRegeneration (biology)
In biology, regeneration is the process of renewal, restoration, and growth that makes genomes, cells, organs, organisms, and ecosystems resilient to natural fluctuations or events that cause disturbance or damage. Every species is capable of regeneration, from bacteria to humans. At its most...
. In that regard, the concept of "immune privilege" within the CNS was once thought to be critical in limiting inflammation. The blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
plays an important role in maintaining the separation of CNS from the systemic immune system but the presence of the blood-brain barrier, does not, on its own, provide immune privilege. It is thought that immune privilege within the CNS varies throughout the different compartments of the system, being most pronounced in the parenchyma
Parenchyma
Parenchyma is a term used to describe a bulk of a substance. It is used in different ways in animals and in plants.The term is New Latin, f. Greek παρέγχυμα - parenkhuma, "visceral flesh", f. παρεγχεῖν - parenkhein, "to pour in" f. para-, "beside" + en-, "in" + khein, "to pour"...
tissue or "white matter".
The concept of CNS as an "immune-privileged" organ system, however, has been overwhelmingly challenged and re-evaluated over the last two decades. Current data do not only indicate the presence of resident CNS macrophages (known as microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
) within the CNS, but there is also a wide body of evidence suggesting the active interaction of the CNS with peripheral immune cells.
Generally, in normal (uninjured) tissue, antigens are taken up by antigen presenting cells (dendritic cells), and subsequently transported to the lymph nodes. Alternatively, soluble antigens can drain into the lymph nodes. In contrast, in the CNS, dendritic cells are not thought to be present in normal parenchymal tissue or perivascular space
Perivascular cell
A perivascular cell is in the periphery of vasculature, and may refer to:*Pericyte, a connective tissue cell that occurs about small blood vessels*Smooth muscle cells...
although they are present in the meninges
Meninges
The meninges is the system of membranes which envelopes the central nervous system. The meninges consist of three layers: the dura mater, the arachnoid mater, and the pia mater. The primary function of the meninges and of the cerebrospinal fluid is to protect the central nervous system.-Dura...
and choroids plexus. Thus, the CNS is thought to be limited in its capacity to deliver antigens to local lymph nodes and cause T-cell activation.
Although there is no conventional lymphatic system in the CNS, the drainage of antigens from CNS tissue into the cervical lymph nodes has been demonstrated. The response elicited in the lymph nodes to CNS antigens is skewed towards B-cells. Dendritic cells from cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
have been found to migrate to B-cell follicles of cervical lymph nodes. The skewing of the response to antigen from the CNS towards a humoral response
Humoral immunity
The Humoral Immune Response is the aspect of immunity that is mediated by secreted antibodies produced in the cells of the B lymphocyte lineage . B Cells transform into plasma cells which secrete antibodies...
means that a more dangerous inflammatory T-cell response can be avoided.
The induction of systemic tolerance to an antigen introduced into the CNS has been previously shown. 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.
History of research
The existence of immune privileged regions of the eye was recognised as early as the late 19th century and investigated by MedawarPeter Medawar
Sir Peter Brian Medawar OM CBE FRS was a British biologist, whose work on graft rejection and the discovery of acquired immune tolerance was fundamental to the practice of tissue and organ transplants...
. The original explanation of this phenomenon was that physical barriers around the immune privileged site enabled it to avoid detection from the immune system altogether, preventing the immune system from responding to any antigens present. More recent investigations have revealed a number of different mechanisms by which immune privileged sites interact with the immune system.