The Immune System plays a very significant role in our body. It acts as a defense mechanism to various kinds of pathogens and infections. There are specialized cells in the Immune System that protect the body from foreign invaders. These specialized cells include the B cells and the T cells. Mature B cells are responsible for the synthesis and display of immunoglobulins, which acts like a receptor for antigens. Thus, B cells play an active role in humoral immunity, while the T cells play an important role in cell mediated immunity.
The immune response is based on two important aspects - recognition and response. The unique feature of an immune response is that it is able to recognize minute differences in the chemical properties and other properties that distinguish the body's self antigens from foreign antigens. Once a foreign antigen is recognized it mounts an immune response or an effector response, by recruitment of the specialized cells described above and this helps in eliminating the foreign antigen from the body.
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This mechanism of responding only to foreign antigens and not to self antigens is known as immunological tolerance. However, if the body acts against it's own antigens, immunological tolerance is lost and this may result in an autoimmune disease.
This review article deals with the various mechanisms of inducing immune tolerance, factors determining the induction and extent of tolerance, mechanisms of tolerance and development of autoimmune diseases due to loss of immune tolerance.
Immune tolerance is the failure to mount a response to a specific antigen. However, it is also specific in the sense that it is an active response to a particular epitope. There are two types of immunological tolerance - Natural tolerance and Acquired tolerance. In natural tolerance, there is unresponsiveness to the self antigen; whereas in acquired tolerance, there is unresponsiveness to the foreign antigen. Acquired tolerance is also called induced tolerance because the immune system has been deliberately manipulated to allow the entry of the foreign antigen. The role of induced tolerance shall be explained later in the article.
In 1945, Ray Owen developed an experimental model that described the process of immune tolerance. He studied dizygotic cattle twins that shared the same placenta and were blood cell chimeras. This meant that they contained blood cells of two different haplotypes in adults. Hence, they were able to accept skin grafts without rejection. In normal circumstances this would not be the case. The cells of one haplotype would have promptly been rejected when they were transferred to cattle with a different haplotype. However, this was not to be seen because immunological tolerance was observed in the dizygotic twins which resulted due to the exposure of the antigen during the development of the immune system.
Immunological Tolerance can be induced during two stages of life - at an early stage in life or after becoming an adult.
Inducing tolerance early in life
The introduction of a foreign or exogenous antigen into the fetus at a time when the immune system is still maturing renders the host immunologically tolerant to that exogenous antigen. Ray Owen's model is an example of inducing tolerance early in life. Another example is that of birds hatched from parabiotic eggs. They are immunologically tolerant of each other. Thus if the host encounters an antigen at the embryonic stage, the immunologically mature individual will remember that antigen as a self antigen.
Inducing tolerance in adults.
It is very difficult to induce tolerance at this stage in life. However, efforts are still being made by providing a high dose of antigen and treatment over a period of time. This method is of prime importance in humans as it helps during transplantation and in autoimmune diseases. However, immunosuppressive drugs which may have side effects are also administered. Hence, research is currently going on to find out novel techniques to induce tolerance.
Factors determining Tolerance.
There are several factors that affect the induction, time period and the intensity of tolerance.
Making a competent immune system
Just like in molecular biology, wherein a cell has to be made competent to take up a plasmid, similarly the immune system is made competent by irradiation, drugs,etc. This helps in the administration of the antigen and helps in the induction of immune tolerance. Even after this treatment is stopped and immunocompetence is regained, the host is still immunologically tolerant to that antigen. Both T cells and B cells can undergo tolerance, but the T cells can be made tolerant more rapidly than B cells.
Molecular pattern of the antigen.
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There is a distinct difference in the molecular characteristics of an antigen that induces an immune response and an antigen that makes the system immune tolerant. A large, aggregated antigen is capable of mounting an immune response, while a soluble, disaggregated antigen is characteristic of a toloregenic antigen. The chemical nature of the antigen is also very important. It has been observed that at the same doses, D-amino acid polymers are tolerogenic while L-amino acid polymers are immunogenic.
Dose of antigen.
High dose of antigen was found to induce immune tolerance but also a paralysis of immune system was observed. Hence, in order to avoid this, studies showed that a low dose level induced tolerance of a lower grade. Any intermediate dose was found to be immunogenic.
Mode of antigen administration
Tolerogenic antigens are administered intraperitoneally or intravenously. This facilitates presentation by B cells. Immunogenic antigens are administered subcutaneously as this favors antigen uptake and presentation by Langerhans cells. Oral administration also induces immune tolerance. However, changing the route of administration can help in making an immunogenic antigen tolerogenic and vice versa.
Termination of Tolerance.
A tolerant state does not last forever, it gradually disappears. It may disappear due to a cross reaction with another antigen. Studies have shown that a rabbit tolerant to the bovine serum albumin loses its tolerant nature when it cross reacts with Human serum albumin.
T cells and B cells require two signals for their complete activation. Signal 1 includes presentation of antigen to the cell, while signal 2 involves the antigen presenting cells providing costimulatory signals thus amplifying the response. Some examples of costimulatory signals for T cells are CD28, CD80, and CD 86; while examples for B cells include B7. Tolerance can be induced when signal 1 is interrupted as this involves the presence of the antigen.
After this I shall be including the central and peripheral modes of tolerance.
Followed by the different terms like clonal deletion, receptor editing, clonal anergy.
Finally, I would be adding a discussion which would include the use of tolerance during transplantation and the various autoimmune diseases that occur due to loss of tolerance.