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TEACHING
OBJECTIVES |
TOLERANCE Introduction Tolerance refers to the specific immunological non-reactivity to an antigen resulting from a previous exposure to the same antigen. While the most important form of tolerance is non-reactivity to self antigens, it is possible to induce tolerance to non-self antigens. When an antigen induces tolerance, it is termed tolerogen.
Tolerance to self antigens We normally do not mount a strong immune response against our own (self) antigens, a phenomenon called self-tolerance. When the immune system recognizes a self antigen and mounts a strong response against it, autoimmune disease develops. Nonetheless, the immune system has to recognize self-MHC to mount a response against a foreign antigen. Thus, the immune system is constantly challenged to discriminate self vs non-self and mediate the right response.
Induction of tolerance to non-self Tolerance can also be induced to non-self (foreign) antigens by modifying the antigen, by injecting the antigen through specific routes such as oral, administering the antigen when the immune system is developing, etc. Certain bacteria and viruses have devised clever ways to induce tolerance so that the host does not kill these microbes. Ex: Patients with lepromatous type of leprosy do not mount an immune response against Mycobacterium leprae.
Tolerance to tissues and cells Tolerance to tissue and cell antigens can be induced by injection of hemopoietic (stem) cells in neonatal or severely immunocompromised (by lethal irradiation or drug treatment) animals. Also, grafting of allogeneic bone marrow or thymus in early life results in tolerance to the donor type cells and tissues. Such animals are known as chimeras. These findings are of significant practical application in bone marrow grafting. |
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Tolerance to soluble antigens A state of tolerance to a variety of T-dependent and T-independent antigens has been achieved in various experimental models. Based on these observations it is clear that a number of factors determine whether an antigen will stimulate an immune response or tolerance (Table 1).
Immunologic features of tolerance Tolerance is different from non-specific immunosuppression and immunodeficiency. It is an active antigen-dependent process in response to the antigen. Like immune response, tolerance is specific and like immunological memory, it can exist in T-cells, B cells or both and like immunological memory, tolerance at the T cell level is longer lasting than tolerance at the B cell level. Induction of tolerance in T cells is easier and requires relatively smaller amounts of tolerogen than tolerance in B cells. Maintenance of immunological tolerance requires persistence of antigen. Tolerance can be broken naturally (as in autoimmune diseases) or artificially (as shown in experimental animals, by x-irradiation, certain drug treatments and by exposure to cross reactive antigens). Tolerance may be induced to all epitopes or only some epitopes on an antigen and tolerance to a single antigen may exist at the B cell level or T cell level or at both levels.
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Mechanism of tolerance induction The exact mechanism of induction and maintenance of tolerance is not fully understood. Experimental data, however, point to several possibilities.
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AUTOIMMUNITY Definition Autoimmunity can be defined as breakdown of mechanisms responsible for self tolerance and induction of an immune response against components of the self. Such an immune response may not always be harmful (e.g., anti-idiotype antibodies). However, in numerous autoimmune diseases it is well recognized that products of the immune system cause damage to the self. Effector mechanisms in autoimmune diseases Both antibodies and effector T cells can be involved in the damage in autoimmune diseases. General classification Autoimmune diseases are generally classified on the basis of the organ or tissue involved. These diseases may fall in an organ-specific category in which the immune response is directed against antigen(s) associated with the target organ being damaged or a non-organ-specific category in which the antibody is directed against an antigen not associated with the target organ (Table 2). The antigen involved in most autoimmune diseases is evident from the name of the disease (Table 2). Genetic predisposition for autoimmunity Studies in mice and observations in humans suggest a genetic predisposition for autoimmune diseases. Association between certain HLA types and autoimmune diseases has been noted (HLA: B8, B27, DR2, DR3, DR4, DR5 etc.).
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Figure 1 Hyperpigmentation of buccal mucosa in Addison's disease © Bristol Biomedical
Archive. Used with permission
Figure 2 Immunofluorescent stain of immunoglobulin G (IgG) showing linear pattern in Goodpasture's
Figure 3 Pemphigus vulgaris - immunofluorescence
©
Bristol Biomedical Archive. Used with permission Figure 4 Mucous membrane pemphigoid - immunofluorescence © Bristol Biomedical Archive. Used with permission
Figure 5 Parotid enlargement in Sjogren's syndrome ©
Bristol Biomedical Archive. Used with permission
Figure 6 Depigmentation in vitiligo ©
Bristol Biomedical Archive. Used with permission |
Etiology of autoimmunity disease The exact etiology of autoimmune diseases is not known. However, various theories have been offered. These include sequestered antigen, escape of auto-reactive clones, loss of suppressor cells, cross reactive antigens including exogenous antigens (pathogens) and altered self antigens (chemical and viral infections).
Lymphoid cells may not be exposed to some self antigens during their differentiation, because they may be late-developing antigens or may be confined to specialized organs (e.g., testes, brain, eye, etc.). A release of antigens from these organs resulting from accidental traumatic injury or surgery can result in the stimulation of an immune response and initiation of an autoimmune disease. Escape of auto-reactive clones Lack of regulatory T cells
Antigens on certain pathogens may have determinants which cross react with self antigens and an immune response against these determinants may lead to effector cell or antibodies against tissue antigens. Post streptococcal nephritis and carditis, anticardiolipin antibodies during syphilis and association between Klebsiella and ankylosing spondylitis are examples of such cross reactivity. Diagnosis Diagnosis of autoimmune diseases is based on symptoms and detection of antibodies (and/or very early T cells) reactive against antigens of tissues and cells involved. Antibodies against cell/tissue associated antigens are detected by immunofluorescence. Antibodies against soluble antigens are normally detected ELISA or radioimmunoassay (see table above). In some cases, a biological /biochemical assay may be used (e.g., Graves diseases, pernicious anemia). Treatment The goals of treatment of autoimmune disorders are to reduce symptoms and control the autoimmune response while maintaining the body's ability to fight infections. Treatments vary widely and depend on the specific disease and symptoms: Anti-inflammatory (corticosteroid) and immunosuppressive drug therapy (such as cyclophosphamide, azathioprine, cyclosporine ) is the present method of treating autoimmune diseases. Extensive research is being carried out to develop innovative treatments which include: anti-TNF alpha therapy against arthritis, feeding antigen orally to trigger tolerance, anti-idiotype antibodies, antigen peptides, anti-IL2 receptor antibodies, anti-CD4 antibodies, anti-TCR antibodies, etc. Models of autoimmune diseases There are a number of experimental and natural animal models for the study of autoimmune diseases. The experimental models include experimental auto-allergic encephalitis, experimental thyroiditis, adjuvant induced arthritis, etc. Naturally occurring models of autoimmune diseases include hemolytic anemia in NZB mice, systemic lupus erythematosus in NZB/NZW (BW), BXSB and MRL mice and diabetes in obese mice.
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Return to the Immunology Section of Microbiology and Immunology On-line
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