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LECTURE: 05 Title: IMMUNOLOGICAL UNRESPONSIVENESS "TOLERANCE" LEARNING OBJECTIVES: The student should be able to: • Define the term "immunological tolerance". • Identify the most important type of tolerance. • Realize the importance of the tolerance mechanism. • Explain how the state of unresponsiveness is generated? • Indicate how the state of tolerance is important in clinical medicine? • Explain the autotolerance. • List the four possible ways in which self reactive lymphocytes may be prevented from responding to self antigens such as: - Clonal deletion. - Clonal abortion. - Clonal anergy. - Suppression. • Explain the central, and post thymic tolerance to self- antigens. • Explain state of B-cell tolerance to self antigens. • Discuss the acquired (immune) tolerance. • List the characteristics of the acquired tolerance. • List the factors (T and B cells) that influence the inductions of tolerance. • Enumerate the methods of immune tolerance induction. • Explain the light and dark zone. LECTURE REFRENCE: 1. TEXTBOOK: ROITT, BROSTOFF, MALE IMMUNOLOGY. 6th edition. Chapter 12. pp. 191-208 2. TEXTBOOK: ABUL K. ABBAS. ANDREW H. LICHTMAN. CELLULAR AND MOLECULAR IMMUNOLOGY. 5TH EDITION. Chapter 10. pg 216. 3. HANDOUT. Immunological tolerance Tolerance mechanisms are needed because the immune system randomly generates a vast diversity of antigen-specific receptors and some of these will be self reactive; tolerance prevents harmful reactivity against the body's own features. Central thymic tolerance to self antigens (autoantigens) results from deletion of differentiating T cell that express antigen-specific receptors with high binding affinity for intrathymic self antigens. Low-affinity self-reactive T cells, and T cells with receptors specific for antigens that are not representative intrathymically, mature and join the peripheral T cell pool. Post-thymic tolerance to self antigens has five main mechanisms. Self-reactive T cells in the circulation may ignore self antigens, for example when the antigens are in tissues sequestered from the circulation. Their response to a self antigen may be suppressed if the antigen is present in a privileged site. Self-reactive cells may under certain conditions be deleted or rendered anergic and unable to respond. Finally a state of tolerance to self antigens can also be maintained by immune regulation. B-cell deletion takes place in both bone marrow and peripheral lymphoid organs. Differentiating B cells that express surface immunoglobulin receptors with high binding affinity for self-membrane-bound antigens will be deleted soon after their generation in the bone marrow. A high proportion of short-lived, low-avidity, autoreactive B cells appear in peripheral lymphoid organs. These cells may be recruited to fight against infection. Tolerance can be induced artificially by various regimens that may eventually be exploited clinically to prevent rejection of foreign transplants and to manipulate autoimmune and allergic diseases. INTRODCTION Immunological tolerance is a state of unresponsiveness that is specific for a particular antigen; it is induced by prior exposure to that antigen. Active tolerance mechanisms are required to prevent inflammatory responses to the many innocuous air-borne and food antigens that are encountered at mucosal surfaces in the lung and gut. The most important aspect of tolerance, however, is self tolerance, which prevents the body from mounting an immune attack against its own tissues. There is potential for such attack because the immune system randomly generates a vast diversity of antigen-specific receptors therefore must be eliminated, either functionally or physically. Self reactivity is prevented by processes that occur during development, rather than being genetically preprogrammed. Thus while homozygous animals of histo-incompatible strains A and B reject each other's skin, and their F1 hybrid offspring (which express the antigens of both the A and B parents) reject neither A skin nor B skin, the ability to reject such skin reappears in homozygotes of the F2 progeny. Thus it is clear that self-non-self discrimination is learned during development: immunological 'self' must encompass all epitopes (antigenic determinants) encoded by the individual's DNA, all other epitopes being considered as non-self. However it is not the structure of a molecule per se that determines whether it will be distinguished as self or non-self. Factors other than the structural characteristics of an epitope are also important. Among these are: • The stage of differentiation when lymphocytes first confront their epitopes. • The site of the encounter. • The nature of the cells presenting epitopes. • The nature of lymphocytes responding to the epitopes. Historical background Soon after the existence of antibody specificity was established, it was realized that there must be some mechanism to prevent autoantibody formation. As early as the turn of the century, Ehrlich coined the term 'horror autotoxicus', implying the need for a 'regulating contrivance' to stop the production of antoantibodies. In 1938, Traub induced specific tolerance by inoculating mice in utero with lymphocytic choriomeningitis virus, producing an infection that was maintained throughout life. Unlike normal mice, these inoculated mice did not produce neutralizing antibodies when challenged with the virus in adult life. In 1945, Owen reported an 'experiment of nature' in non-identical cattle twins which showed that cells carrying self and non-self antigens could develop within a single host. These animals exchanged haemopoietic (stem) cells via their shared placental blood vessels and each animal carried the erythrocyte markers of both calves. They exhibited life-long tolerance to the otherwise foreign cells, in being unable to mount antibody responses to the relevant erythrocyte antigens. Following this observation, Brnet and Fenner postulated that the age of the animal at the time of first encounter was the critical factor in determining responsiveness, and hence recognition, of non-self antigens. This hypothesis seemed logical, as the immune system is usually confronted with most self components before birth and only later with non-self antigens. Experimental support came in 1953, when Medawar and his colleagues induced immunological tolerance to skin allografts (grafts that are genetically non-identical, but are form the same species) in mice by neonatal injection of allogeneic cells (Figure-1). This phenomenon waqs easily accommodated in Burnet's clonal selection theory (1957), which states that a particular immunocyte (a particular B to T cell) is selected by antigen and then divides to give rise to a clone of daughter cells, all with the same specificity. According to this theory, antigens encountered after birth active specific clones of lymphocytes, whereas when antigens are encountered before birth the result is the deletion of the clones specific for them, which Burnet termed 'forbidden clones'. Implicit in the theory is the need for the entire immune repertoire to be generated before birth, but in fact lymphocytes differentiation continues long after birth. The key factor in determining responsiveness is thus not the development stage of the individual, but rather the state of maturity of the lymphocyte at the time it encounters antigen. This was suggested by Lederberg in 1959, in his modification of the clonal selection theory: immature lymphocytes contacting antigen would be subject to 'clonal abortion', whereas mature cells would be activated. It is now established that the neonate is in fact immunocompetent. The reason that one can induce tolerance to certain antigens in the neonate is simply that the type of immune response to antigen can be functionally different in the neonate compared with that in the adult. Past description of neonatal tolerance may therefore have been early examples of this type of 'immune deviation' (see below). Key discoveries in the 1960s established the immunological competence of the lymphocyte, the crucial role of the thyms in the development of the immune system, and the existence of two interacting subsets of lymphocytes: T and B cells. This set the scene for a though investigation of the cellular mechanism involved in tolerance. EXPERIMENTAL INDUCTION OF TOLERANCE Transgenic technology has allowed the study of tolerance to authentic self antigens Until recently, only artificially induced tolerance was amenable to experimental study: antigens or foreign cells were inoculated into an animal and the fate of responding T or B cells was investigated under a variety of circumstances. It was not clear, however, to what extent these experimental models resembled natural self tolerance. Transgenic methods have now made possible the direct investigation of self tolerance. These methods allow one to introduce a specific gene into mice of defined genetic background and to analysis its effects upon the development of the immune system. Furthermore, if the introduced gene is linked to a tissue-specific promoter, its expression can be confined to specific cell types. The protein product encoded by a 'transgene' is treated by the immune system essentially as an authentic self antigen (autoantigen), and its effects can be studies in vivo without the trauma and inflammation associated with grafting foreign cells or tissues. In addition, the parent strain and the transgenic strain are ideal for control experiments and lymphocyte transfer studies because they are congenic – that is they
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