Dr. Fadwah Al-Ghalib Diagnostic Immunology 3rd Year 3rd Yr Diagnostic Immunology Dr. Fadwah Alghalib IMMUNOLOGICAL TOLERANCE Read Chapter 12 in Roitt's Book of immunology OBJECTIVES: 1234567- What is immunological tolerance? Historical background, Mechanism of tolerance induction Types of Tolerance : Central and peripheral tolerance B cell tolerance to self antigens Artificial induction of tolerance Therapeutic applications of tolerance -----------------------------------------Immunological tolerance is the failure to mount an immune response to an antigen. It can be: o Natural or "self" tolerance. This is the failure (a good thing) to attack the body's own proteins and other antigens. If the immune system should respond to "self", an autoimmune disease may result. o Induced tolerance. This is tolerance to external antigens that has been created by deliberately manipulating the immune system. Its importance: (allergic reactions, to avoid graft rejection, To stop the mechanism of autoimmunity). Tolerance prevents harmful reactivity against the body's own tissue. Definitions: Tolerance: is a state of unresponsivness that is specific for a particular antigen. Self tolerance: it is an aspect of tolerance that prevents the body from mounting an immune attack against its own tissue. Self reactivity: is prevented during development rather than being genetically programmed. Factors that influence Tolerance: 1- Molecular structure 2- The stage of differentiation when lymphocytes first confront their epitopes 3- The site of the encounter 4- The nature of the cells presenting epitopes 5- The number of lymphocytes responding to the epitopes. 1 Dr. Fadwah Al-Ghalib Diagnostic Immunology 3rd Year Historical Background: 1- Traub (1938): induced specific tolerance by inoculating mice in utero with lymphocytic choriomeningitis virus producing an infection that was maintained throughout life, they did not produce neutralizing antibodies when challenged with the virus in adult life. 2- Medawar (1953): induced immunological tolerance to skin allografts in mice by neonatal injection of allogenic cells. (See fig 1.1 ) (Fig -1.1) 3- Burnet (1957): Clonal selection: A particulate immunocyte (a particular B or 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 encounter after birth activate specific clones of lymphocytes, whereas when antigens are encountered before birth, results in the deletion of the clones specific for them. 4- Leaderburg (1959): modification of the clonal selection theory. [ immature lymphocyte contacting antigen would be subjects to clonal abortion whereas mature cells would be activated. 5- Key discoveries in 1960s: a. Crucial role of the thymus in the development of the immune system. b. The existing of the two interacting subsets of lymphocytes (T cell & B cells). 2 Dr. Fadwah Al-Ghalib Diagnostic Immunology 3rd Year A ) T-Cell Central Tolerance: 1. T cells develop in the thymus 2. The immune system generates a vast array of TCRs. 3. T cells are not only effector cells but are also regulators of the immune system. 4. T cell become educated in the thymus and become dependent on self MHC for survival. 5. T cell development involves positive and negative selection and lineage commitment. (See figure 12.3 in Roitt's Book) T cell selection is compartmentalized in the thymus: a. Immature lymphocytes are found in the cortical region associated with cortical epithelial cells. b. In the outer cortex cells are proliferating immature cells c. In the inner cortex are more mature double positive (DP) cells under-going positive selection. d. The medulla contains mature single positive (SP) lymphocytes, medullary epithelial cells and bone marrow derived macrophages and dendritic cells. Q 1: How could the thymus express all the antigens that a T cell might encounter outside the thymus? T cell development is subjected to several checkpoints: 1- selection checkpoint: Only cells with a rearranged chain mature from double negative to double positive cells. It is Independent on MHC. 2- selection checkpoint: Cells expressing an complex must interact with MHC to survive. 3- Lineage commitment checkpoint: Cells are instructed to repress expression of either CD4 or CD8 and to develop into single positive cells. 4- Negative selection checkpoint: Cells that interact strongly with MHC and antigen in the thymus are deleted. B) T cell peripheral Tolerance: Many autoreactive T cells escape central tolerance due to : a. Antigens are absent 3 Dr. Fadwah Al-Ghalib Diagnostic Immunology 3rd Year b. Antigens are insufficient to induce tolerance in the thymus. Tolerance is maintained by various mechanisms in the peripheral lymphoid organs:T cells cells are capable of making a response but are unaware of the presence of their auto-antigens. Due to 2 reasons: 1- Sequestration of antigen in some tissues: Many self antigens are hidden in the tissues away from T lymphocytes either because of their location or may never processed by functional APCs. OR antigen is present in too low concentrations in which it will not trigger a response. 2- Privileged sites are protected by regulatory mechanisms: Examples of such "privileged sites": interior of the eye testes the brain 3- Receiving of Death Signals: by two processes either : a- Activation-induced cell death (AICD): Some cells of the body express the Fas ligand, FasL. Activated T cells always express Fas. When they encounter these cells, binding of Fas to FasL triggers their death by apoptosis. b- passive cell death (PCD): Many activated cells die by PCD because their antigen is eliminated (following clearance of an infection). The removal of the antigen deprives cells of essential survival stimuli including growth factors. 4- Control by Regulatory T Cells: Both low and high doses of antigen may induce suppressor T cells which can specifically suppress immune responses of both B and T cells, either directly or by production of cytokines, most importantly, TGF-beta and IL-10. A minor population of CD4+ T cells, called regulatory T cells, suppresses the activity of other T cells. They may be important players in protecting the body 4 Dr. Fadwah Al-Ghalib Diagnostic Immunology 3rd Year from attack by its other T cells. [ Th1 cells produce cytokines e.g. INF and TNF- that has a role in autoimmune diseases] [Th2 cells produce cytokines e.g. IL-4, IL-5, IL-6, & IL-10, support Antibody production] SUMMARY OF MECHANISMS OF CENTRAL & PERIPHERAL TOLERANCE Thymus Deletion Escape Sequestration Antigen Privileged sites Deletion By Prevention by Fas And cytokines Activationinduced cell death Hidden from immune system Immune regulation by Supressive T cells And Cytokines e.g IL-2 T-Cell Anergy: • Auto-reactive T cells, when exposed to antigenic peptides which do not possess co-stimulatory molecules (B7-1 or B7-2), become anergic to the antigen. (see fig- 1.2) B Cell Tolerance: -High affinity IgG production is T cell dependent -Without help from T cells B cells remain harmless (non-self reactive). Central Tolerance B cells are formed and mature in the bone marrow. In humans, over half of the developing B cells produce a BCR able to bind self components. 5 Dr. Fadwah Al-Ghalib Diagnostic Immunology 3rd Year Self-reactive B cells are either: a- undergo receptor editing Any cells that produce a receptor for antigen (BCR) that would bind self components too tightly undergo a process of receptor editing.(IgM receptor on immature B cell reacts with self antigen further cell differentiation is blocked. If IgM receptor does not react with self antigen in bone marrow, B cell development can proceed). b- or undergo apoptosis if receptor editing has failed to eliminate auto-reactive B cells they are likely to be eliminated by apoptotic death. Peripheral Tolerance: Self-reactive B cells are eliminated in the spleen by negative selection, as does the thymus to the unwanted T cells. Auto-reactive B cells that escape deletion may not find the antigen or the specific helper T-cells and hence not be activated and die out. B-cell anergy: (fig: 1.4) • • more than 5%* of the sIgM molecules are normally occupied by monomeric soluble antigen the B cell becomes anergic. This anergic state can be recognised in the case of B cells by the downregulation of surface IgM. Potential therapeutic applications of tolerance: Better understanding of tolergenesis could be valuable in many ways: 1234- is used to promote tolerance of foreign tissue grafts to control the damaging immune-responses in hypersensitivity states to control the damaging immune-responses in autoimmune diseases limit tumor growth. 6 Dr. Fadwah Al-Ghalib Diagnostic Immunology fig: 1.3 Fig:1.2 fig : 1.4 7 3rd Year Dr. Fadwah Al-Ghalib Diagnostic Immunology 8 3rd Year