Tolerance

1. Tolerance

2. Weapons are designed to attack the enemy while ensuring the self defense • Lack of skill or malfunctioning of a weapon may lead to self damage • Therefore in order to avoid self damage our body’s immune system must be educated against self and non-self • Physiologic meaning of tolerance is the non- reactivity of the immune system against body’s own or self proteins

3. Immunological tolerance and associated terms… • Immunologic tolerance is defined as unresponsiveness to an antigen that is induced by previous exposure to that antigen • Antigens that induce tolerance are called tolerogens, or tolerogenicantigens • Antigens that induce immunity are called immunogens • A single antigen may be an immunogenor a tolerogen, depending on the conditions in which it is displayed to specific lymphocytes (e.g., in the presence or absence, respectively, of inflammation and innate immune responses) • Tolerance to self antigens, also called self-tolerance, is a fundamental property of the normal immune system, and failure of self-tolerance results in immune reactions against self (autologous) antigens • Such reactions are called autoimmunity, and the diseases they cause are called autoimmune diseases • Tolerance unlike immunosuppression is antigen specific

4. RECOGNITION OF MICROBES AND DAMAGED SELF BY THE INNATE IMMUNE SYSTEM • The innate immune system recognizes molecular structures that are characteristic of microbial pathogens but not mammalian cells • The microbial substances that stimulate innate immunity are called pathogen-associated molecular patterns (PAMPs) • These PAMPs recognize a limited number of fundamental differences between microbial molecules and the molecules that higher organisms produce

5. PAMPs The innate immune system recognizes microbial products that are often essential for survival of the microbes!!!

6. DAMPs • The innate immune system also recognizes endogenous • molecules that are produced by or released from damaged • and dying cells • These substances are called damage associated • molecular patterns (DAMPs) • DAMPs may be produced as a result of cell damage caused by infections, but they may also indicate sterile injury to cells caused by any of myriad reasons, such as • chemical toxins, • burns, • trauma, • or decreased blood supply. • DAMPs are generally not released from cells dying by apoptosis • In some cases, healthy cells of the immune system are stimulated to produce and release DAMPs, which enhances an innate immune response to infections

7. RECOGNITION OF MICROBES AND DAMAGED SELF BY THE ADAPTIVE IMMUNE SYSTEM • In contrast to the innate immune system, the adaptive immune system is capable of recognizing a much wider array of foreign substances whether or not they are products of microbes • Adaptive immune system may recognize the microbial components which may be dispensable for the survival of the microbe • With what biological consequences?

8. microbe may mutate or lose many of the antigens that are recognized by the adaptive immune system, thereby enabling the microbes to evade host defense without compromising their own survival

9. How can a large number of diverse lymphocytic receptors be generated?

10. General features of physiological tolerance • The immune system must learn or be educated to discriminate between self and non-self • Normal individuals are tolerant of their own (self) antigens • All individuals inherit essentially the same antigen receptor gene segments, and these recombine and are expressed in lymphocytes as they arise from stem cells • The specificities of the receptors encoded by the recombined genes are irrespective of foreign or self • Therefore, there is a risk for lymphocytes to react against that individual’s cells and tissues, causing disease • The mechanisms of immunologic tolerance are designed to prevent such reactions

11. OVERVIEW OF LYMPHOCYTE DEVELOPMENT • The maturation of B and T lymphocytes involves a series of events that occur in the generative lymphoid organs • These events include the following: • The commitment of progenitor cells to the B cell or T cell lineage • Proliferation of progenitors and immature committed cells at specific early stages of development, providing a large pool of cells that can generate useful lymphocytes. • The sequential and ordered rearrangement of antigen receptor genes and the expression of antigen receptor proteins • Selection events that preserve cells that have produced correct antigen receptor proteins and eliminate potentially dangerous cells that strongly recognize self antigens. • These checkpoints during development ensure that lymphocytes that express functional receptors with useful specificities will mature and enter the peripheral immune system • Differentiation of B and T cells into functionally and phenotypicallydistinct subpopulations • B cells develop into follicular, marginal zone, and B-1 B cells, • and T cells develop into CD4+ and CD8+ T lymphocytes and γδ T cells

12. Checkpoints in lymphocyte maturation. During development, • the lymphocytes that express receptors required for continued proliferation and maturation are selected to survive, • and cells that do not express functional receptors die by apoptosis • Positive selection and negative selection further preserve cells with useful specificities. • The presence of multiple checkpoints ensures that only cells with useful receptors complete their maturation.

13. Positive selection • The process called positive selection facilitates the survival of potentially useful lymphocytes • Positive selection is linked to the lineage commitment, the process by which lymphocyte subsets are generated • In the T cell lineage, positive selection ensures the maturation of T cells whose receptors recognize self MHC molecules and also that the expression of the appropriate co-receptor on a T cell (CD8 or CD4) is matched to the recognition of the appropriate type of MHC molecule (MHC class I or MHC class II) • Mature T cells whose precursors were positively selected by self MHC molecules in the thymus by the same self MHC molecules on antigen-presenting cells in peripheral tissues. • In the B cell lineage, positive selection preserves receptor-expressing cells and is coupled to the generation of different subsets,

14. Negative selection • Negative selection of immature lymphocytes is an important mechanism for maintaining tolerance to many self antigens; this is also called central tolerance because it develops in the central (generative) lymphoid organs • Negative selection is the process that eliminates or alters developing lymphocytes whose antigen receptors bind strongly to self antigens present in the generative lymphoid organs • Both developing B and T cells are susceptible to negative selection during a short period after antigen receptors are first expressed • Developing T cells with a high affinity for self antigens are eliminated by apoptosis, a phenomenon known as clonal deletion • Strongly self-reactive immature B cells may be induced to make further Ig gene rearrangements and thus evade self-reactivity. This phenomenon is called receptor editing • If editing fails, the self-reactive B cells die, also called clonal deletion

15. Positive and negative selection during lymphocyte maturation • After immature clones of lymphocytes in generative lymphoid organs express antigen receptors, they are subject to both positive and negative selection processes. • In positive selection, lymphocyte precursors with antigen receptors that bind some self ligand with low avidity are selected to survive and mature further • Developing B cells receive survival signals simply because of expression of complete antigen receptors, without recognition of a self antigen. • However, as in T cells, self antigen of different affinities can drive the differentiation of different B cell subsets. • Positive selection in both B and T lineages is therefore tightly linked to the process of generating lymphocyte subsets, also referred to as lineage commitment. • Positively selected lymphocytes enter peripheral lymphoid tissues, • where they respond to foreign antigens. • In negative selection, cells that bind antigens present within the generative organs, with high avidity, receive signals that either lead to cell death or induce further rearrangement of antigen receptor genes, a process known as receptor editing. • As a result, the repertoire of mature lymphocytes lacks cells capable of responding to these self antigens. • The diagram illustrates selection of B cells; the principles are the same for T lymphocytes, except that there is no receptor editing in the T lineage.

16. Macfarlane Burnet added to his clonal selection hypothesis the corollary that lymphocytes specific for self antigens are eliminated to prevent immune reactions against one’s own tissues. • As we shall see later in this chapter, self tolerance is maintained by several different mechanisms that prevent the maturation and activation of potentially harmful self-reactive lymphocytes. • Tolerance results from the recognition of antigens by specific lymphocytes • In other words, tolerance, in its strict definition, is antigen specific

17. FIGURE 14–1 Central and peripheral • tolerance to self antigens. • Immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid organs and are deleted, change their specificity (B cells only), or (in the case of CD4+ T cells) develop into regulatory lymphocytes (central tolerance). • Someself-reactive lymphocytes may mature and enter peripheral tissues and may be inactivated or deleted by encounter with self antigens in these tissues or are suppressed by the regulatory T cells (peripheral tolerance). • (Note that T cells recognize antigens presented by antigen-presenting cells, which are not shown.)

18. FIGURE 14–2 Central T celltolerance. • Recognition of self antigens by immature T cells in • the thymus may lead to death of the cells (negative selection, or deletion) or the development of regulatory T cells that enter peripheral tissues

19. FIGURE 14–3 Mechanisms of peripheral T cell tolerance. The signals involved in a normal immune response and the three major mechanisms of peripheral T cell tolerance

20. FIGURE 14–4 Mechanisms of T cell anergy. • T cell responses are induced when the cells recognize an antigen presented by a professional antigen-presenting cell (APC) and activating receptors on the T cells (such as CD28) recognize costimulators on the APCs (such as B7). • If the T cell recognizes a self antigen without costimulation, the T cell becomes unresponsive to the antigen because of a block in signaling from the TCR complex or engagement of inhibitory receptors (such as CTLA-4) • The signaling block may be the result of recruitment of phosphatases to the TCR complex or the activation of ubiquitinligases that degrade signaling proteins • The T cell remains viable but is unable to respond to the self antigen

21. FIGURE 14–5 Mechanisms of action of CTLA-4. A, The top panel shows the activation of T cells by antigen recognition and costimulation through CD28. B, The bottom panel shows the two postulated mechanisms of action of CTLA-4: delivery of inhibitory signals that block TCR- and CD28-mediated signals, and engagement of B7 molecules on APCs so they are inaccessible to CD28. Note that regulatory T cells may also use CTLA-4 to block B7 and thus inhibit immune responses. There is some evidence that in addition to blocking B7, CTLA-4 may remove these molecules from the APC surface and internalize them

22. FIGURE 14–6 Regulatory T cells. • Regulatory T cells are generated by self antigen recognition in the thymus ( • sometimes called natural regulatory cells) • and (probably to a lesser extent) by antigen recognition in peripheral lymphoid organs (called inducible or adaptive regulatory cells) • The development and survival of these regulatory T cells require IL-2 and the transcription factor FoxP3 • In peripheral tissues, regulatory T cells suppress the activation and effector functions of other, self-reactive and potentially pathogenic lymphocytes