ITOLERANCE............................pptx

Immunity depends on several factors. Tolerance is same as immunity.

1. IMMUNE TOLERANCE

2. Tolerance The term tolerance applies to the many layers of protection imposed by the immune system to prevent the reaction of its cells and antibodies against host components. In other words, individuals should not typically respond aggressively against their own antigens, although they will respond to pathogens or even cells from another individual of the same species.

3. TOLERANCE individuals should not typically respond aggressively against their own antigens, although they will respond to pathogens or even cells from another individual of the same species. Until fairly recently, this was thought to be mediated by the elimination of cells that can react against self antigens, yielding a state of unresponsiveness to self. Rather than ignore self proteins, the immune system protects them.

4. Mechanisms of tolerance The possibility of damage from self-reactive lymphocytes is further limited by the life span of activated lymphocytes, which is regulated by programs that induce cell death (apoptosis) following receipt of specific signals

5. TOLEROGENS Antigens that induce tolerance are called tolerogens rather than immunogens . the same chemical compound can be both an immunogen and a tolerogen, depending on how and where it is presented to the immune system. For instance, an antigen presented to T cells without appropriate costimulation results in a form of tolerance known as anergy (unresponsiveness to antigenic stimulus) whereas the same antigen presented with costimulatory molecules can become a potent immunogen.

6. ROUTE OF Ag Administration When some antigens are introduced orally, tolerance can be the result, whereas the same antigen given as an intradermal or subcutaneous injection can be immunogenic. In other instances, mucosally administered antigens provide protective immunity, such as in the case of Sabin’s oral polio vaccine. tolerogens are antigen specific. The inactivation of an immune response does not result in general immune suppression, but rather is specific for the tolerogenic antigen

7. Tolerance in Fetus In adults, most encounters with foreign antigen lead to an immune response aimed at eradication. This is not true in the fetus, where, due to the immature state of the immune system, exposure to antigens frequently results in tolerance.

8. Factors Promoting Tolerance High doses of antigen Long-term persistence of antigen in the host • Intravenous or oral introduction • Absence of adjuvants (compounds that enhance the immune response to antigen) • Low levels of costimulation • Presentation of antigen by immature or unactivated antigen-presenting cells (APCs)

9. POINT TO PONDER: REACTIVE T/B CELLS Healthy individuals have been shown to possess mature, recirculating, self-reactive lymphocytes. Since the presence of these self-reactive lymphocytes in the periphery does not predict or inevitably result in autoimmune reactions, their activity must be regulated in healthy individuals through other mechanisms.

10. SEQUESTER ANTIGENS the anterior chamber and lens of the eye are considered sequestered sites, without lymphatic drainage and possessing tissue- specifi c privileged antigens that are normally isolated from interaction with immune cells. Th is sequestration allows these antigens to avoid encounter with reactive lymphocytes under normal circumstances; if the antigen is not exposed to immune cells, there is little possibility of reactivity. However, one possible consequence of sequestration is that the antigen is never encountered by developing lymphocytes, and thus active tolerance to the sequestered antigen is not established.

11. Encounter with sequestered Self Ag If barriers between immune cells and the sequestered antigens are breached (by trauma, for example), the newly exposed antigen may be seen as foreign because it was not previously encountered. Trauma to one eye that allows entry of immune cells can result in inflammation in that eye, leading to tissue destruction and impaired vision. In these cases, the other eye may also become inflamed due to the sudden entry of clones of these recently activated immune cells recognizing newly discovered tissue-specific antigens.

12. Protected sites A locally immunosuppressive microenvironment in tissues conventionally considered immune privileged, such as the eye and central nervous system (CNS), in addition to other active mechanisms, is believed to bias the immune response toward tolerance in these locations.

13. Activation -induced cell death Cell death plays an important role in establishing and maintaining both central and peripheral tolerance. This is evidenced by the development of systemic autoimmune diseases in mice with naturally occurring mutations of either the death receptor, Fas , or Fas ligand ( FasL ) activated T cells express increased levels of Fas and FasL . In both B and T cells, engagement of Fas by FasL induces a rapid apoptotic death known as activation-induced cell death (AICD). Mice that carry inactivating mutations in Fas or FasL are not able to engage the AICD pathway and develop autoimmune disease early in life

14. Central tolerance mechanism strongly influencing central tolerance is the deletion during early stages of maturation of lymphocyte clones that have the potential to react with self components later Consider the mechanisms that generate diversity in T-cell or B-cell receptors. the genetic rearrangements that give rise to a functional T-cell receptor (TCR) or immunoglobulin (Ig) occur through a process whereby any V-region gene segment can associate with any D or J gene segment. This means that the generation of variable regions that react with self antigens is almost inevitable. If this were allowed to occur frequently, such TCR or Ig receptors could produce mature functional T or B cells that recognize self antigens, and autoimmune disease would ensue.

15. Negative selection cells undergo a developmentally regulated event called negative selection. This results in the induction of death in some, but not all, cells that carry potentially autoreactive TCR or Ig receptors.

16. Receptor editing David Nemazee and colleagues showed that some developing B cells can undergo receptor editing. In this process, the antigen-specific V region is “edited” or switched for a different V-region gene segment via V(D)J recombination, sometimes producing a less autoreactive receptor with an affinity for self antigens below a critical threshold that would lead to disease, allowing the cell to survive. the central tolerance processes of negative selection and receptor editing work to eliminate many autoreactive T cells in the thymus and autoreactive B cells in the bone marrow

17. Peripheral Tolerance Regulates Autoreactive Cells in the Circulation lymphocytes with specificity for self antigens are not uncommon in the periphery. Two factors contribute to this: (1) not all self antigens are expressed in the central lymphoid organs where negative selection occurs, and (2) there is a threshold requirement for affinity to self antigens before clonal deletion is triggered, allowing some weakly self-reactive clones to survive the weeding-out process.

18. Anergy T cells to become activated, the TCR must bind antigen presented by self-MHC (major histocompatibility complex molecules) (signal 1), while at the same time the T cell must undergo costimulatory engagement (signal 2). Early experiments by Marc Jenkins and colleagues showed that when CD4 T-cell clones are stimulated in vitro through the TCR alone, without costimulation , they become anergic.

19. CTLA-4. Subsequent data showed that the interaction between CD28 on the T cell and CD80/86 (B7) on the APC provided the costimulatory signal required for T-cell activation. Th is led to a careful examination of costimulation , revealing the existence of other molecules that could bind to CD80/86 and the discovery of a related molecule, called CTLA-4. Th is molecule inhibits rather than stimulates T-cell activation upon binding CD80/86.

20. Many such molecules deliver supplementary signals during T-cell activation, and the group of molecules that regulate T-cell behavior are now oft en referred to as immunomodulatory, to cover both costimulatory and inhibitory behavior. CTLA-4 expression is induced only after T cells are activated, providing a mechanism to dampen T-cell activity and regulate the immune response. Mice lacking CTLA-4 display massive proliferation of lymphocytes and widespread autoimmune disease, suggesting an essential role for this molecule in maintaining peripheral tolerance

21. Peripheral tolerance in B cells For instance, experiments with transgenic mice have demonstrated that when mature B cells encounter most soluble antigens in the absence of T-cell help, they become anergic and never migrate to germinal centers. In this way, maintenance of T-cell tolerance to self antigens enforces B-cell tolerance to the same antigens.

22. T REG cells Acting in secondary lymphoid tissues and at sites of infl ammation , T REG cells recognize specific self antigens, and sometimes foreign antigens, via TCR interactions. However, they down-regulate immune processes when they engage with these antigens in the periphery. These cells can be generated both naturally, in the thymus ( nTREG ), and after induction by antigen in the periphery ( iTREG cells;).

23. In fact, many of the circulating T cells with specifi city for self antigens may be such regulatory cells. Some scientists postulate a division of labor, with nTREG cells specializing in regulating responses against self antigen to inhibit autoimmune disease iTREG cells controlling reactions against benign foreign antigens at mucosal surfaces, where the immune system comes in constant contact with the outside world (e.g., gut commensals or respiratory allergens).

24. Regulatory CD4 T Cells TREG cells were most recently characterized as a unique subset of CD4 T cells that express high levels of the IL-2R chain (CD25), the low- affi nity receptor for this cytokine. Naturally occurring nTREG cells arise from a subset of T cells expressing receptors with intermediate affi nity for self antigens in the thymus Certain of these cells develop into cells that migrate out of the thymus and are capable of suppressing reactions to self antigens.

25. CD4 TREG cells have also been found to suppress responses to some nonself antigens. For example, these cells may control allergic responses against innocuous environmental substances and/or responses to the commensal microbes that make up the normal gut flora