1. Tolerance

2. Introduction
Immunologic tolerance is defined as unresponsiveness to an antigen that is induced by previous exposure to that antigen.
The term arose from the experimental observation that animals that had encountered an antigen under particular conditions would not respond to, i.e., would tolerate, subsequent exposures to the same antigen.
When specific lymphocytes encounter antigens, the lymphocytes may be activated, leading to immune responses, or the cells may be inactivated or eliminated, leading to tolerance.

3. Introduction
The same antigen may induce an immune response or tolerance, depending on the conditions of exposure and the presence or absence of other concomitant stimuli such as costimulators.
Antigens that induce tolerance are called tolerogens, or tolerogenic antigens.
Tolerance to self antigens, also called self-tolerance, is a fundamental property of the normal immune system,

4. Introduction
The mechanisms of tolerance eliminate and inactivate lymphocytes that express high-affinity receptors for self antigens.
Tolerance is antigen specific, resulting from the recognition of antigens by individual clones of lymphocytes.
Self-tolerance may be induced in immature self-reactive lymphocytes in the generative lymphoid organs (central tolerance) or in mature lymphocytes in peripheral sites (peripheral tolerance)

5. Introduction
Central tolerance occurs during a stage in the maturation of lymphocytes when an encounter with antigen may lead to cell death or replacement of a self-reactive antigen receptor with one that is not self-reactive.
Mature lymphocytes that recognize self antigens in peripheral tissues become incapable of activation by re-exposure to that antigen or die by apoptosis.

6. Introduction
Peripheral tolerance is also maintained by regulatory T cells (Tregs) that actively suppress the activation of lymphocytes specific for self and other antigens.
Some self antigens are sequestered from the immune system by anatomic barriers, such as in the testes and eyes, and other antigens are ignored.
The induction of immunologic tolerance is a possible therapeutic strategy for preventing harmful immune responses.

8. T LYMPHOCYTE TOLERANCE

9. Central T Cell Tolerance
During their maturation in the thymus, many immature T cells that recognize antigens with high avidity die (deletion, or negative selection), and some of the surviving cells in the CD4+ lineage develop into Tregs.

10. Central T Cell Tolerance
The two main factors that determine if a particular self antigen will induce negative selection of self-reactive thymocytes:
The presence of that antigen in the thymus, by local expression or delivery by the blood
The affinity of the thymocyte T cell receptors (TCRs) that recognize the antigen.

11. The thymus also has a special mechanism for expressing many protein antigens that are expressed in different peripheral tissues (which reach to medulla from circulation), so that immature T cells specific for these antigens can be deleted from the developing T cell repertoire.
These peripheral tissue antigens are produced in medullary thymic epithelial cells (MTECs) under the control of the autoimmune regulator (AIRE) protein.
Mutations in the AIRE gene are the cause of a multiorgan autoimmune disease called autoimmune polyendocrine syndrome type 1 (APS1).

13. Peripheral T Cell Tolerance
The mechanisms of peripheral tolerance are:
Anergy (functional unresponsiveness)
Suppression by Tregs
Deletion (cell death)

15. 1) Anergy
Exposure of mature CD4+ T cells to an antigen in the absence of costimulation or innate immunity may make the cells incapable of responding to that antigen.
the concept that full activation of T cells requires the recognition of the antigen by the TCR (which provides signal 1) and recognition of costimulators, mainly B7-1 and B7-2, by CD28 (signal 2). Prolonged signal 1 (i.e., antigen recognition) alone may lead to anergy.

16. Several mechanisms may function to induce and maintain the anergic state:
TCR-induced signal transduction is blocked in anergic cells; Due to decreased TCR expression (perhaps because of increased degradation) and recruitment to the TCR complex of inhibitory molecules such as tyrosine phosphatases.
Self antigen recognition may activate cellular ubiquitin ligases, which ubiquitinate TCR-associated proteins and target them for proteolytic degradation in proteasomes or lysosomes. The net result is loss of these signaling molecules and defective T cell activation.

17. When T cells recognize self antigens, they may engage inhibitory receptors of the CD28 family, whose function is to terminate T cell responses; like:
CTLA-4
PD-1

19. CTLA-4 CTLA-4 inhibits T cell activation in two different ways:
In the cell-intrinsic mechanism, upon activation, the responding T cells begin to express CTLA-4, and it shuts off further activation, thus terminating the response.
In a cell-extrinsic pathway, Tregs express high levels of CTLA-4 and use it to prevent the activation of responding cells.
CTLA-4 functions as a competitive inhibitor of CD28 and reduces the availability of B7 for the CD28 receptor

23. PD-1
Another inhibitory receptor of the CD28 family is PD-1 (programmed death-1, so called because it was originally believed to be involved in programmed cell death, but now is known not to have a role in T cell apoptosis).
PD-1 recognizes two ligands, called PD-L1 and PD-L2; PD-L1 is expressed on APCs and many other tissue cells, and PD-L2 is expressed mainly on APCs. The receptor PD-1 is expressed on antigen-activated T cells.

24. PD-1
Engagement of PD-1 by either of its ligands leads to the recruitment of phosphatases to the cytoplasmic tail of PD-1. These enzymes counteract kinase-induced signaling and inhibit signals from the TCR-coreceptor complex and from CD28 and other costimulatory receptors, resulting in inactivation of the T cells.

26. 2018 Nobel prize winner in medicine
Thomas Perlmann targeted CTLA-4 receptor and PD-1 using antibodies to disable their function.
These antibodies eliminate the borders against full T cells activation and used for cancer therapy.

27. 2) Suppression by Tregs
Regulatory T cells are a subset of CD4+ T cells whose function is to suppress immune responses and maintain self-tolerance.
Most of these CD4+ Tregs express high levels of the interleukin-2 (IL-2) receptor α chain (CD25) and the transcription factor called FoxP3.
FoxP3 is a member of the forkhead family of transcription factors and is critical for the development and function of most Tregs.

29. Phenotypic Markers of Ttregs
Although numerous T cell populations have been described as possessing suppressive activity, the cell type whose regulatory role is best established is CD4+ FoxP3+ CD25high.
FoxP3 and CD25 are essential for the generation, maintenance, and function of these cells.
These cells usually express low levels of the receptor for IL-7 (CD127), and as predicted from this pattern of receptor expression, they use IL-2 but not IL-7 as their growth and survival factor.
FoxP3+ Tregs typically express high levels of CTLA-4, which is also required for their function.

30. Generation and Maintenance of Tregs
Tregs are generated mainly by self antigen recognition in the thymus and by recognition of self and foreign antigens in peripheral lymphoid organs.
The generation of some Tregs requires the cytokine transforming growth factor (TGF)-β.
The survival and functional competence of Tregs are dependent on the cytokine IL-2.
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31. Mechanisms of Action of Tregs
Production of the immunosuppressive cytokines IL-10 and TGF-β.
Reduced ability of APCs to stimulate T cells. The proposed mechanism of this action is the binding of CTLA-4 on the Tregs to B7 molecules on APCs, resulting in competitive inhibition of CD28-mediated costimulation.
Consumption of IL-2. Because of the high level of expression of the IL-2 receptor, these cells may absorb IL-2 and deprive other cell populations of this growth factor, resulting in reduced proliferation and differentiation of other IL-2–dependent cells.
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33. Inhibitory Cytokines Produced by Tregs (TGF-β)
TGF-β functions:
TGF-β inhibits the proliferation and effector functions of T cells and the activation of macrophages.
TGF-β regulates the differentiation of functionally distinct subsets of T cells.
TGF-β stimulates production of immunoglobulin A (IgA) antibodies by inducing B cells to switch to this Isotype
TGF-β promotes tissue repair after local immune and inflammatory reactions subside.

34. Inhibitory Cytokines Produced by Tregs (IL-10)
IL-10 functions:
IL-10 inhibits the production of IL-12 by activated dendritic cells and macrophages.
IL-10 inhibits the expression of costimulators and class II MHC molecules on dendritic cells and macrophages.

35. 3) Deletion of T Cells by Apoptotic Cell Death
intrinsic (mitochondrial) pathway.
Extrinsic (death receptor) pathway.

38. B LYMPHOCYTE TOLERANCE

39. Central B Cell Tolerance
Tolerance in B lymphocytes is necessary for maintaining unresponsiveness to thymus-independent self antigens, such as polysaccharides and lipids. B cell tolerance also plays a role in preventing antibody responses to protein antigens. There are three mechanisms involved in central B cell tolerance:
Receptor editing
Deletion
Anergy

40. Receptor editing:
If immature B cells recognize self antigens that are present at high concentration in the bone marrow, and especially if the antigen is displayed in multivalent form (e.g., on cell surfaces), many antigen receptors on each B cell are cross-linked, thus delivering strong signals to the cells.
One consequence of such signaling is that the B cells reactivate their RAG1 and RAG2 genes and initiate a new round of VJ recombination in the Ig κ light chain gene locus

41. A Vκ segment upstream of the already rearranged VκJκ unit is joined to a downstream Jκ.
As a result, the previously rearranged VκJκ exon in the self-reactive immature B cell is deleted, and a new Ig light chain is expressed, thus creating a B cell receptor (BCR) with a new specificity.

42. If the edited light chain rearrangement is nonproductive, additional Vκ-to-Jκ rearrangements will be made in the same locus, and if these fail, the process may proceed at the κ locus on the other chromosome, and if that is nonproductive, rearrangements at the λ light chain loci may follow.

43. A B cell expressing a λ light chain is frequently a cell that has undergone receptor editing.
It is estimated that among peripheral blood B cells in humans, as many as one-quarter to one-half of all the cells, and the majority of λ-expressing cells, may have undergone receptor editing during their maturation.

44. Deletion
If editing fails, the immature B cells may die by apoptosis. The mechanisms of deletion are not well defined.
3. Anergy
If developing B cells recognize self antigens weakly (e.g., if the antigen is soluble and does not cross-link many antigen receptors or if the BCRs recognize the antigen with low affinity), the cells become functionally unresponsive (anergic) and exit the bone marrow in this unresponsive state.

46. Peripheral B Cell Tolerance
Anergy and deletion
Some self-reactive B cells that are repeatedly stimulated by self antigens become unresponsive to further activation.
Anergic B cells require higher than normal levels of the growth factor BAFF (B-cell activating factor, also called BLys [B lymphocyte stimulator]) for survival, and they cannot compete with normal naive B cells for BAFF.

47. Peripheral B Cell Tolerance
As a result, the B cells that have encountered self antigens have a shortened life span and are eliminated more rapidly than cells that have not recognized self antigens.
B cells that bind with high avidity to self antigens in the periphery may also undergo apoptotic death by the mitochondrial pathway.

48. Peripheral B Cell Tolerance
Signaling by inhibitory receptors.
B cells that recognize self antigens may be prevented from responding by the engagement of various inhibitory receptors.
The function of these inhibitory receptors is to set a threshold for B cell activation, which allows responses to foreign antigens because these typically elicit strong signals from the combination of BCR, coreceptors, innate immune receptors, and helper T cells (for protein antigens), but does not allow responses to self antigens, which engage only the BCR.

49. Peripheral B Cell Tolerance
Signaling by inhibitory receptors.
B cells that recognize self antigens may be prevented from responding by the engagement of various inhibitory receptors.
The function of these inhibitory receptors is to set a threshold for B cell activation, which allows responses to foreign antigens because these typically elicit strong signals from the combination of BCR, coreceptors, innate immune receptors, and helper T cells (for protein antigens), but does not allow responses to self antigens, which engage only the BCR.

51. IMMUNE-PRIVILEGED TISSUES

52. Introducrion
Immune responses and associated inflammation in certain parts of the body, including brain, eye, testes, placenta, and fetus, carry a high risk of lethal organ dysfunction or reproductive failure.
These tissues, which have evolved to be protected, to a variable degree, from immune responses, are called immune-privileged sites.

53. The Eyes
Anatomic features of the anterior chamber that contribute to immune privilege include:
The tight junctions of the epithelial layer
Resistance to leakiness of blood vessels in the tissues adjacent to the anterior chamber (the so-called blood-eye barrier)
The avascular nature of the cornea
The absence of lymphatics draining the anterior

54. The Eyes
There are several soluble factors with immunosuppressive and anti-inflammatory properties in the aqueous humor that fills the anterior chamber, including neuropeptides (α−melanocyte– stimulating hormone, vasointestinal peptide, somatostatin), TGF-β, and indolamine 2,3-dioxygenase (IDO).
Cells lining the anterior chamber, including the epithelium of the iris and the endothelium, constitutively express Fas ligand and PD-L1, which can induce death or inactivation of T cells, respectively.

55. The Brain
Anatomic features of the brain that impair initiation of adaptive immunity to antigens include a scarcity of DCs, and the nature of the tight junctions between brain microvascular endothelial cells (the so-called blood-brain barrier), which impair delivery of immune cells and inflammatory mediators into the brain.
Some of the mechanisms operative in the eye may also apply to the brain, including the action of neuropeptides.

56. The Brain
The brain is rich in resident macrophages, called microglia, which become activated in response to tissue damage or infections in the brain.
The threshold for their activation, however, may be higher than that of macrophages in other tissues.
One putative mechanism for maintaining this high threshold is inhibitory signaling by the CD200 receptor, which is expressed by microglia. CD200 serves as its own ligand and is highly expressed in the brain on neurons and other cell types.

57. The Testis
Immune privilege in the testis serves to limit inflammation that may impair male fertility.
Many self antigens in the adult testis are first expressed at the time of puberty, well after the development of a competent immune system that could generate testis antigen–specific T and B cells.
Therefore, immune privilege in the testis may also serve to prevent autoimmunity.

58. The Testis
The testis, like the eye and brain, has a blood-tissue barrier that limits delivery of cells and molecules to the sites of spermatogenesis. This barrier is formed by Sertoli cells, which line the outer layer of the seminiferous tubules where spermatogenesis takes place.
The hormonal milieu of the testis, which is rich in androgens, has an antiinflammatory influence on macrophages.
TGF-β is produced by Leydig, Sertoli, and peritubular cells and likely contributes to local immune suppression.

59. Mammalian Fetus
In eutherian mammals (mammals with placentae), the fetus expresses paternally inherited genes that are foreign to the mother, but fetuses are not normally rejected by the mother
Several experimental observations indicate that the anatomic location of the fetus is a critical factor in the absence of rejection.
One simple explanation for fetal survival is that trophoblast cells fail to express paternal MHC molecules.

60. Mammalian Fetus Possible tolerance mechanisms:
The uterine decidua may be a site where immune responses are functionally inhibited.
Maternal tolerance of the fetus may be mediated by Tregs.
Immune responses to the fetus may be regulated by local concentrations of tryptophan and its metabolites in the decidua, which inhibit T cell responses.

61. Mammalian Fetus
The enzyme indoleamine 2,3-dioxygenase (IDO) catabolizes tryptophan, generating a byproduct, kynurenine. Tryptophan is required for proliferating cells, including lymphocytes, and kynurenine is toxic to these cells.

62. TOLERANCE INDUCED BY FOREIGN PROTEIN ANTIGENS
Foreign antigens may be administered in ways that preferentially induce tolerance rather than immune responses.
Understanding how to induce tolerance by antigen administration is the key to developing antigen-specific tolerance as a treatment strategy for immunologic diseases.
In general, protein antigens administered subcutaneously or intradermally with adjuvants favor immunity, whereas high doses of antigens administered systemically without adjuvants tend to induce tolerance.

63. TOLERANCE INDUCED BY FOREIGN PROTEIN ANTIGENS
The likely reason for this is that adjuvants stimulate innate immune responses and the expression of costimulators on APCs, and in the absence of these second signals, T cells that recognize the antigen may become anergic or die or may differentiate into regulatory cells.
The oral administration of a protein antigen often leads to suppression of systemic humoral and cell mediated immune responses to immunization with the same antigen. This phenomenon, called oral tolerance.

64. TOLERANCE INDUCED BY FOREIGN PROTEIN ANTIGENS
Some systemic infections (e.g., with viruses) may initiate an immune response, but the response is impaired before the virus is cleared, resulting in a state of persistent infection.
In this situation, virus-specific T cell clones are present but do not respond normally and are unable to eradicate the infection.
This phenomenon has been called clonal exhaustion, implying that the antigen-specific lymphocyte clones make an initial response but then become anergic, or “exhausted.” There is some evidence that clonal exhaustion is due to upregulation of inhibitory receptors such as PD-1 on virus-specific CD8+ T cells.

66. Oral Tolerance

67. Oral Tolerance
Oral tolerance is defined as the lack of a humoral or cellular immune response to ingested food antigens. it is mediated by T cells, and the mechanisms for maintaining it depend on the dose of ingested antigen.
Low dose antigen induces TH3 suppressor T cells, whereas high dose antigen induces T cell anergy or deletion.

68. Oral tolerance is first initiated when orally administered antigen encounters GALT.
Dendritic cells process and present most ingested antigens.
When large dose of food antigen are administered, some food antigens are absorbed intact, the antigen is then processed by APCs in the absence of co-stimulatory interactions which results in unresponsiveness of TH1 cells.

69. Low dose tolerance is induced locally, in the gut-cytokines of GALT contain high levels of IL-4, IL-10, TGF which promote differentiation into TH2 and TH3 and inhibits differentiation into TH1 cells.
TH3 mediate suppression via secretion of TGF.
Triggering TH3 is antigen specific, but their suppression is antigen nonspecific.

70. The End