1. Tolerance
Ray Owens in 1945 showed that dizygotic cattle twins, which shared a common vascular system in utero, were mutually tolerant of skin grafts from one another as adults.
Peter Medawar and Co-workers showed that adult mice of strain A rejected skin grafts from mice of strain B that differed in expression of MHC molecules.
However if mice of strain A were injected within 24 h of birth with spleen cells from strain B, they would not reject skin grafts from the donor B strain when they grew to adulthood. This phenomenon is known as neonatal tolerance.

2. The basis for neonatal tolerance is that the recipient mouse would become chimeric(cells from genetically different individuals coexist in one body) with T cells and APCs derived from both the host and the donor spleen.
Mature T cells would become tolerant to the MHC antigens of the donor cells because the developing T cells in these mice would be negatively selected on APCs from the donor cells.

3. Central Tolerance
Tolerance is defined as a state of unresponsiveness to antigen.
It occurs when the interaction of an antigen with antigen-specific lymphocytes results in signals that either do not activate or inactivate the cell.
Only cells with antigen-specific receptors "lymphocytes" can be tolerized.
Tolerance induced during the early stages of lymphocyte development is referred to as Central tolerance, whereas tolerance induced in mature lymphocytes is referred to as Peripheral tolerance.
Central tolerance occurs in the primary lymphoid organs.

4. Mechanisms for maintaining self Tolerance
Anergy
Receptor editing
Deletion
Clonal ignorance

6. Anergy
Anergy is defined as the functional inactivation of a cell, resulting in nonresponsiveness upon contact with self antigen.
B cells cannot differentiate into antibody-secreting cells.
T cells do not proliferate and unable to produce cytokines.
B cells specific for T-dependent antigens require two signals to be activated; antigen provides the first signal, while T cell provides the second signal. In the absence of the second signal, B cells would be rendered unresponsive.
The second signal is provided by CD40L on T cell with CD40 on B cell.

7. T cells also require two signals to be activated, signal one is provided by MHC-peptide complex, second signal is provided by an interaction between costimulatory molecules on APCs "B-7" and their ligand on T cells "CD28".
Delivery of the first signal leads to the induction of several transcription factors e.g the one which binds the promoter of IL-2 gene, allowing its transcription.
If the first signal "MHC-peptide complex" is not accompanied by the costimulatory B7-CD28 interaction, IL-2 mRNA is rapidly degraded and IL-2 protein is not made. Thus T cell is anergized.

10. Receptor editing
B cell can undergo a second rearrangement of its L chain variable gene segments, after it has formed a recombined VJ unit. Unrearranged elements "e.g V1 and J5" and be used in a second rearrangement. Thus the diversity is increased [altering "editing" the receptor specificity] it may lead to BCR that often lacks autoreactivity.
Receptor editing has been observed at the V locus of double positive T cells undergoing negative selection in the thymus.

11. Deletion
Autoreactive B and T cells are eliminated.
Apoptosis is the basis for much of the negative selection of developing T and B cells in the thymus and bone marrow, respectively.
Double positive T cells that bind with high affinity to antigens plus MHC in the thymus have been shown to undergo rapid deletion. Likewise, immature B cells that bind with strong affinity to self antigen in the bone marrow undergo deletion.

12. Clonal ignorance
It refers to a state whereby autoreactive lymphocytes are neither anergized, deleted, nor receptor edited. Instead, they co-exist with antigen and remain in an unactivated state because of their weak affinity for the autoantigen or a low concentration of autoantigen.
Clonally ignorant cells can be activated under certain conditions; therefore, their presence poses a potential threat to the host.
If B cells with a low affinity for a self antigen undergo somatic mutation and acquire a higher affinity for self antigen, they can subsequently be activated by the self antigen.
In addition, clonally ignorant T cells exposed to a low level of self peptide can be activated if the concentration of the self peptide is increased.

13. Peripheral Tolerance
Occasionally autoreactive B and T cells escape negative selection and enter the periphery. In addition, B cells undergo somatic mutation in the periphery and sometimes the mutations result in the acquisition of autoreactive specificities.
Therefore, peripheral tolerance has evolved as a safety net to catch autoreactive B and T cells that escape to or arise in the periphery.
Mechanisms of peripheral tolerance include T cell anergy, deletion, activation-induced cell death and the induction of regulatory T cells.

14. T cell anergy is believed to be a major mechanism for inducing unresponsiveness to self antigen that is encountered in the periphery.
Cells from pancreas, kidney, liver, and other organs do not normally express costimulatory molecules. Thus antigens presented by these cells are likely to induce anergy.
B cells encountering antigen in the periphery but lacking T cell help will undergo anergy induction. Deletion also occurs in the periphery.

15. Fas-Fas L Interactions
Fas-mediated apoptosis is thought to play critical role in the removal of mature autoreactive B and T lymphocytes.
Fas is a monomer expressed by activated lymphocytes and is a member of TNF family.
The ligation of Fas by Fas ligand "Fas L", delivers an apoptotic signal to the cell expressing Fas.

16. Fas L is expressed by several cell types, including activated T cells and certain epithelial cells. Fas L is a trimer, when it binds to Fas, it causes it to trimerize. This then activates a "death" domain in Fas that interacts with the death domains of several cytosolic adaptor proteins, the major one being Fas-associated death domain "FADD". This then triggers the activation of a series of cysteine proteases known as caspases resulting in apoptosis of the cell (Fig P 169 coico).
People with a mutated Fas have an autoimmune condition known as autoimmune lymphoproliferative syndrome "ALPs".
Fas-Fas L mediated apoptosis eliminate T cells in the periphery. It may be involved in mediating negative selection of thymocytes. Anergized B cells are also susceptible to Fas-mediated apoptosis.

18. Regulatory / Suppressor T cells
There is a population of CD4+ T cells which have the ability to downregulate T cell function.
These cells (T reg) express CD25, IL-2 receptor  chain.
CD4+CD25+ suppressor T cells constitute 10% of peripheral CD4+ cells.
Mice depleted of CD4+CD25+ T suppressor cells developed autoimmune diseases such as thyroiditis, gastritis, insulitis and glomerulonephritis.
T suppressor cells suppresses graft versus host disease induced by CD4+CD25– T cells.

19. CD4+CD25+ T suppressor cells produce either no or very low levels of IL-2. some may produce the immunosuppressive cytokine TGF.
They express the chemokine receptors CCR4 and CCR8 which aid in their migration to inflamed organs and draining lymph nodes.
Their suppressive action is antigen-nonspecific and requires contact with responder T cells. They inhibit the proliferation and activation of CD4+ and CD8+ T cells and prevent the transcription of IL-2 in these responder T cells.
Two other types of T cells that have suppressive activity have been identified within the CD4+ T cell subset:
Type 1 regulatory cells Tr1
TH3 cells.
Tr1 produce high levels of IL-10 and TGF- and mediate suppression via these cytokines, they produce little or no IL-2 and IL-4.

20. It is suggested that interaction of CD80 and CD86 on APCwith CTLA-4 on Treg cells delivers a costimulatory signal to the Treg that induces their suppressive activity (fig.12.4). Lymphocyte activation gene3(LAG3), a CD4-associated adhesion molecule that binds MHC class II molecules, is expressed on the surface of Treg cells. IL-10 and TGF-β are needed for Treg suppression.
TH3 cells have been identified in oral tolerance studies, they produce TGF- and mediate suppression via secretion of this cytokine.

22. 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.
Oral tolerance is first initiated when orally administered antigen encounters GALT.

23. 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.
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.

24. Immune Privilege
There are several sites in the body that do not develop immune responses to pathogens, tumor cells, and histocompatible tissue transplants.
These sites known as immune privileged sites, include the eye, testis, brain, ovary and placenta.
Corneal transplants do not require tissue matching or immuno-suppressive therapy.

25. Immunosuppressive cytokines and the expression of Fas L, play a predominant role in establishing immune privilege.
Interaction of Fas L with Fas on T cells leads to their apoptosis.
Human retinal pigment epithelial cells and corneal endothelial cells have been observed to express Fas L and to induce apoptosis of inflammatory T cells.