Tolerance

Tolerance it’s a state of immunonologic unresponsiveness to Ags, ie an immune response to a certain Ag (or epitope) does not occur, although the immune system is otherwise functioning normally. This state of unresponsiveness can involve T- or B- cells at any stage of maturation. Tolerance mediated by a different mechanisms like: 1-clonal abortion: which occur when immature B orT cells exposed to a low concentration of the Ag, thus the maturation of that cell is arrested.   2-Clonal deletion: is removal of autoreactive T or B cells by induction of apoptosis (programmed cell death).

Tolerance   3-Clonal anergy (functional deletion): it’s a functional inactivation due to inappropriate presentation of Ag to T-cell by APC and failure of signal transduction due to failure of costimulatory signals. Or due to deprivation of B-cell from the T-helper help, when B-cell exposed to T-dependent Ag, thus T-cell cannot mature. 4-Clonal exhausion: repeated exposure of T- or B- cells to T-dependent or T-independent Ag respectively, all mature T- or B-cells expressing the receptor for that Ag removed.

Tolerance T-cells tolerance occur by clonal abortion, clonal deletion, clonal anergy, clonal exhusion in addition to Ts-cell suppression. T-cell become tolerant more readily, remain tolerant longer than B-cells and required less level of Ags than B-cells. B-cells tolerance occur by clonal abortion, clonal deletion, clonal anergy, clonal exhusion in addition to AFC-blocked (when excess Ag bind to all the receptors and Igs secretion is inhibited). B-cell required 100-1000 folds higher level of Ag than that require for T-cell tolerance and B-cell tolerance is less complete than T-cell tolerance. * Tolerance is maintained best if the Ag (to which the immune system is tolerant) continues to be present.

Self antigens Ags that are present during emberyonic life consider ‘self’ and do not stimulate immune responses, whereas, self Ag which not present during the emberyonic life consider ‘foreign’ and stimulate immune response such Ags (sperm, CNS, the lenes and uveal tract of the eye) which known as “immunologically privileged sites” and when such Ags enter the circulation accidentally, for instance after damage or trauma, they elicit both humoral and cellular responses.

Tolerance to self antigens The state of unresponsiveness to self Ags is the result of both central and peripheral tolerance: a- Central tolerance: it’s a clonal deletion of autoreactive T or B cells which occur in central immune system (thymus or bone marrow) by the negative selection (which involves the killing of T- or B- cells that react with self-Ag by apoptosis).

:  All the cells of immune system were arise from pluripotent stem cells in the bone marrow which in turn give raise into two stem cell lineage lymphoid and myeloid lineage , the primitive T-cells arise from lymphoid lineage these cells are double negative cells (they carry neither CD4 nor CD8) these cells inter thymus gland at its medullary-cortex junction in the cortex they develop to a double positive cells (they express in their surface CD4, CD8, CD3 and TCR)

these double positive thymocytes under pass through two checkpoint to survive, these are the positive selection where Thymic epithelial “nurse” cell (thymic stroma cell) functions as ( APC) expresses class I & II MHC molecules and presents self-peptides to DOUBLE POSITIVE T CELLS those cells with a TCR can interact with MHC + self-peptide Lives (T cell is “saved”) while T CELLS DID NOT INTERACT With MHC+SELF-PEPTIDE die via apoptosis.

:   The next checkpoint is the negative selection in which Dendritic cells & macrophages at the corticomedullary junction are: APCs express class I & II MHC molecules present self-peptides to DOUBLE POSITIVE T CELLS - that were “positively selected” ( live) by interaction with MHC + self-peptide and the T CELLS THAT BIND TOO TIGHTLY: DIE (via apoptosis).   Thus, Only 5-10% of maturing lymphocytes survive and eventually leave the thymus and about 90-95% of all thymocytes die in the thymus.

T cell development involves positive and negative selection and lineage commitment

T-cells tolerance: b- Peripheral tolerance: it’s a clonal anergy of autoreactive T or B-cells which escape negative selection and involve functional inactivation of the surviving autoreactive cells by inappropriate presentation of Ag and failure of costimulatory signals in T-cells or by lack of the Th-help in case of B-cells. Thus, effector cells of autoimmunity are present in normal individual but in anergic state. If autoreactive T cells enter the circulation, there are several mechanisms that can prevent an autoimmune reaction.  :

Intra cellular component of the cells were protected from exposure to immune system by the anatomical barrier. CD4+CD25+ immunoregulatory T Cells Suppress Polyclonal T Cell activation In Vitro by Inhibiting Interleukin 2 Production and by CTLA-4 which is expressed constitutively on these cells.

In certain privilige site CD95 ligand(Fas-L) were expressed constitutively expressed, so when activated T-cell reach these area they were die by apoptosis.

B-cells tolerance •CENTRAL : by Clonal deletion of autoreactive B cells in the bone marrow, spleen & lymph nodes. •PERIPHERAL B-cells tolerance Lack of help from T cells is the predominant factor.  

Under certain circumstances tolerance may be lost and immune reaction to host Ags may develop result in autoimmunity. Its important, however to differentiate between autimmune phenomena and autoimmune diseases. Autoimmune phenomena may develop in a varity of diseases while having little to do with the pathogenesis of the disease. Diseases causing injury or death of tissue may cause the release of immunogenic tissue Ags that had been sequestered and hidden from the immune system. In myocardial infarction, for example, the immune response, including the Abs produced, is incidental and has little to do with the myocardial pathology resulting from coronary occlusion.