Tolerance

1.         Self Tolerance

a.            Tolerance is specific immunologic unresponsiveness; i.e. an immune response to a certain antigen does not occur, although the immune system is otherwise functioning normally.

b.         In general, antigens that are present during embryonic life are considered ‘self’ and do not stimulate an immunologic response.

c.            Antigens that are not present during the process of maturation, i.e., that are encountered first when the body is immunologically mature, are considered ‘nonself’ and usually elicit an immunologic response.

d.         There are two types of tolerance:

i.          central tolerance: acquired within the thymus.

ii.            peripheral tolerance: acquired outside the thymus.

2.            Central Tolerance

a.         The main process by which T lymphocytes acquire the ability to distinguish self from nonself occurs in the fetal thymus.

b.         T-cell development involves two types of selection:

i.          positive selection for recognition of self MHC:peptide complexes.

ii.            negative selection for cells bearing receptors for recognition of self peptide:self MHC complexes that would trigger the T cell in the periphery.

c.         The development of T cells:

i.            thymocyte progenitors enter the thymus in the subcapsular region where they express neither CD4 or CD8 receptors.

ii.          the double negative cells proliferate and undergo gene rearrangement to express CD3, CD4 and CD8 receptors on their surface.

iii.         as the cells mature, they move deeper into the thymus where they then become sensitive to peptide:MHC complexes.

iv.         these double-positive cells are found in the thymic cortex where they undergo positive selection and negative selection.

d.         Avidity model:

i.            thymocytes encounter self-MHC:self-peptide complexes on thymic epithelial cells that have different effects depending upon the specificity of the T-cell receptor.

ii.          for some receptors, no self peptide bound to self-MHC molecules will signal at all and cells with these receptors undergo apoptosis.

iii.         for other receptors, a self peptide bound by self-MHC acts as an agonist, triggering apoptosis.

iv.         some cells, bear receptors that are partially signaled by self peptides bound to self-MHC molecules and are rescued by positive selection from apoptosis.

3.            Peripheral Tolerance

a.            Immunologically privileged site:

i.          antigens from these sites do not elicit destructive responses.

ii.            extracellular fluid in these sites do not pass through lymphatics.

iii.            cytokines produced in these sites leave them together with antigens induces T-cell responses that do not damage tissues.

iv.         these tissues such as brain, eye, testis, uterus, may express high levels of Fas ligands which protects the tissue from attack by T cells through ligation of Fas.

b.            However, damage to an immunologically privileged site can induce an autoimmune response.

c.            Systemic ophthalmia:

i.          trauma to one eye releases the sequestered eye antigens into the surrounding tissues, making them accessible to T cells.

ii.          the effector cells elicited attack the traumatized eye, and also infiltrate and attack the healthy eye.

iii.         thus, although the sequestered antigen do not induce a response by themselves, if a response is induced elsewhere they can serve as targets for attack.

d.         Co-stimulatory signals:

i.          T cells require co-stimulatory signals besides antigen binding for activation and clonal expansion.

ii.          one co-stimulatory molecule on antigen-presenting cells are the glycoproteins B7, which bind to CD28 on T cells.

iii.         normal cells lack these co-stimulatory molecules on their surface and therefore do not elicit an immune response.

e.         Anergy:

i.          antigen recognition and binding in the absence of co-stimulation inactivates naive T cells, inducing a state known as anergy.

ii.          this leads to the inability to produce IL-2.

iii.         T cells are prevented from proliferating and differentiating into effector cells when they encounter antigen, even if the antigen is subsequently presented by antigen-presenting cells.

iv.         this helps ensure tolerance of T cells to self-tissue antigens.

f.          Immune suppression:

i.          some activated T cells secrete TGF-b and IL-10.

ii.          TGF-b inhibits TH1 T-cell responses.

iii.         IL-10 acts on the antigen-presenting cell, causing the preferential induction of TH2 cells.

g.            Breaking Tolerance:

h.            Whether an antigen will induce tolerance or immunologic response depends on:

i.            immnologic memory of host: neonatals are immunologically immature and do not respond to foreign antigens.

ii.          the structure and dose of the antigen: a simple molecule induces tolerance more readily than a complex one, and very high or low doses of antigen may result in tolerance instead of an immune response.

I.          Other aspects of the induction or maintenance of tolerance are as follows:

i.          T cells become tolerant more readily and remain tolerant longer than B cells.

ii.            administration of a cross-reacting antigen tends to terminate tolerance.

iii.            administration of immunosuppressive drugs enhances tolerance, e.g. in transplants.

iv.            tolerance is maintained best if the antigen continues to be present.