| Themes > Science > Life Sciences > General Biology > Immunology > The Immune System & Disease > Tolerance > Peripheral Tolerance |
Because many of the proteins which the body uses are not expressed in thymus or serum, and in some cases not expressed until after the immune system has matured there need to be some mechanisms to prevent autoreactivity of lymphocytes after they have emigrated from the thymus/bone marrow. In fact there are several such mechanisms:
There are a number of factors which affect
which of these mechanisms operates. IgnoranceIt can be shown that there are in fact both T cells and B cells specific for autoantigens present in circulation. In some cases these cells are quite capable of making a response but are unaware of the presence of their autoantigen. This arises for 2 reasons. The first is that the antigen may simply be present in too low concentration. Since all lymphocytes have a threshold for receptor occupancy which is required to trigger a reponse then very low concentrations of antigen (in the case of T cells these are very low, see below) will not be sensed. The second possibility is a more interesting one. Some antigens are sequestered from the immune system in locations which are not freely exposed to surveillance. These are termed immunologically privileged sites. Examples of such sites are the eye, CNS and testis. Split ToleranceThis term simply means that some part of the immune system is tolerant and some other is not. The most frequent situation is that where T cell tolerance has been established but autoreactive B cells are still present. This arises because T and B cells have different thresholds for activation and therefore tolerance. In this situation the B cells are 'helpless'. That is to say, as we have already discussed for most antigens B cells require help from an antigen-specific T cell in order to make a response. Thus autoreactive B cells can be present without being able to become activated provided that there is no T cell help available. If T cell help is provided, for example by injecting the autoantigen chemically coupled to an immunogenic foreign carrier, then these B cells will mount a response. |
| Experiments of this kind
indicate that it takes 100 -1000 × more antigen to tolerise B cells that
T cells. As a result this type of split tolerance situation is reasonably
common for self serum proteins.
Anergy - T cells As mentioned in a previous lecture, naive T cells need co-stimulatory signals to become activated. The expression of these co-stimulatory molecules is restricted so that most tissue cells lack either B7.1/B7.2 or CD40 or both. Such cells also normally lack class II MHC molecules. Thus tissue cells normally present a spectrum of peptides from their endogenously synthesised proteins on self MHC class I in the absence of co-stimulation. Interaction of such cells with autoreactive T cells leads to the T cell becoming refractive to later encounter with the same antigen even when co-stimulation is present. This refractory state is termed anergy.
Anergy - B cellsAs implied from the section on split tolerance, there is a mechanism for tolerising B cells to soluble antigens if they are present at sufficiently high concentration. The general rules for this tolerance mechanism were worked out using mice transgenic for rearranged immunoglobulin molecules and a transgenic soluble protein whose concentration in serum could be regulated. It is apparent that the critical parameter is receptor (surface Ig) occupancy. When more than 5%* of the sIgM molecules are normally occupied by monomeric soluble antigen the B cell becomes anergic. This anergic state can be recognised in the case of B cells by the downregulation of surface IgM. Note the level of surface IgD remains unaffected and the precise explanation for why such B cells are refractory to stimulation even when T cell help is available is not known. Added Value
SuppressionIt is also clear that in some cases there are autoreactive T cells present which are capable of reacting to their cognate antigen as presented within the host [ ie. they are not anergic or ignorant], yet do not express this reactivity in the normal intact animal. These cells appear to be prevented from reacting by the presence of other T cells, a phenomenon which has been termed Dominant Regulation or Suppression. The mechanism is again obscure, but the following experiments make it likely that this form of tolerance is at least as important as anergy. |
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