To what extent can autoimmunity be described as the breakdown of self tolerance and how far have animal models contributed to our understanding of human autoimmune disease?

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Felicity J Walker-Buckton        

Magdalen College                

To what extent can autoimmunity be described as the breakdown of self tolerance and how far have animal models contributed to our understanding of human autoimmune disease?


Autoimmunity is the propagation of adaptive immunity specific for self antigens.  The obligation of preventing such an occurrence was recognised by Ehrlich who described the possibility of ‘Horror autotoxicus’.  In his ‘clonal selection’ theory, Burnet proposed that tolerance to self antigens is achieved by clonal deletion or inactivation of developing lymphocytes in the thymus or the periphery.  In the present day it is realised that this self/non-self reductionism is insufficient to explain a number of characteristics of the immune system; firstly, the content of self changes in host life, for example the production of sperm at puberty in males; secondly, most of self antigens, e.g. heat shock proteins are not absolutely different from non-self structures; thirdly, recognition of self is indeed required for the continued survival of mature lymphocytes; fourthly, antigenic recognition by MHC is promiscuous and imprecise and finally (and perhaps most convincingly); autoreactive T and B cells are present even in healthy individuals.  These considerations indicate that antigens (Ag) can reside in a ‘no mans land’ of the immune system in which they do not induce self tolerance and yet do not activate the immune response; they invoke a state of immunological ignorance and retain the potential to activate immune responses.  Hence autoimmunity is unlikely to reflect a general failure of the main mechanisms of tolerance (clonal deletion and inactivation), instead reflecting awakened awareness of these antigens by the immune system.

The positive selection of thymocytes by low affinity self peptide

The process of positive selection in the thymus encourages survival of T cells whose TCRs have high affinity for a MHC bound epitope of foreign origin.  In addition, epitopes that are truly immunodominant are tolerogenic (e.g. HEL and HBV responses in transgenic mice) encouraging deletion of any potentially self reactive cells.  This therefore promotes epitopes of low affinity to a position of immunodominance.  Positive selection of thymocytes can thus occur through interactions with self epitopes that have such low affinity for the TCR that they do not trigger deletion.  In the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), the immunodominant epitope AC1-9 of myelin basic protein (MBP) shows an association with I-Au that is so transient that the half life of the interaction is not measurable in vitro.  Administration of high levels of AC1 MBP to transgenic encephalitogenic TCR mice has no impact on repertoire selection in the thymus, i.e. there is no clonal deletion of potentially autoreactive cells as the association between the epitope and the TCR is of such a low affinity.  The immune system is essentially ignorant of the self reactive nature of such cells, and hence when the epitope appears to the immune system with a background of inflammation or ‘Danger’ (e.g. in a mix of Freund’s adjuvant) a full immune response is mounted against self.

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It is also possible that the TCR may retain a residual specificity for the self peptide on which it was positively selected.  Marrack et al demonstrated vestigial reactivity among mature T cells to the ligand presented on the original selecting thymic epithelial cells, which leads to the question as to whether certain low affinity self peptides that contribute to positive selection act as potential targets during subsequent autoimmune disease.  

In these ways, autoimmunity may be better described as a ‘side-step’ of self tolerance rather than a complete breakdown:  it is necessary that self antigen is used to ...

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