The Clonal Selection Paradigm

According to the classic formulation of the clonal selection theory (2), the essence of the immune system and its distinctive feature is its repertoire of antigen receptors. These receptors, which include the T- and B-cell antigen receptors and the antibodies, are produced by somatic genetic recombinations and mutations (3) and so are created anew in each individual. The selective force that determines the frequencies of the various receptors in the repertoire is exerted by the antigens that happen to activate clones of receptor-bearing cells in the individual. The dominant specificities of the receptor repertoire are the products of cell selection by antigens, a selection that takes place in the individual and not in the germ-line of the species where Darwinian selection usually proceeds. Thus, the elaboration of the receptor repertoire, according to classic clonal selection, reflects the immune history of the individual rather than that of the species.

The classic clonal selection theory proposed that tolerance to self-antigens required that the repertoire be purged of all cells bearing receptors capable of recognizing self-molecules (4). The recent demonstration of negative selection in the thymus is seen as the modern vindication of the classic notion of clonal deletion of anti-self reactivity as the cornerstone of self-tolerance (5). Thus, the potentially open-ended receptor repertoire of the immune system is hedged by a developmental bias against autoimmunity. But the bias against self-recogni-tion does not weaken the classic view that the structure of the immune system is in the hands of the arrant antigens that select those clones of lymphocytes bearing complementary receptors. The fundamental view of the clonal selection paradigm is that the immune response is regulated by two factors: the concentration of available antigen and the concentration of lymphocytes with specific receptors.

A. The Clonal Selection View of Autoimmunity

The concept of positive selection of particular lymphocyte clones by the foreign antigens and the negative selection by the self-antigens has fostered a number of derivative ideas about autoimmunity and autoimmune diseases:

1. The healthy immune system, by definition, can have no autoimmune lymphocytes because autoimmune lymphocytes, by their nature, must cause autoimmune disease.

2. An autoimmune disease expressed against a particular organ should be attributed to a self-antigen specific for that organ; a target antigen expressed in many organs should lead to a disease in each of them.

3. An autoimmune disease can best be terminated by getting rid of the autoimmune lymphocyte clone or by paralyzing or blocking its activity;

the cure of a disease is contingent on the removal of its cause. Therapy should be based on inactivating the autoimmune lymphocytes.

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