The stochastic approach to disease

Abstract

In 1957-8 I was already deeply interested in what was coming to be called auto-immune disease and it became immediately obvious that if a clonal selection theory of immunity was to be accepted it must be applicable, with appropriate modifications, to pathological manifestations of immunity as well. The concept of the ‘forbidden clone’ emerged almost at once and I have seen no reason to withdraw the phrase or the idea since. It is a concept which can accept infinite elaboration to fit specific instances but yet remain basically very simple. In essence, a forbidden clone arises from a stem cell line in which two types of genetic individuality develop in the course of differentiation and somatic mutation. One is concerned with the nature of the ‘immune receptor’. It must allow the immunologically reactive cell (immunocyte) to react specifically with some accessible component of the body acting as an antigenic determinant. The second is a genetic anomaly that makes the cell more resistant than normal to the processes which should result in the elimination of such autoreactive cells from the body. Instead, when conditions are appropriate, it is stimulated to proliferate to form a forbidden clone with potentially pathogenic effect.