What Distinguishes Self from Nonself

As a general rule, the immune system does not respond to self, a concept that Ehrlich called 'horror autotoxicus' (reviewed by Silverstein, 1989). What, then, is self? Chemical differences between self and nonself are often extremely subtle. Even though the DNA sequences of different humans are typically 99% identical, grafts between unrelated humans are virtually always rejected by the immune system, because they are recognized as nonself. A single amino acid substitution can often be detected by the immune system. How can the immune system make such fine discrimina-

tion? Perhaps the most useful concept is that self is what is present all the time. Nonself appears sporadically. The most common example of nonself would be a protein that has an amino acid sequence that is different to that encountered in self.

A moment's reflection can tell us that the ability to distinguish between self and nonself is unlikely to be encoded in the germline, but must be learned by the immune system during development. A child inherits half its genes (haplotype) from the mother and half from the father, and is tolerant to the products of both sets of received genes. However, the genes that the child inherits from the father cannot have been preprogrammed to be tolerant to the mother, because the father's genes could not have anticipated who the father would marry. Providing that the union was not incestuous (as in inbred mice), a father will not be tolerant to the mother's antigens, as shown by the fact that skin grafted between the mother and father would always be rejected. Each haplotype of the child must therefore learn what is in the other haplotype, and indeed what is in its own haplotype. In other words, self-tolerance is learned by the immune system as it develops in each individual.

An experiment of nature illustrates this concept. 'Freemartin' cattle are genetic females that have been masculinized by intra-uterine exposure to Miillerian inhibiting substance from a twin male fetus that shares the same placenta (Hunter, 1995). While the intersex nature of these calves has no immunological significance in itself, it allows the identification of calves that, as a result of the shared intra-uterine circulation, are stable haemopoietic chimeras (genetic mosaics). These calves are tolerant to each other's cells, indicating that they have acquired tolerance in utero (Owen, 1945).

The immune system thus defines self as the sum of all the protein and other macromolecular structures that are present in the body and available to the immune system in sufficient concentration to learn of its presence. However, there are many 'holes' in self tolerance. In the case of T cells, the major site of tolerance induction is in the thymus. The immune system will not be tolerant to substances that are present only at minute concentrations in the body or which are sequestered away from the immune system ('immune ignorance'; reviewed by Miller and Heath, 1993). If a self antigen is not present in sufficient amounts in the thymus, T cells may emerge that are not tolerant to that antigen.

The immune system sometimes appears to have a second chance to 'toler-ize' such T cells. This form of tolerance is known as 'peripheral tolerance' and may occur in both T and B cells (reviewed by Miller and Morahan, 1992; Nossal, 1992b). The cellular basis for self tolerance will be examined in Chapter 3.

The phenomenon of self tolerance means that it is usually difficult to generate antibodies to self antigens, although sometimes self-tolerance can be destroyed or bypassed (see Chapters 3 and 4).

20 Monoclonal Antibodies: Principles and Practice

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