Muriel Moser

From clonal selection to immune networks: induction of silent idiotypes.

This year is the 100th anniversary of Darwin’s death, during which there has been a flood of papers, conferences, and debates. The basic idea of Darwinism is nicely illustrated by the title of the famous book by Jacques Monod: le Hasard et la N6cessitk.I The chance corresponds to the randomness of mutations at the DNA level and necessity can be equated with selective pressure. This basic idea has played a significant role in immunology. The clonal selection theory24 is an extension of the Darwinian concept at the lymphocyte level. It seems to some of us, however, that Darwin did not sufficiently explain the rate of evolution and the emergence of complex networks and regulatory mechanisms that require the simultaneous presence of interacting elements. Let us take a simple example. lmagine that one has two RNAs in a “prebiotic soup,” each coding for one enzyme, its own replicate. E, , the products of RNA , is the replicate of RNA,; the same holds for the other couple. If we leave things as such, all that can happen is competition between the two. Eventually, the most stable, the most accurate, and the fastest replicator will win the game. Similarly, one can describe the immune system as a library of independent clones. If we admit that the beauty of imagination and the logics of complex regulatory mechanisms cannot stem from competition and selection alone, another basic principle should be added. This new principle could look like the emergence of a hyper~ycle .~ .~ Suppose simply that enzyme one becomes the replicase of RNA, and that enzyme two is the replicase of R N A , (see TABLE 1 ) . Now instead of being put into competition, the two RNAs are forced to cooperate and to evolve together. In the words of Eigen “the first catalytic couplings must have been weak and complex and the number of genetic participants very large. The hypercycle principle is nonetheless simple: enforced cooperation among otherwise competing genes allowed their mutual survival and regulated their growth. It also made possible a more refined kind of evolution than that open to quasi species alone.” If we apply the hypercycle principle to the immune system, we go immediately from the clonal selection theory (competition between quasi species of lymphocytes) to idiotypic networks.’-I2 Clones are no more independent, but they are coupled, connected by the products that distinguish them from each other, namely by their idiotypes.

Induction of anti-arsonate CRI positive antibodies in BALB/c mice

When injected with the same antigen, different individuals of the same species generally synthesize specific antibodies bearing different idiotypic specificities. Crossreactive idiotypes, however, are frequently expressed by all members of an inbred strain of mice immunized with a given antigen. Recurrent idiotypes provide an attractive model system for the study of immune regulation and repertoire expression. One system involving such a public idiotype is the arsonate system.’ After immunization with arsonate-coupled keyhole limpet hemocyanin (KLH-Ars), all A/J mice synthesize anti-arsonate antibodies bearing a cross-reactive idiotype (CRI,+). Expression of this major idiotype is linked to the IgC, locus (d or e allotype). Amino acid sequence analysis of monoclonal anti-arsonate antibodies have shown that CRI,+ proteins constitute a family of closely related but distinct molecules that appear to be encoded for by one, or a very few germ-line genes2.’ Recent data4.’ suggest that the CRIA+ structural gene is absent in the genome of CRI,strains as BALB/c mice (a allotype). In this report, we demonstrate that it is possible, by idiotypic manipulation, to induce CRI,+ anti-arsonate antibodies in BALB/c mice that never express this idiotype upon antigen stimulation.