CORRESPONDENCE

undifferentiated (indeed, inter- proclaims that a specific can The specificity of the changeable) use of the terms be explained in terms of the selection of a “SNS” and “CST.” However, it specific by a specific . clonal selection is not the distinction between In this sense, it is somewhat misleading to central tenets and subsidiary uniformly discuss the “challengers” of the hypotheses that is at stake. It is CST. For example, some of the adherents of theory the different notions of the danger theory still seem to implicitly immunological specificity that assume that the specificity of the reaction OHAD S. PARNES lie at the heart of the problem. (albeit not the decision to react) is determined 3 Wellcome Trust Centre for the History of Medicine. Department of Nothing in is by the specificity of the antigen . On the other Anatomy and Developmental Biology. University College, London. 24 more obvious than the ability hand, Irun Cohen’s conception of the Eversholt St. London NW1 1AD, UK. ([email protected]) of the to dis- “immunological homunculus” is based on a criminate and react specifical- total detachment of the specificity of the anti- Arthur M. Silverstein directed a recent paper ly. What is usually overlooked, however, is the gen from that of the reaction (the latter is pos- at those “challenging” the clonal selection fact that the concept of immunological speci- tulated as “emergent specificity”4). At the theory (CST) because of its obsolete notions ficity has at least two major meanings, with same time, it should be noted that phenomena of tolerance and self-nonself discrimination partially conflicting implications. On the one like physiological and multi- (SNS)1. What is overlooked, according to hand is the specificity of the immune signaling do not necessarily challenge the Silverstein, is the fact that SNS and tolerance response, on the other, the specificity of the SNS scheme, as long as SNS is understood as are merely “subsidiary hypotheses,” which antigen. The specificity of the immune the ability of the immune system to react only address “questions raised by the theory.” response is that which is characteristically specifically—regardless of the underlying These should not be confused with the “core defined in terms of recognition, discrimina- mechanism. http://www.nature.com/natureimmunology theory” or the “central hypotheses of clonal tion, rejection or tolerance (that is, SNS). The A typical example of the implications of selection”: “antigen selects cells, and this specificity of the antigen, in contrast, is this confusion is the problem of adjuvants. results in the clonal proliferation and differen- defined in terms of (receptors or The understanding of these peculiar reactivity tiation of these cells.” This, claims Silverstein, determinants). An immunological reaction pathways may profit from a careful use of the remains unchallenged. may be specific, and there is some mechanism two notions of immunological specificity. In his analysis, Silverstein relies on what he at work. But the reaction’s specificity does not Thus while the reaction to the antigen plus believes was ’s original necessarily have to be reducible to a single adjuvant may be defined as specific, this conception of the CST. However, this histori- or to a single clonal selection event. specificity must not necessarily be reducible cal interpretation is far from being evident: These are very different conceptions of speci- to the specificity of the single antigen. Burnet himself repeatedly contended that the ficity. The fact that in many cases the two Instead, the antigenic specificity of the anti- central tenet of the CST was the fact that “no specificities are highly correlated does not gen plus adjuvant may be considered unique. immunological reaction takes place against mean that they are the same thing. Thus the CST may indeed still be a valid the normal constituents of the body.” For The reasons for this equivocal meaning of account of the way a specific antigen selects © Group 2003 Nature Publishing Burnet, this was definitely not a matter of a “immunological specificity” are historical, specific cells. It fails to explain, however, how subsidiary hypothesis; in fact, he even defined and their tracing would require a long excur- this antigenic event brings about a specific it as an “axiom”2. sion into the origins of immunology. immune reaction. At the same time, Silverstein is right to Important to note, however, is that the CST, in 1. Silverstein,A.M. Nat. Immunol. 3, 793–796 (2002). identify a conceptual fallacy prevailing in the its classic form, is a statement about the rela- 2. Burnet, F.M. in The Clonal Selection Theory of Acquired ,32 current heated debate on the role of SNS in tion between the notions of specificity of the (Cambridge University Press, Cambridge, 1959). 3. Anderson, C.C. & Matzinger, P. Semin. Immunol. 12, 231–238 (2000). immunology: namely, the unqualified and reaction and of the antigen. The CST 4. Cohen, I. J.Autoimmunity 16, 337–340 (2001).

www.nature.com/natureimmunology • february 2003 • volume 4 no 2 • nature immunology 95