Immunology, as laid down in textbooks and reviews, reflects 150 years of intense research about protection against infectious disease and responses to chemically defined antigens. The data have been gathered through the use of various experimental animal species and ultimately embrace all of cell biology, down to the molecular level. Many of the basic questions and ideas in immunology, however, were coined more than 100 years ago and have not changed much since; this includes concepts such as tolerance, the specificity of cells and antibodies, and immunological memory. Although these concepts are explained in textbooks, much remains unclear and the question arises: do we really know what is in our textbooks? And what may have been misleading us into thinking that we know what, in fact, we don’t?

This commentary is an attempt to review ideas and seemingly established concepts in immunology on only a few pages. To do this is probably unrealistic, unfair to the subject and necessarily incomplete, but hopefully will help to point out some important open questions about immunity. Immune responses will be analyzed here from an evolutionary point of view, based on the following two assumptions: protection against infectious disease is the primary function of the immune system; and, like all biological processes, immune reactivity falls under a Gaussian-type (that is, bell-shaped) distribution and therefore can be selected for a survival advantage1, 2. Compared to humans or mice, infectious agents have a very much shorter generation time and are more numerous by several orders of magnitude. The overall unfavorable numbers game between vertebrate hosts and infectious agents is somewhat compensated by the host’s basic resistance mechanisms (such as interferons) and great numbers of rapidly expanding B and T lymphocytes. Nevertheless, for optimal cohabitation, adaptation to the host of infectious agents by mutation and selection must be relatively rapid to guarantee their survival, as it is also dependent on survival of the host species.