The immune system was recognized in ancient times and rediscovered by Jenner and Pasteur based on its ability to confer protection against repeat exposure to a pathogen. Through subsequent studies by von Behring and others, it rapidly became apparent that the immune system has the potential to respond not only to whole microorganisms, but to virtually any molecule that is 'foreign' to the host. However, although injection of such molecules often provokes a robust immune response, this does not always occur. Immunization protocols improved in the 1920s with the discovery by Ramon and Glenny of immunostimulatory molecules (adjuvants) that could boost immune responses to coadministered antigens. Adjuvants were typically of microbial origin and became widely used to increase the effectiveness of immunizations. In the 1960s, Dresser showed that a highly purified foreign protein would only elicit an immune response if it was admixed with a microbial adjuvant 1 . If it was injected by itself, the foreign antigen not only failed to elicit immunity but actually induced a state of tolerance 2 . However, the significance of these observations was not well appreciated and adjuvants remained one of those things that everyone used simply because they were part of standard operating procedures.
In 1989, Janeway put these empirical observations into a conceptual framework 3 (FIG. 1). He proposed that the immune system does not respond to all foreign antigens but only to those that are potentially associated with infection. The underlying idea to this model was that the immune system has evolved to protect the host against microorganisms and that this discrimination between infectious and non-infectious antigens focuses defences on real threats rather than innocuous situations.
At this time, it was already known that to stimulate T-cell responses, antigens had to first be acquired and presented on MHC molecules of an antigen-presenting cell (APC). Moreover, it was also known that APCs provide additional co-stimulatory signals necessary to activate T cells. Janeway incorporated these principles into his model (FIG. 1). He postulated that the discrimination between infectious and non-infectious, non-self molecules is made by the APCs of the innate immune system through receptors that recognize pathogenassociated molecular patterns (PAMPs) made by microorganisms that are molecularly distinct from those made by mammals. PAMPs are naturally associated with infections and are the active ingredients of many adjuvants. Upon recognition of such molecules, the APCs are stimulated to express all of the signals required to activate naive T cells. This idea preceded the discovery of Toll-like receptors (TLRs) and other microbial sensors 4,5 .
We now know that Janeway's model is largely correct. However, it cannot explain all immune responses. In this article, we discuss the evidence supporting the concept that the immune system has also evolved mechanisms to sense primary and secondary necrotic cell death (which we refer to here simply as necrotic cell death) and respond to it with innate and adaptive immune responses. We highlight both what is known and what is as yet unknown about the mechanisms underlying these processes and how they might contribute to health and disease.