Conceptual aspects of self and nonself discrimination

Due to the variety and complexity of microorganisms, the mechanisms needed for pathogen recognition are diverse. Innate immune recognition is mainly based on a series of germ-line encoded receptors that have been selected by evolution to recognize nonself molecules present in microorganisms. Innate immunity also recognizes changes in our cells caused by infection, such as the lack or induction of self molecules. Adaptative immunity somatically generates large repertories of receptors which collectively recognize any nonself antigen. These receptors are randomly generated, and the adaptative immune system has to learn how to eliminate or inactivate cells with high avidity receptors for self molecules. Given the enormous variety of microbe structures and immune receptors, the difference between self and nonself is not absolute; it depends on the threshold of activation. In genetically diverse populations, individuals who have this activation threshold too far from the average may suffer an autoimmune reaction. Accumulation of mutations in cancer cells generates neoantigens that may be also recognized as nonself molecules, but the extent of self and nonself discrimination limits immune responsiveness to them. Surprisingly, most of the molecules expressed by cancer cells recognized by the immune system are non mutated self molecules.