Critical to the functioning of the immune system is the ability to recognize pathogens as foreign. That is, it must be able to distinguish the molecules and cells of its own organism, described as host or self, from molecules and cells of other organisms, described as foreign or nonself, and then respond only to those that are nonself.

The ability of the immune system to distinguish self from nonself depends largely on proteins that normally reside on the surface of cells. For example, in organ transplants, the immune system sometimes recognizes proteins on the surface of transplanted organs as nonself. The transplanted organs are then attacked by the immune system, and they are rejected.

Sometimes, the immune system mistakes self and nonself. If the immune system reacts inappropriately to self, it can end up attacking its own cells or tissues. This occurs in autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. Alternatively, the immune system sometimes recognizes as nonself harmless substances such as pollen or dust, leading to allergic reactions. Or the immune system may not react when it should and therefore does not adequately protect an organism. A weak immune system is most likely to occur at the extremes of age or when infections or diseases compromise its function, a condition called immunodeficiency.

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As a result, the activity of the immune system is carefully regulated. One way this regulation occurs is by keeping immune cells and biochemical processes in an inactive state that is activated only when they come into contact with a foreign molecule or cell. In this way, the immune system reacts only when it is needed to attack a pathogen.

The distinction between self and nonself is a useful way to think about how the immune system functions, but it has limitations. For example, as we will see, the immune system is able to recognize and attack diseased or infected self cells, but it also tolerates bacteria and other nonself microorganisms that make up our microbiome (Case 5: The Human Microbiome). French immunologist Polly Matzinger suggested that another way to think about the immune system is that it recognizes and attacks agents that cause injury or damage, not necessarily those that are foreign. Her idea suggests that there is more work to do to fully understand how the immune system functions.