Evolving strategies for cancer and autoimmunity: back to the future

Abstract

Although current thinking has focused on genetic variation between individuals and environmental influences as underpinning susceptibility to both autoimmunity and cancer, an alternative view is that human susceptibility to these diseases is a consequence of the way the immune system evolved. It is important to remember that the immunological genes that we inherit and the systems that they control were shaped by the drive for reproductive success rather than for individual survival. It is our view that human susceptibility to autoimmunity and cancer is the evolutionarily acceptable side effect of the immune adaptations that evolved in early placental mammals to accommodate a fundamental change in reproductive strategy. Studies of immune function in mammals show that high affinity antibodies and CD4 memory, along with its regulation, co-evolved with placentation. By dissection of the immunologically active genes and proteins that evolved to regulate this step change in the mammalian immune system, clues have emerged that may reveal ways of de-tuning both effector and regulatory arms of the immune system to abrogate autoimmune responses whilst preserving protection against infection. Paradoxically, it appears that such a detuned and deregulated immune system is much better equipped to mount anti-tumor immune responses against cancers.

Keywords: CD4 T cell; autoimmunity; cancer; keyword; memory; regulation; tolerance mechanisms.

Figure 1

Emergence of traits along the mammalian lineage. Amniotes split into the sauropsids (leading to birds and reptiles) and synapsids (leading to mammal-like reptiles). These small early mammals developed hair, homeothermy, and lactation (red lines). Monotremes diverged from the therian mammal lineage ~166 Myr ago and developed a unique suit of character (dark-red text). Therian mammals with common characters split into marsupials and eutherians around 148 Myr ago (dark-red text). Geological eras and periods with relative times (million years ago) are indicated on the left. Mammal lineages are in red; diapsid reptiles, shown as archosaurs (birds, crocodilians, and dinosaurs), are in blue; and lepidosaurs (snakes, lizards, and relatives) are in green.