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Study Upends Long-Held Belief About “Self-Reactive” Immune Cells

Decades’ worth of textbook precepts about how our immune systems manage to avoid attacking our own tissues may be wrong, according to researchers at the Stanford University Medical Center. The study was published in May 2015 in the journal Immunity.

A release from Stanford reports that the results contradict a long-held belief that self-reactive immune cells are weeded out early in life in an organ called the thymus. In the current study the scientists revealed that vast numbers of these cells remain in circulation well into adulthood.

The release quotes Mark Davis, PhD, professor of microbiology and immunology and director of Stanford’s Institute for Immunity Transplantation and Infection, as saying, “This overturns 25 years of what we’ve been teaching.” Davis, the senior author of the new study, is the Burt and Marion Avery Family Professor and a Howard Hughes Medical Institute investigator. The lead author of the study is Wong Yu, MD, PhD, a clinical instructor in hematology and a research associate in the Department of Microbiology and Immunology.

The vertebrate immune system is a complex of many specialized cell types working together to recognize and wipe out foreign invaders and developing tumors. T cells — so-named because they mature in the thymus — come in two major varieties. One particular class of these cells, called cytotoxic T cells or “killer T cells,” is particularly adept at attacking cells harboring viruses or showing signs of being or becoming cancerous.

As T cells proliferate in early development, they undergo frequent DNA “scrambling” in a critical part of their genome. This DNA rearrangement results in an astounding diversity with respect to which kinds of pathogens or unfamiliar tissues individual T cells can identify and distinguish from healthy, familiar tissues. Numerous rounds of cell replication bequeath the immune system a formidable repertoire of such cells, collectively capable of recognizing and distinguishing between a vast array of different antigens — the biochemical bits that mark pathogens or cancerous cells (as well as healthy cells) for immune detection. For this reason, pathogenic invaders and cancerous cells seldom get away with their nefarious plans.

The current theory

But this same random-mutation process yields not only immune cells that can become appropriately aroused by any of the billions of different antigens characteristic of pathogens or tumors, but also immune cells whose activation could be triggered by myriad antigens in the body’s healthy tissues. This does happen on occasion, giving rise to autoimmune disease. But it happens among few enough people and, mostly, late enough in life that it seems obvious that something is keeping it from happening to the rest of us from day one.

Much of the reasoning regarding why we aren’t all under constant autoimmune attack derives from mouse studies, carried out with techniques that by today’s standards are relatively primitive.