The first keynote presentation of this week's Keystone meeting on autoimmunity and transplantation tolerance ended in a rather surprising way -- the speaker was actually heckled during the question answer session for comparing autoimmunity to cancer.

When the mechanisms that keep the immune system from attacking itself break down, diseases like diabetes type 1, lupus, and psoriasis can result. Many in the field have focused on how particular inherited mutations change the immunological landscape and looked for environmental triggers that ultimately initiate the disease. But Christopher Goodnow from Australian National University, one of the leaders in this field, thinks genetics trumps environmental signals in kicking off autoimmunity.

He started his keynote talk by describing just how difficult it is to break natural tolerance to self-antigens. In most cases, he pointed out, this doesn't happen all at once - autoimmune diseases develop over many years. He gave the example of the AIRE gene, which, when mutated, causes autoimmune polyglandular syndrome (APS). The different diseases in the syndrome -- hypoparathyroidism, chronic mucocutaneous candidiasis, and type 1 diabetes -- appear one by one, often over the course of decades. The reason, says Goodnow, is that the immune system has many checkpoints to prevent an auto-reactive immune cell from attacking the body. He argued that it is the accumulation of multiple genetic mutations - just as in cancer - that causes autoimmunity rather than a single mutation combined with an environmental stressor.

In a recent review in Cell describing his theory, Goodnow notes that lymphocytes have a higher mutation rate than other cells, which could explain how a single auto-reactive cell could accumulate additional somatic mutations. He admits that there are several genes that initiate autoimmunity immediately, and are usually fatal, like mutations in the Foxp3 gene, but argues that those are the exceptions, not the rule. If he's correct, he writes, clinicians could tailor specific therapies for autoimmune patients based on their somatic and inherited mutations.

The audience of immunologists, many of whom helped define the major cellular players in self-tolerance, such as T-regulatory cells, seemed skeptical. Some questioned the idea that a single cell could accumulate so many mutations without other stressors. At the end of the question/answer session, Philippa Marrack from National Jewish Medical and Research Center sauntered up to the microphone and asked Goodnow if he really thought that autoimmunity could be boiled down to a series of genetic mutations. When he said yes, she turned to the audience with a mischievous smile and asked: "With a show of hands, how many of you really believe that this theory is true?" Perhaps five of the several hundred in the room raised their hands.

Immunologists hold strongly to their beliefs, Goodnow said, "and I'm probably the worst offender." Time will tell if Goodnow's theory does in fact hold true.