Molecular Medicine Israel

Do Commensal Microbes Stoke the Fire of Autoimmunity?

Molecules produced by resident bacteria and their hosts may signal immune cells to attack the body’s own tissues

When immunologist Rachel Caspi began studying an inflammatory eye disease called autoimmune uveitis in the mid-1980s, she had to inoculate mice with a protein found in the mammalian retina to spark the disease. Injecting interphotoreceptor retinoid-binding protein (IRBP) along with an immune-stimulating compound called an adjuvant into the animals’ bloodstream prompted the mice’s own T cells to attack their eyes. That led to inflammation, tissue damage, and eventual blindness.

Caspi wanted to work with a model that better represented human uveitis, in which IRBP-specific T cells attack the retina spontaneously, without the need for any sort of exogenous immune stimulation. Ten years ago, she and her team at the National Eye Institute in Bethesda, Maryland, developed a genetic mouse model of the disease in which mice produced artificially large numbers of T cells that bound to IRBP. As in humans, these T cells traveled to the animals’ eyes and caused inflammation in the retina despite the mice having never received injections of the protein or adjuvant.1

This model allowed Caspi to explore the paradox of autoimmune uveitis: that T cells were activated by a protein that was only known to be produced by retinal cells and the pineal gland, tissues that normally have very little interaction with the immune system. The cells of the eye even typically release molecules that keep T cells out, and only T cells in an activated state can enter the immune-privileged organs. And there was no IRBP outside of the eyes and pineal gland to activate T cells in the mouse models.

Caspi reasoned that the T cells might be activated by encountering something that looked like IRBP elsewhere in the body. But she knew the protein alone wasn’t enough; T cells need a second signal to switch into attack mode. “What we think is the T cells need not only the antigenic signal, but also the immunologist’s dirty little secret—the adjuvant—the innate danger signals that are provided by bacteria,” she says….

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