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Commensal Gut Microbes Produce Retinal-Like Protein That Is Likely the Long-Mysterious Trigger for Autoimmune Uveitis, a Major Cause of Human Blindness

One major cause of human blindness is autoimmune uveitis, which is triggered by the activation of T cells, but exactly how and where the T cells become activated in the first place has been a long-standing mystery. A study, published as an open-access “Featured Article” in the August 18, 2015 issue of the journal Immunity, reveals that gut microbes produce a molecule that mimics a retinal protein, which most likely activates the T cells responsible for the disease. The article is titled “Microbiota-Dependent Activation of an Autoreactive T Cell Receptor Provokes Autoimmunity in an Immunologically Privileged Site." By shedding light on the cause of autoimmune uveitis in mice, the study could contribute to a better understanding of a broad range of autoimmune disorders and pave the way for novel prevention strategies in the future. "Given the huge variety of commensal bacteria, if they can mimic a retinal protein, it is conceivable that they could also mimic other self-proteins that are targets of inappropriate immune responses elsewhere in the body," says senior study author Dr. Rachel Caspi of the National Institutes of Health. "We believe that activation of immune cells by commensal bacteria may be a more common trigger of autoimmune diseases than is currently appreciated." Autoimmune uveitis, which accounts for up to 15% of severe visual handicap in the Western world, affects the working-age population and significantly affects public health. Patients often have detectable immune responses to unique retinal proteins involved in visual function, and these proteins can elicit the disease in animal models. However, these observations present a paradox: because of the blood-retinal barrier, retinal proteins remain sequestered within the healthy eye and cannot reach T cells in the rest of the body, and T cells cannot enter the eye unless they have already been activated by the retinal proteins or similar antigens. Therefore, it has remained a mystery as to how and where the T cells become activated and cause the disease.

One potential clue came from studies showing that gut microbes are important for the development and activation of T cells that have been linked to autoimmune uveitis. Moreover, gut microbes contribute to a range of autoimmune diseases, and, in particular, there have been anecdotal reports that uveitis is reactivated after bacterial infections. Based on these findings, Dr. Caspi and her team reasoned that gut microbes could be the culprits behind uveitis.

To test this idea, the researchers examined natural triggers of the disease by using a mouse model that spontaneously develops uveitis. Before the clinical onset of uveitis, the intestines of these mice showed high numbers of activated T cells. Treatment with antibiotics reduced numbers of these T cells in the gut and delayed and attenuated the development of the disease in the mice.

Moreover, bacteria-rich protein extracts from the gut contents of these mice activated retina-specific T cells, making them capable of breaching the blood-retinal barrier to enter the eye and cause uveitis.

Taken together, the findings provide compelling evidence that gut microbes activate the T cells that cause uveitis, and they offer a novel mechanism explaining how a tissue-specific autoimmune disease can arise from responses to gut microbes at a distal site in the body.

Dr. Caspi and her team are now trying to identify specific bacteria that could produce the protein mimicking the retinal antigen in their animal model of uveitis. They will also look for additional signals that could contribute to the activation of disease-causing immune cells.

"Bioinformatic analyses combined with biological tests will help us to reach this goal, but there is still much work to be done," Dr. Caspi says.

If researchers are able to identify the bacteria and signals that activate the retina-specific T cells, she says. "we may be able in the future to use this knowledge to selectively eliminate the responses that lead to the development of this disease."

[Press release] [Immunity "Featured Article"]