Study reveals how T-cells traverse blood-retinal barrier in eye disease.


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.   Due to 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 how and where the T cells become activated and cause the disease.  Now, a study from researchers at the Federal University of Santa Catarina, reveals that gut microbes produce a molecule that mimics a retinal protein, which most likely activates the T cells responsible for the disease. The team state that 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.  The opensource study is published in the journal Immunity.

Previous studies show 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 the researchers hypothesized that gut microbes could be the culprits behind uveitis.

To test this idea the current study examined natural triggers of the disease by using a mouse model that spontaneously develops uveitis. It was observed that before the clinical onset of uveitis, the intestines of these mice showed high numbers of activated T cells. Data findings showed that treatment with antibiotics reduced numbers of these T cells in the gut and delayed and attenuated the development of the disease in the mice.

The lab state that 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 results 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.

The researchers note that 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.  The team conclude that activation of immune cells by commensal bacteria may be a more common trigger of autoimmune diseases than is currently appreciated.

For the future the lab are now trying to identify specific bacteria that could produce the protein mimicking the retinal antigen in their animal model of uveitis and they will also look for additional signals that could contribute to the activation of disease-causing immune cells.   They go on to surmise that if they are able to identify the bacteria and signals that activate the retina-specific T cells the medical community may be able to use this knowledge to selectively eliminate the responses that lead to the development of this disease.

Source:  Federal University of Santa Catarina

 

It is unknown where and how T cells reactive to self antigens residing behind blood-tissue barriers first become activated. New research shows that retina-specific T cells receive an activation signal in the gut from an antigen dependent on commensal microbiota and trigger autoimmunity in the eye.  Credit:  Horai and Zarate-Blades et al./Immunity 2015.

It is unknown where and how T cells reactive to self antigens residing behind blood-tissue barriers first become activated. New research shows that retina-specific T cells receive an activation signal in the gut from an antigen dependent on commensal microbiota and trigger autoimmunity in the eye. Credit: Horai and Zarate-Blades et al./Immunity 2015.

 

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