Researchers from Washington University School of Medicine and Oxford University have developed a way to find critical protein fragments that drive autoimmunity. The findings pave a potential way for diagnosing and treating autoimmune diseases.

The findings are published in Nature in an article titled, “Autoimmune-associated T cell receptors recognize HLA-B*27-bound peptides.”

“Of all genes, the HLA genes have the greatest amount of variation across the human population. There are many, many autoimmune diseases that are associated with specific variants of the HLA genes, and in most cases we don’t know why,” explained co-senior author Wayne M. Yokoyama, MD, the Sam J. Levin and Audrey Loew Levin professor of arthritis research at Washington University.

“This paper outlines a strategy for figuring out why certain HLA variants are linked to certain diseases. It also provides strong evidence that cross-reactivity between human and microbial proteins drives autoimmunity in at least two diseases and probably many others. Now that we understand the underlying drivers, we can start focusing on the approaches that are most likely to yield benefits for patients.”

The autoimmune diseases ankylosing spondylitis and acute anterior uveitis are both strongly associated with an HLA variant called HLA-B*27.

The research team identified certain T cells that were abundant in the blood and joints of people with ankylosing spondylitis, and in the eyes of people with uveitis.

The researchers then devised a way to identify protein fragments that drive a T-cell response when combined with HLA-B*27, and mapped the fragments against the human genome and five bacterial genomes to identify proteins from which the fragments may have originated.

“This study reveals the power of studying T cell specificity and activity from the ground up; that is, identifying the T cells that are most active in a given response, followed by identifying what they respond to,” said K. Christopher Garcia, PhD, the Younger Family Chair, Stanford University. “Clearly these patient-derived TCRs are seeing a spectrum of common antigens, and that may be driving the autoimmunity. Proving this in humans is very difficult, but that is our future direction and could lead to therapeutics.”

“By combining recently developed technologies, we have revisited an old hypothesis that asks if the traditional antigen-presenting function of HLA-B*27 contributes to disease initiation or pathogenesis in the autoimmune conditions ankylosing spondylitis and uveitis,” said Geraldine M. Gillespie, PhD, associate professor, Oxford University. “Our findings that T cells at the sites of pathology recognize HLA-B*27 bound to both self and microbial antigens adds a very important layer of understanding to these complex conditions that also feature strong inflammatory signatures. Our hope is that this work will one day pave the way for more targeted therapies, not only for these conditions but ultimately, for other autoimmune diseases.”

By providing strong support for the idea that T cells that react to microbes also may react to normal human proteins, the findings promise to accelerate efforts to improve diagnostic tools and treatments for autoimmune diseases.

“For ankylosing spondylitis, the average time between initial symptoms and actual diagnosis is seven to eight years,” said Michael A. Paley, MD, PhD, an assistant professor of medicine, of ophthalmology, and of pathology & immunology at Washington University School of Medicine. “Shortening that time with improved diagnostics could make a dramatic impact on patients’ lives, because treatment could be initiated earlier. As for therapeutics, if we could target these disease-causing T cells for elimination, we could potentially cure a patient or maybe even prevent the disease in people with the high-risk genetic variant. There’s a lot of potential for clinical benefit here.”

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