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A study published in Nature by researchers from Washington University School of Medicine in St. Louis, Stanford University School of Medicine and Oxford University have developed a way to find the crucial protein fragment that drives autoimmunity, as well as the immune cells that respond to it.

On the fundamental level, in autoimmune diseases the immune cells mistake healthy cells for infected cells. Finding the source of the confusion has been a challenge for researchers. “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,” said co-senior author Professor Wayne M. Yokoyama, 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 HLA family of proteins helps immune cells detect invading pathogens and distinguish between microbial and human proteins, and is highly variable across individuals. HLA proteins function like hands that pick up fragments of whichever proteins are lying about — microbial or human — and show them to immune cells called T cells to figure out if they’re a sign of danger (microbial) or not (human). T cells don’t recognize protein fragments by themselves; they recognize the fragment plus the hand that holds it. Scientists have long assumed that the combination of this particular hand ‘HLA-B*27’ plus a bit of an unknown human protein was being misidentified as dangerous in people with either of the two diseases, triggering autoimmune attacks in the eye or the spine. But for decades, they couldn’t find the fragment.

Co-corresponding author of this paper published in Nature Prof K. Christopher Garcia, and co-first author Dr Xinbo Yang, from Stanford Medicine, along with co-corresponding authors Dr Geraldine M. Gillespie, and Prof Andrew J. McMichael, and co-first author Lee Garner from the Nuffield Department of Medicine collaborated with Yokoyama and co-first author Dr Michael Paley of Washington University on a novel way to find the elusive fragment. 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. Then, they determined the structures of the detector molecules known as ‘T cell receptors’ on T cells from both groups of patients and compared them. The similarities were striking.

Knowing what a detector molecule looks like is a big step toward figuring out what it detects.

Prof Garcia and Dr Yang 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. Using that approach, they were able to narrow down the millions of possibilities to a very short list of human and microbial proteins.

Prof Gillespie said: ‘‘By combining recently developed technologies, we have re-visited 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.  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.’’

The findings reveal key aspects of the biological mechanisms underlying ankylosing spondylitis, anterior uveitis and potentially many other autoimmune diseases. By providing strong support for the idea that T cells that react to microbes may also react to normal human proteins, the findings promise to accelerate efforts to improve diagnostic tools and treatments for autoimmune diseases.

Dr Paley said: “For ankylosing spondylitis, the average time between initial symptoms and actual diagnosis is seven to eight years. 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.”