A study involving Oxford researchers has outlined a way to find the crucial peptides (protein fragments) that drive autoimmunity, as well as the immune cells that respond to it.
On a fundamental level, in autoimmune diseases immune cells mistake healthy cells for infected cells. Finding the source of the confusion has been a challenge for researchers for many years.
This new study, published in the journal Nature, identifies peptides presented by the HLA B27 gene, the strongest genetic risk factor contributing to the arthritic disease ankylosing spondylitis (AS) and also the inflammatory eye condition acute anterior uveitis (AAU).
The study, which was supported by the NIHR Oxford Biomedical Research Centre, was a collaboration between researchers from the University of Oxford, Washington University School of Medicine in St. Louis, and Stanford University School of Medicine.
“The HLA genes have the greatest amount of variation across the human population. There are 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 Wayne M. Yokoyama of 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 recognise protein fragments by themselves; they recognise the fragment plus the hand that holds it. Scientists have long assumed that the combination of a 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 could not find the fragment.
The research team devised a novel way to find the elusive fragment. They 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. They then 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.
Paul Bowness, Professor of Experimental Rheumatology at the University of Oxford’s Nuffield Department for Orthopaedics, Rheumatology and Musculoskeletal Sciences, was one of the clinicians involved in the study.
He said: “Carrying the HLA-B*27 gene has long been known to strongly predispose to developing both ankylosing spondylitis, a common form of inflammatory arthritis, and to anterior uveitis, a painful and sight-threatening eye disease. HLA-B*27 is known to play a key role in the immune system and can ‘present’ small fragments of proteins, for example derived from viruses, to cytotoxic T cells.
“In a fantastic collaboration between groups in Stanford, Oxford and Saint Louis, we here show that the receptors of individual cytotoxic T cells present in the inflamed joints of AS patients and eyes of uveitis patients can recognise both bacterial peptides and self peptides derived from our own bodies. This supports a ‘molecular mimicry’ model of how these diseases are caused and opens up new avenues for future therapeutic trials, with a long-term goal development of a cure for these debilitating 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.
Co-first author Michael Paley of Washington University 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.”