A team involving researchers from Washington University School of Medicine in St. Louis, Stanford University School of Medicine and Oxford University has developed a way to find crucial protein fragments that drive autoimmunity, as well as the immune cells that respond to them. The findings, published December 7 in Nature, open a promising pathway to diagnose and treat autoimmune diseases.
The HLA family of proteins is involved in helping immune cells detect invading pathogens and distinguishing 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. Some scientists began to speculate that the misidentification hypothesis was wrong and some other reason accounted for the association between HLA-B*27 and the two diseases.
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.
Garcia and Yang 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. Using that approach, they were able to narrow down the millions of possibilities to a very short list of human and microbial proteins. 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.
The findings reveal key aspects of the biological mechanisms underlying ankylosing spondylitis, anterior uveitis and potentially many other autoimmune diseases.
