Autoimmune diseases are thought to be the result of mistaken identity. Immune cells on patrol, armed and ready to defend the body against invading pathogens, mistake normal human cells for infected cells and turn their weapons on their own healthy tissues. In most cases, though, finding the source of the confusion — the tiny fragment of normal human protein that looks dangerously similar to a protein from a pathogen — has been challenging for scientists. That missing piece of the puzzle has hampered efforts to develop effective diagnostics and specific therapies for many autoimmune conditions.
That finally may be changing. 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 Dec. 7 in Nature, open a promising pathway to diagnose and treat autoimmune diseases.
“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 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, which involves arthritis in the spine and pelvis, and acute anterior uveitis, which is characterized by inflammation in the eye, are both strongly associated with an HLA variant called HLA-B*27. The link between ankylosing spondylitis and HLA-B*27 was discovered 50 years ago — making it one of the first such associations identified between disease and HLA variants — and it remains one of the strongest known associations between any disease and an HLA variant.
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.
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