However, HLA-B27 testing cannot be used to make a diagnosis of AS because not everyone with AS has HLA-B27, he says. It also cannot be used reliably to predict development of the disease among people who have no symptoms of arthritis, because only about 1–5% of people with HLA-B27 will ever develop spondyloarthritis.
Treatment of AS has improved with the use of TNF inhibitors, and other treatments are being tested. Biologics that block other cytokine pathways, such as the interleukin (IL) 23/IL-17 axis, show much promise for treatment of the disease, he says.
One of the toughest questions in rheumatology has been and continues to be how HLA-B27 promotes development of spondyloarthritis. Answering that question could eventually lead to new and better therapies.
“There are still major questions about how to treat the aberrant bone formation that is a major contributor to morbidity in AS,” Dr. Colbert says. “If we could understand more about this major genetic risk factor, HLA-B27, then we might be able to figure out even better ways to treat the disease.”
Family of Proteins
Several theories have driven research about the pathogenic role of HLA-B27 over the past 40 years.
HLA-B27 is part of a family of proteins that carries peptides to the cell surface, “displaying them on the cell surface as a signal to CD8+ T cells and NK cells in the immune system that everything is OK,” Dr. Colbert explains. When a cell is infected with a virus or perhaps certain bacteria, the proteins from the viruses and bacteria are displayed, and the immune system is able to distinguish those from the self-peptides and recognize that the cell is in trouble and needs to be destroyed.
One among the several hypotheses generated about HLA-B27 has been that it presents self-peptides from the cell that somehow triggers the immune system, making it attack cells in the joints and the spine. The hypothesis was that it was this ability to present arthritogenic peptides that was the problem, but that “doesn’t seem to be the right answer. It hasn’t been completely ruled out, but many studies suggest that this is not the problem in AS,” Dr. Colbert says.
Investigators have found that HLA-B27 has some aberrant features and has a tendency to fold improperly or misfold. Part of this entails dimerization of two molecules of HLA-B27, which “causes stress for the cell and the triggering of stress-relief pathways that send signals out to neighboring cells. Some of these signals may promote inflammation and may eventually lead to arthritis,” he says.
