Dimerization of the HLA-B27 molecules also happens when HLA-B27 on the cell surface is “brought inside the cell for recycling. Normally, this process can lead to degradation, but sometimes for HLA-B27 when this happens, it actually forms dimers and they get back out on the cell surface. It has been shown that these dimers can trigger T cells—specifically CD4+ T cells—that are predisposed to make pro-inflammatory cytokines.
“Researchers are still trying to figure out if these mechanisms explain all or part of the HLA-B27 story,” he adds.
In the May issue of Arthritis & Rheumatology, Loll and colleagues published a very interesting observation, according to Dr. Colbert.1 Their research asked a different question, which was based on the understanding that not all HLA-B27 molecules predispose people to AS.
Many of the subtypes are similar, but not identical. In fact, two subtypes—B*27:06 and B*27:09—are either not strongly associated with or, perhaps for B*27:06, not at all associated with AS. However, two other common subtypes-B*27:05 and B*27:04-“clearly do increase your chances of having disease,” Dr. Colbert says.
There are more than 100 subtypes of HLA-B27, & the predominant subtypes differ between populations, such as among European, Thai & Indonesian populations, & a rare subtype has been found nearly exclusively in people of Sardinian descent, according to Dr. Bowness.
“Since B*27:06 and B*27:09 are very closely related to B*27:05 and B*27:04, researchers have thought for a long time that by comparing them very carefully, any differences might explain the differential disease association.” Previous studies have shown that the B*27:05 subtype could hold the same peptide in two different conformations, but not B*27:09, suggesting that the two conformations would promote autoreactivity and perhaps explain arthritogenicity.
The current research by Loll et al probed the differences between the subtypes and found that the dual peptide conformation theory “did not hold for B*27:06 and B*27:04, because the non-associated subtype B*27:06 held the same peptide in two conformations, while the disease-associated B*27:04 subtype had only one conformation.”
Using infrared spectroscopy, they looked at conformational flexibility and found that the disease-associated subtypes are “floppy or non-rigid, whereas the non-disease-associated subtypes are more rigid. This inherent flexibility may help to explain why the HLA-B27 protein behaves differently, has a tough time folding, and tends to unfold more readily, both of which may contribute to dimerization,” Dr. Colbert says.
Does This Change Therapy?
“The HLA-B27 story continues to unfold,” he says. Although these research results are intriguing, they don’t change how rheumatologists should use the test for HLA-B27, but they are “one step forward in the path toward understanding how HLA-B27 causes disease.”
