Fifty-three male and 41 female patients with diagnosed AS were included in the study, matched for age and sex with 70 healthy controls. Subsets of the cohort were selected for serum analysis, flow cytometric analysis and gene expression analysis.
Analysis of peripheral blood revealed that the male patients with AS had significantly higher levels of IL-17A and TNF than female patients, whereas men and women had comparable serum levels of IFNγ. The male patients had significantly higher levels of Th17 cells compared with the female patients. The investigators say the Th17 axis is unlikely to be the primary inducer of AS, but that it is possible that “a distinct immunologic event, perhaps one that is mediated by CD8+ T cells and orchestrated by class I MHC, such as HLA‑B27, precipitates the inflammatory cascade leading to AS, while alterations in the Th17 axis modify disease expression and severity.”
In an effort to define a mechanistic basis for the male sex bias in the Th17 axis, the investigators examined the influence of sex hormones and found that levels of estrogen or testosterone were not significantly different between AS patients and those in the control group.
Study investigator Eric Gracey, BSc, a PhD graduate student in Dr. Inman’s lab at the University of Toronto, says the pathogenic role of IL-17 producing cells in patients with the disease remains unclear. “There is a lot of evidence from in vitro studies and from animal studies that IL-17 itself, as well as being an inflammatory molecule, actually promotes arthritic changes by promoting osteoclast and osteoblast function. IL-17 producing cells can be found at the sites of inflammation in spondyloarthritis, mainly where the tendons and ligaments insert into the bone.”
Cells of the Th17 axis, including TH17 cells, also play important protective roles. They promote healthy gut function and help combat fungal and bacterial infections. “They are a double-edged sword, in that they are absolutely necessary but too much can be a bad thing,” Mr. Gracey says.
Gene expression studies that he and his colleagues have conducted with AS patients indicate the sex bias may exceed the Th17 axis. “In future studies we are going to explore the function of genes differentially expressed in male and female patients and how they may impact on the immune response in male patients,” he says.
Sex is an incredibly important variable in research, he adds. “Often, with sex-dominated diseases, it is hard to balance the sexes in your studies, making it difficult to statistically compare the groups. With RA, for example, most of the studies are centered on female patients, but there may be important differences [when compared with male patients] that researchers are missing. Lessons learned from these studies cannot always be applied to both males and females.”
Additional research is needed into which differentially regulated genes may serve to identify biomarkers in AS.
Therapeutic Implications
One aspect of this current study points toward a future that will offer more personalized approaches to therapeutics. “The study looking at gene expression profiles of patients begins to usher in a new era of targeted personalized therapeutics that are based directly on the patient’s own immune profile,” Dr. Inman says.