Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Objective. To identify an immunologic basis for the male sex bias in ankylosing spondylitis (AS). Methods. Cohorts of male and female patients with AS and age- and sex-matched healthy control subjects were selected, and the levels of serum cytokines (interferon-gamma [IFN gamma], tumor necrosis factor alpha , interleukin-17A [IL-17A], and IL-6) were examined by enzyme-linked immunosorbent assay, the frequencies of Th1 and Th17 cells were assessed by flow cytometry, and whole blood gene expression was analyzed using both microarray and NanoString approaches. Results. The frequency of IL-17A and Th17 cells, both of which are key factors in the inflammatory Th17 axis, was elevated in male patients with AS but not in female patients with AS. In contrast, AS-associated alterations in the Th1 axis, such as the frequency of IFN gamma and Th1 cells in serum, were independent of a patient's sex. Results of microarray analysis supported an altered Th17 axis in male patients, with a specific increase in IL17RA. In addition, male and female patients with AS displayed shared gene expression patterns, while male patients with AS had additional alterations in gene expression that were not seen in female patients with AS. The differential sex-related immune profiles were independent of HLA-B27 status, clinical disease activity (as measured by the Bath Ankylosing Spondylitis Disease Activity Index), or treatment (with nonsteroidal antiinflammatory drugs or biologic agents), implicating intrinsic sexual dimorphism in AS. Conclusion. The results of this study demonstrate distinct sexual dimorphism in the activation status of the immune system in patients with AS, particularly in the Th17 axis. This dimorphism could underlie sex-related differences in the clinical features of AS and could provide a rationale for sex-specific treatment of AS.