Sexual Dimorphism in Th17 Immune Axis Tied to Gender Differences in AS

According to research published in Arthritis & Rheumatology, sexual dimorphism exists in the Th17 axis of the immune systems of patients with ankylosing spondylitis (AS), possibly isolating an underlying mechanism for gender differences in the clinical presentation of AS.¹

Prior research has shown that AS is diagnosed more frequently in males than females² and that there are variations in disease course and presentation depending on patient gender.³ Although AS is characterized as an inflammatory arthritis involving the axial spine, women tend to present with peripheral joint and cervical spine involvement and have less radiographic evidence of spinal involvement compared with men.^1,3

However, there is no consensus on whether or how the approach to AS should differ with patient gender. The current study by Inman and colleagues found that AS is not only more common in males but also has a different clinical expression and there is a different response to treatment in males and females.¹ 

“The distinctive profile of Th17 cells in blood which is characteristic of AS is clearly influenced by sex, with male AS patients having a more robust Th17 profile than female AS patients,” Dr. Robert Inman, MD, Professor of Medicine and Immunology at the University of Toronto noted in an email to Rheumatology Advisor. “The difference in clinical disease expression in male vs female [patients with] AS has a biological basis, which includes the Th17 cells,” continued Dr. Inman.

To examine a potential immunologic mechanism for sex differences in AS, Dr. Inman and colleagues examined results of serum obtained from a cohort of females and males with AS and from sex- and age-matched controls. Participants’ serum was assessed for cytokine levels, Th1 and Th17 frequencies, and whole-blood gene expression.

Those with AS demonstrated elevated interleukin (IL)-6 and interferon (IFN)-ƴ levels compared with healthy participants.¹ The investigators found significantly higher IL-17A and tumor necrosis factor levels in males with AS compared with females. Conversely, both males and females with AS had similar IFN-ƴ levels, which are linked to the Th1 axis. 

Using flow cytometry, males with AS were found to have significantly higher frequency of Th17 cells and a similar frequency of Th1 cells compared with females with AS. Finally, whole-blood RNA microarray analysis demonstrated upregulation of IL-17RA in males with AS.

Although there was evidence of shared patterns of gene expression in males and females with AS, males with AS demonstrated some gene expression variations that were not observed in females with AS.

Summary and Clinical Applicability

In this cohort study, sexual dimorphism was observed in the immunologic expression of AS. Specifically, Th17 axis elevation was identified in males with AS.¹

These findings have potential clinical significance because they may explain the underlying mechanism of gender differences in AS and could open the door for sex-specific therapies.

“Clinicians should be alert to different clinical features of AS in females and the greater propensity for nonerosive sacroiliitis than [in] males. These findings may begin to shed light on some differential biologic mechanisms at play in AS vs nonradiographic axial spondyloarthritis. It also lays the groundwork for precision medicine in AS, whereby specific therapies can be tailored to the specific immune profile of the patient being treated,” noted Dr. Inman.

“The better we understand the basic mechanisms underlying chronic inflammatory conditions like AS, the better we can apply targeted therapies in a patient-specific way, with improved long-term outcomes.”

The authors highlight that the results should be interpreted with caution in light of the inability to test axial skeletal tissue and the use of artificial cell stimulation for cytokine production. In addition, causality has not been clearly defined with cross-sectional studies.

The current study was supported by the Canadian Institutes of Health Research and Arthritis Research Center.

Reference

1. Gracey E, Yao Y, Green B, et al. Sexual dimorphism in the Th17 signature of ankylosing spondylitis. Arthritis Rheumatol. 2016;68(3):679-689.

2. Dean LE, Jones GT, Macdonald AG, Downham C, Sturrock RD, Macfarlane GJ. Global prevalence of ankylosing spondylitis. Rheumatology (Oxford). 2014;53(4):650-657.

3. Lee W, Reveille JD, Weisman MH. Women with ankylosing spondylitis: a review. Arthritis Rheum. 2008;59(3):449-454.