Annica Andersson and colleagues from the Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden published in Arthritis Research & Therapy a study indicating that the regulation exerted by estrogens, to the Th17 cell traffic and migration, may play an important role in the well established protective role of female hormones in rheumatoid arthritis (RA).
The sexual dimorphism in autoimmune diseases is a well-known but still not fully understood phenomenon. Thus, maladies such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis and autoimmune thyroid diseases have an increased incidence and prevalence in females.
In rheumatoid arthritis, the female-to-male ratio is 3:1, with the peak RA’s incidence in women during menopause, when estrogen levels rapidly drop. Interestingly, estrogen levels are lower in postmenopausal women than in men of corresponding age.
During pregnancy, when sex hormone levels rise, up to 75% of RA patients experience relief of disease symptoms. In a well-established experimental model of RA, collagen-induced arthritis (CIA), it has repeatedly been shown that estrogen ameliorates disease development. Regarding human RA, some studies indicate that hormone replacement therapy including estradiol might be beneficial; however, the results of studies in this field are inconsistent.
In contrast to RA, estrogen aggravates systemic lupus erythematosus. Indeed, estrogen is a potent immunomodulatory agent and can exert stimulatory as well as regulatory effects on the immune system, such as enhancing B cell antibody production, reducing B and T lymphopoiesis and inhibiting T cell-dependent inflammation.
Moreover, IL-17 plays a role in inflammation-induced bone loss by stimulating osteoclastogenesis. Migration of Th17 cells to the site of inflammation is mainly orchestrated by the interaction of C-C chemokine ligand 20 (CCL20) with C-C chemokine receptor 6 (CCR6) that is expressed on the Th17 cell.
However, effects of estrogen on the Th17 cell population in arthritis have been scarcely studied, and are limited to studies on IL-17 production.
Now, the research group from Gothenburg, Sweden found that in the murine collagen-induced arthritis model, estrogen regulates traffic of Th17 cells during the development of arthritis, by increasing the migration of Th17 in early arthritis to the lymph nodes and decreasing Th17 migration to joints in established arthritis.
As estradiol increased CCR6 expression on lymph nodes’ Th17 cells and the production of CCL20, the authors suggest that the interactions within the CCR6-CCL20 pathway are responsible for the retention of Th17 cells within the lymph nodes. This may explain why the Th17 cell migration to joints is prevented, which contributes to the diminished neutrophils’ recruitment and reduced joint’s inflammation.
Of note, migration of Th17 cells to the joints in arthritis is orchestrated mainly by CCL20 and corresponding receptor CCR6 expressed on Th17 cells.
In conclusion, estrogens influence Th17 migratory pathways in arthritis, suggesting that E2 treatment might result in Th17 cell retention in LNs thus preventing migration of Th17 cells to joints.
The study increases the understanding of the role of estrogen in autoimmune arthritis and opens up new fields for research concerning the sex bias in autoimmune disease. Thus, this study may provide new insights into mechanisms driving the sexual dimorphism in rheumatoid arthritis.