Well, it’s been a long time since the last post! Sorry about that.
Here’s a topic that came up recently: pregnancy. It’s well known that pregnancy is a particularly dangerous time for women with lupus – flares of disease seem to increase, possibly related to elevated levels of female hormones (eg. estrogen and progesterone). There are a lot of theories about why this happens, and why women are disproportionately affected by lupus. In vitro, estrogen downregulates Fas-mediated apoptosis, and also can inhibit IL-2 production. However, the precise role of these hormones in regulating the immune system remain unclear (Moulton and Tsokos 2012).
What’s funny is that rheumatoid arthritis, another female-predominant disease, gets better with pregnancy, and flares post-partum. The same observations have been made with uveitis (Chan, CC et al. Br J Ophthal 2004). So – why?
Some progesterone-related effects have been invoked. For example, progesterone at pregnancy levels can inhibit Th1 and Th17 responses, skewing towards Th2 and also increasing Treg responses. IgG glycosylation patterns may also be affected. These effects have been observed both in vitro as well as in mouse models of collagen-induced arthritis (reviewed in Hughes, GC 2012).
The SKG mouse spontaneously develops rheumatoid factor-positive inflammatory arthritis, along with other RA-type manifestations such as pneumonitis and rheumatoid nodules. This arthritis remits completely with pregnancy, and is made significantly worse by ovariectomy (Inoue, K et al. 2013). The effects of ovariectomy are ameliorated by exogenous administration of estradiol and, to a lesser extent, progesterone. Treatment with estradiol decreased serum levels of TNFα and IL-6, while progesterone only affected IL-6 levels.
This study did not address what happens to male SKG mice – apparently they do not have as severe arthritis as gonadally intact females. However, castration (orchiectomy) of male SKG mice also worsens the arthritis phenotype, suggesting a protective role for testosterone as well! (Keith RC, et al. 2013). Huh.
Obviously, these observations are rather simplistic. If Th17 responses are important for the pathophysiology of both SLE and RA, why would progesterone be beneficial only for one? Lots of citations in this post, but I don’t feel any closer to understanding this complicated issue. Thoughts appreciated.
1. Moulton, VR and Tsokos, GC. Why do women get lupus? Clin Immunol. 2012 Jul;144(1):53-6.
2. Chan CC, Reed GF, Kim Y, Agrón E, Buggage RR. A correlation of pregnancy term, disease activity, serum female hormones, and cytokines in uveitis. Br J Ophthalmol. 2004 Dec;88(12):1506-9.
3. Hughes GC. Progesterone and autoimmune disease. Autoimmun Rev. 2012 May;11(6-7):A502-14.
4. Inoue K, Inoue E, Imai Y. Female sex hormones ameliorate arthritis in SKG mice.
Biochem Biophys Res Commun. 2013 Apr 11.
5. Keith RC, Sokolove J, Edelman BL, Lahey L, Redente EF, Holers VM, Sakaguchi S, Robinson WH, Riches DW. Testosterone is protective in the sexually dimorphic development of arthritis and lung disease in SKG mice. Arthritis Rheum. 2013 Mar 25.