Background/Purpose:

Female sex steroids are important modulators of autoimmunity.  Estrogen appears to favor the development of lupus autoimmunity via activation of adaptive and innate immune responses, especially type 1 interferon (IFN) (e.g., IFN-a).  In contrast, progesterone may have protective effects.  In mice, treatment with depot medroxyprogesterone acetate (DMPA, a widely used contraceptive) suppresses IFN-a production and the emergence of lupus-like autoimmunity.  In vitro, DMPA selectively inhibits IFN-a release from human plasmacytoid DCs (pDCs), a major source of IFN-a in SLE patients.  Whether DMPA suppresses IFN-a production by pDCs in humans is unknown. 

Methods:

Peripheral blood mononuclear cells (PBMCs) were isolated from healthy women immediately before and 2 weeks after first dose of DMPA birth control and stimulated with toll-like receptor (TLR) 3, 7 and 9 specific ligands to induce IFN-a production, which was assayed by ELISA.  Under these conditions, all measurable IFN-a induced by TLR7 and TLR9 ligands comes from pDCs.  In addition, percentages and activation status of various PBMC subsets were determined by flow cytometry.  Paired t-tests were used to compare pre- and post-DMPA values.  RNA from PBMCs was stored for later analysis.     

Results:

DMPA treatment had no statistically significant impact on IFN-a production.  However, in 3 of the 4 subjects tested, DMPA markedly reduced TLR7-induced IFN-a production by pDCs, which could not be accounted for by changes in pDC numbers.  In these same 3 subjects, DMPA generally increased TLR9-induced IFN-a, suggesting that DMPA can selectively suppress IFN-a production by pDCs encountering TLR7 ligands, e.g., RNA-containing lupus immune complexes or RNA viruses.  There were no consistent effects on PBMC subset numbers or activation status, except in the case of B cell percentages, which were significantly increased after DMPA treatment.         

Conclusion:

In healthy women, DMPA may selectively suppress TLR7-induced IFN-a production by pDCs, an innate immune pathway involved in lupus pathogenesis as well as protection against RNA viruses.  Thus, DMPA could be a dual-benefit contraceptive for certain SLE patients.  On the other hand, DMPA’s ability to suppress protective IFN-a responses may help explain why women using DMPA in HIV-endemic areas are at increased risk of HIV infection.  Further investigation into the immunomodulatory properties of this widely used form of contraception is warranted.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/depot-medroxyprogesterone-acetate-birth-control-may-suppress-toll-like-receptor-7-induced-interferon-alpha-production-by-plasmacytoid-dendritic-cells-in-women/