Date Published: December 23, 2009
Publisher: Public Library of Science
Author(s): Xiaoxi Li, Yixin Xu, Ling Ma, Lingyun Sun, Gengfeng Fu, Yayi Hou, Wasif N. Khan. http://doi.org/10.1371/journal.pone.0008412
Abstract: Gender differences in immune capabilities suggest that sex hormones such as estrogens were involved in the regulation of the immunocompetence. Numerous studies also suggest that plasmacytoid dendritic cells (PDCs) play a pathogenic role in SLE. However, it is unclear whether estrogen can modulate the function of PDCs to influence the development of SLE. In the present study, PDCs from murine spleens were treated with 17β-estradiol (E2) and CpG respectively or both in vitro, then cell viability, costimulatory molecule expression, cytokine secretion of PDCs, as well as stimulatory capacity of PDCs to B cells were analyzed. Results showed that E2 and CpG increased the cell viability and costimulatory molecule expression on PDCs synergistically. Moreover, the intracellular and extracellular secretion of IFN-α was increased by E2 or E2 plus CpG. In addition, E2 and CpG also increased the stimulatory capacity of PDCs to B cells, and the viability of B cells was decreased after neutralizing IFN-α significantly. In the experiments in vivo, mice received daily s.c. injections of E2 and CpG respectively or both, then we found that the plasma concentration of IgM were elevated by E2 and CpG synergistically and the expression of IFN-α/β in spleens were noticeably increased by CpG plus E2 compared with the treatment of E2 or CpG only. This study indicates that E2 could exacerbate PDCs’ activation with CpG, which further activates B cells to upregulate susceptibility to autoantigens. IFN-α plays an important role in the stimulatory effect of PDCs on B cells. E2 stimulation of IFN-α production may result in female prevalence in autoimmune diseases such as SLE through activation of PDCs. This study provides novel evidence of relationship between estrogen and SLE and also sheds light on gender biases among SLE patients.
Partial Text: The female prevalence in autoimmune diseases has been recognized for over 100 years. Evidence from murine models also showed the difference in basic immune responses between male and female . Some reports suggested that systemic lupus erythematosus (SLE) patients experience an increase in flares during pregnancy, possibly due to the sustained increased levels of estrogen –. Lupus precipitated or exacerbated after commencement of oral contraceptive use . Lahita and Bradlow reported that patients with SLE and their first-degree relatives had elevated serum levels of 16 -hydroxyestrone, an actively femianizing metabolite of 17β-estradiol (E2) , . Moreover, Pisetsky et al reported that female mice displayed high levels of circulating DNA . Our previous study showed that E2 could increase lymphocyte apoptosis . It has proved that the average length of DNA separated from the anti-DNA antibody immune complex of SLE blood was 180 bp, in accordance with the size of apoptosis chromatin . So scientists and physicians have suspected that steroid hormones such as estrogen may be a key regulator of autoimmune diseases including SLE .
E2 is believed to etiology of both human and murine SLE, but there is little knowledge about the immune state of PDCs under the E2 environment. Recent studies have identified PDC as the central cell type which could secret a large amount of IFN-α upon CpG motifs, and the purified PDC but not mDC represents the primary target for CpG. CpG increased survival, activation and maturation of PDCs . So the purified PDCs from murine spleens were used for our studies in vitro to explain the higher prevalence of SLE in females.