Analogous to other physiological systems, the immune system also demonstrates remarkable sex differences. Although the reasons for sex differences in immune responses are not precisely understood, it potentially involves differences in sex hormones (estrogens, androgens, and differential sex hormone receptor-mediated events), X-chromosomes, microbiome, epigenetics among others. Overall, females tend to have more responsive and robust immune system compared to their male counterparts. It is therefore not surprising that females respond more aggressively to self-antigens and are more susceptible to autoimmune diseases. Female hormone (estrogen or 17β-estradiol) can potentially act on all cellular subsets of the immune system through estrogen receptor-dependent and -independent mechanisms. This minireview highlights differential expression of estrogen receptors on immune cells, major estrogen-mediated signaling pathways, and their effect on immune cells. Since estrogen has varied effects in female-predominant autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus, we will mechanistically postulate the potential differential role of estrogen in these chronic debilitating diseases.

BackgroundRecent reports have shown that microRNAs (miRNAs) regulate vital immunological processes and have emerged as key regulators of immune system development and function. Therefore, it is important to determine miRNA dysregulation and its pathogenic contribution in autoimmune diseases, an aspect not adequately addressed thus far.Methodology/Principal FindingsIn this study, we profiled miRNA expressions in splenic lymphocytes from three murine lupus models (MRL-lpr, B6-lpr and NZB/WF1) with different genetic background by miRNA microarray assays and Real-time RT-PCR. Despite the genetic differences among these three lupus stains, a common set of dysregulated miRNAs (miR-182-96-183 cluster, miR-31, and miR-155) was identified in splenocytes when compared with age-matched control mice. The association of these miRNAs with the disease was highlighted by our observation that this miRNA expression pattern was evident in NZB/W mice only at an age when lupus disease is manifested. Further, we have shown that the miRNA dysregulation in MRL-lpr mice was not simply due to the activation of splenocytes. By Real-time RT-PCR, we confirmed that these miRNAs were upregulated in both purified splenic B and T cells from MRL-lpr mice. miR-127 and miR-379, which were greatly upregulated in splenocytes from lpr mice, were moderately increased in diseased NZB/W mice. In addition, Real-time RT-PCR revealed that miR-146a, miR-101a, and miR-17-92 were also markedly upregulated in splenic T, but not B cells from MRL-lpr mice.Conclusions/SignificanceThe identification of common lupus disease-associated miRNAs now forms the basis for the further investigation of the pathogenic contribution of these miRNAs in autoimmune lupus, which will advance our knowledge of the role of miRNAs in autoimmunity. Given that miRNAs are conserved, with regard to both evolution and function, our observation of a common lupus disease-associated miRNA expression pattern in murine lupus models is likely to have significant pathogenic, diagnostic, and/or therapeutic implications in human lupus.

MicroRNAs (miRNAs), IntroductionThe innate immune system is the first line of defense protecting the host from invasion by diverse microbial pathogens. To date, 13 members of the Toll-like receptor (TLR) family have been identified in mammalian cells, and each TLR recognizes and binds to specific microbial products called pathogen-associated molecular patterns (PAMPs). 1,2 For example, TLR4 recognizes and binds to lipopolysaccharide (LPS), a gram-negative bacterial component, to trigger the myeloid differentiation primary-response protein 88 (MyD88)-dependent signaling pathway and/or the MyD88-independent signaling pathway, resulting in the production of inflammatory molecules such as type I interferon (IFN) and nitric oxide. 1,3 While TLR-mediated inflammatory responses are important for controlling infections, overwhelming activation of TLR signaling is deleterious and can cause severe inflammatory disease. Thus, the activation of TLRs should be tightly regulated in vivo. Various mechanisms employed by different classes of negative regulators have been identified to regulate TLR triggered inflammatory immune responses. 4,5 Recent publications indicate that microRNAs (miRNAs) fine-tune innate immune responses; thus, an entirely new paradigm of regulation of innate immunity is proposed. 6,7 miRNAs are small (18-25 nucleotide long), noncoding RNAs that suppress gene expression at the posttranscriptional level by binding to the 3ЈUTR of target genes, resulting in either translation inhibition or mRNA degradation. 8 Despite their recent identification, the impact of miRNAs on gene regulation is profound. miRNAs have been shown to be involved in the regulation of a variety of biologic processes including development, signal transduction, apoptosis, cell proliferation, and tumorigenesis. 9-13 The role of miRNAs in normal immune function, as well as in inflammatory processes, is now emerging. 7,14 The direct role of miRNAs in regulation of innate immune responses was first suggested by a study that indicated that miR-146 is a negative feedback regulator of TLR signaling. 15 Additionally, a recent report indicates that miR-155 and miR-125b, which are induced and inhibited by LPS stimulation, respectively, have opposite effects on TNF␣ induction and may regulate endotoxin shock responses. 16 Let-7i was shown to target the TLR4 receptor. Microbial infection decreased the expression of let-7i, which is associated with up-regulation of TLR4 in infected cholangiocytes. 17 The direct role of miRNAs in innate immunity is further suggested by the function of miRNAs in combating viral infections. 13,18 It was shown that IFN␤ inhibits hepatitis C virus replication in the human hepatoma cell line Huh7 by inducing miRNAs that target the RNA genome of viruses. 13 Estrogen, a sex hormone, has been well recognized as an important immune modulator and plays a central role in gender differences in disease susceptibility. [19][20][21] Moreover, estrogen has been implicated in autoimmune diseases. 22 Estrogen has also been shown to physi...