Anja E. Sørensen

MicroRNAs Related to Polycystic Ovary Syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is the most common, though heterogeneous, endocrine aberration in women of reproductive age, with high prevalence and socioeconomic costs. The syndrome is characterized by polycystic ovaries, chronic anovulation and hyperandrogenism, as well as being associated with infertility, insulin resistance, chronic low-grade inflammation and an increased life time risk of type 2 diabetes. MicroRNAs (miRNAs) are small, non-coding RNAs that are able to regulate gene expression at the post-transcriptional level. Altered miRNA levels have been associated with diabetes, insulin resistance, inflammation and various cancers. Studies have shown that circulating miRNAs are present in whole blood, serum, plasma and the follicular fluid of PCOS patients and that they might serve as potential biomarkers and a new approach for the diagnosis of PCOS. In this review, recent work on miRNAs with respect to PCOS will be summarized. Our understanding of miRNAs, particularly in relation to PCOS, is currently at a very early stage, and additional studies will yield important insight into the molecular mechanisms behind this complex and heterogenic syndrome.

MicroRNA Species in Follicular Fluid Associating With Polycystic Ovary Syndrome and Related Intermediary Phenotypes.

CONTEXT Polycystic ovary syndrome (PCOS) has a largely unknown etiology and presents with a clinical heterogeneous patient group. Small noncoding microRNA (miRNA) might prove promising as biomarker candidates for PCOS patient stratification. Altered miRNA expression profiles have been observed in few studies. OBJECTIVE The aim was to assess the miRNA expression profile in follicular fluid from PCOS patients and healthy, regularly cycling, matched controls. DESIGN AND SETTING Experimental case-control study including 49 PCOS women (19 of which were hyperandrogenic and 30 normo-androgenic) and 21 healthy matched women all undergoing in vitro fertilization treatment. INTERVENTIONS AND MAIN OUTCOME Anthropometric and relevant clinical baseline measurements were obtained. Relative expression of miRNA levels were estimated using miRNA quantitative PCR arrays and validated by quantitative RT-PCR. Correlation between miRNAs and clinical relevant measurements was estimated. RESULTS PCOS women, both normo-androgenic and hyperandrogenic, had decreased levels of miR-24-3p, -29a, -151-3p, and -574-3p compared with controls. Furthermore, miR-518f-3p was differentially expressed within the PCOS group with high levels observed in the hyperandrogenic group compared with the normo-androgenic PCOS patients. Serum levels of total and free T were positively correlated with miR-518f-3p in PCOS subjects (P = .001). Distinction between PCOS and controls could be made using miR-151-3p alone with an area under the curve of 0.91 or a combination of four selected miRNAs (area under the curve, 0.93). Bioinformatic target analysis points to an involvement of these miRNAs in biological pathways involving regulation of cell proliferation, extracellular matrix, and processes in intermediary metabolism. CONCLUSION Our study provides evidence that the miRNA expression profile in follicular fluid is altered in PCOS and indicates that specific follicular fluid miRNAs are associated with phenotypical traits of PCOS. An altered miRNA profile holds potentials for new methods of PCOS patient stratification and may contribute to and in part explain the heterogeneous nature found within PCOS women.

MicroRNAs related to androgen metabolism and polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a frequent endocrine disorder in women. PCOS is associated with altered features of androgen metabolism, increased insulin resistance and impaired fertility. Furthermore, PCOS, being a syndrome diagnosis, is heterogeneous and characterized by polycystic ovaries, chronic anovulation and evidence of hyperandrogenism, as well as being associated with chronic low-grade inflammation and an increased life time risk of type 2 diabetes. A number of androgen species contribute to the symptoms of increased androgen exposure seen in many, though not all, cases of PCOS: Testosterone, androstenedione, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS), where the quantitatively highest amount of androgen is found as DHEAS. The sulfation of DHEA to DHEAS depends on a number of enzymes, and altered sulfate metabolism may be associated with and contribute to the pathogenesis of PCOS. MicroRNAs (miRNAs) are small, non-coding RNAs that are able to regulate gene expression at the post-transcriptional level. Altered miRNA levels have been associated with diabetes, insulin resistance, inflammation and various cancers. Studies have shown that circulating miRNAs are present in whole blood, serum, plasma and the follicular fluid of PCOS patients and that these might serve as potential biomarkers and a new approach for the diagnosis of PCOS. In this review, recent work on miRNAs with respect to PCOS will be summarized. Our understanding of miRNAs, particularly in relation to PCOS, is currently at a very early stage, and additional studies will yield important insight into the molecular mechanisms behind this complex and heterogenic syndrome.

Human Leukocyte Antigen-G and Regulatory T Cells during Specific Immunotherapy for Pollen Allergy

Background: T_H2-biased immune responses are important in allergy pathogenesis. Mechanisms of allergen-specific immunotherapy (SIT) might include the induction of regulatory T cells (Tregs) and immunoglobulin (Ig) G₄ blocking antibodies, a reduction in the number of effector cells, and skewing of the cytokine profile towards a T_H1-polarized immune response. We investigated the effects of SIT on T cells, on immunomodulation of human leukocyte antigen (HLA)-G, which has been associated with allergy, on regulatory cytokine expression, and on serum allergen-specific antibody subclasses (IgE and IgG₄). Methods: Eleven birch and/or grass pollen-allergic patients and 10 healthy nonatopic controls were studied before and during SIT. Tregs, chemokine receptors, soluble HLA-G (sHLA-G), Ig-like transcript (ILT) 2, specific IgE, and IgG₄ were studied. Peripheral blood mononuclear cells (PBMCs) were stimulated with pollen extract in vitro and immune factors were evaluated. Results: During SIT, the main changes in the peripheral blood were an increase in CXCR3⁺CD4⁺CD25⁺CD127^low/- Tregs and a decrease in CCR4⁺CD4⁺CD25⁺CD127^low/- Tregs, an increase in allergen-specific IgG₄, and a decrease in sHLA-G during the first half of the treatment period. In the PBMC in vitro experiments, the following changes were observed upon allergen-stimulation: an increase in CD4⁺CD25⁺CD127^low/- Tregs and ILT2⁺CD4⁺CD25⁺CD127^low/- Tregs, an increase in IL-10 and IL-2 levels, and an increase in sHLA-G that was most pronounced at the start of SIT. Conclusions: The changes in CXCR3⁺CD4⁺CD25⁺CD127^low/- Treg, IgG₄, and sHLA-G levels in the peripheral blood and in ILT2⁺ Treg, IL-10, IL-2, and sHLA-G levels upon in vitro allergen stimulation suggest an upregulation in immunomodulatory factors and, to some degree, a shift towards T_H1 during SIT.

MicroRNA and Diabetes Mellitus

Abstract MicroRNAs, first considered a nematode curiosity, constitute an abundant class of regulatory molecules with widespread functions in regulation of glucose homeostasis. MicroRNAs act by sequence-specific inhibition of target mRNAs via binding to sites in their 3′ untranslated region and decreasing the levels of target proteins. MicroRNAs expressed in pancreatic β-cells control multiple parts of glucose-stimulated insulin secretion, regulate β-cell proliferation and responses to altered environments, such as overfeeding or maternal malnutrition. Furthermore, microRNAs are important for fetal β-cell development. Several microRNAs have been associated with alterations in insulin sensitivity by controlling metabolic functions in key target organs of insulin such as liver, skeletal muscle, and adipose tissue. Levels of individual microRNA species are also regulated by, for example, malnutrition or obesity. Moreover, since microRNAs are very stable in the extracellular compartment, it is possible to measure levels of serum microRNAs accurately, which may constitute novel biomarkers for monitoring glucose homeostasis.

Associate Editor Hirohisa Saito

Prof. Hirohisa Saito, Deputy Director of the National Research Institute for Child Health and Development, serves as a board member of the Japanese Society of Allergology (JSA), Editor in Chief of Allergology International (official journal of the JSA) and Associate Editor of the Journal of Allergy and Clinical Immunology . He graduated from Jikei University School of Medicine in 1977 and started his career as a Pediatrician. After receiving his PhD, he taught immunology, especially mast cell biology, at the Johns Hopkins University, under the supervision of Prof. Teruko Ishizaka, from 1986 until 1988. In 1996, after serving as a clinical allergy specialist, he was appointed as Director of the Department of Allergy and Immunology, National Children’s Medical Research Center. In 2002, his Institute was unified and renamed as National Research Institute for Child Health and Development. Since 2003, he has been Professor of Pediatrics at Jikei University, Toho University and Juntendo University. He was concurrently serving as Leader of the Allergy Transcriptome Unit at the Research Center for Allergy and Immunology, RIKEN, from 2002 until 2006. In 2010, he was promoted to Deputy Director of the Research Institute for Child Health and Development. In 2013, he was elected President of the Japanese Society of Allergology. Published online: September 5, 2013

Associate Editor Andreas Radbruch

A biologist by education, Andreas Radbruch did his PhD at the Genetics Institute of the Cologne University with Klaus Rajewsky. He later became Associate Professor there and was a visiting scientist with Max Cooper and John Kearney at the University of Alabama, Birmingham. In 1996, Andreas Radbruch became Director of the German Rheumatism Research Center in Berlin, a Leibniz Institute, and in 1998, Professor of Rheumatology at the Charité Medical Center and Humboldt University of Berlin. Andreas Radbruch has been President of the German Society for Rheumatology, the German Society for Immunology and is incoming President of the International Society for Advancement of Cytometry (ISAC). He serves on a number of advisory and editorial boards and is a fellow of many academic organizations. He is Editorial Chair of the European Journal of Immunology . Most recently, he was awarded the Carol Nachman Prize and an advanced research grant of the European Research Council. Andreas Radbruch has authored more than 250 original publications on immunological memory, antibody class switching, T and B lymphocyte differentiation, cytometry and cell sorting. His research group described the organization of memory plasma cells and memory T helper (Th) lymphocytes in bone marrow and identified memory plasma cells secreting pathogenic antibodies as novel target in chronic immune-mediated diseases. Andreas Radbruch demonstrated, by targeted mutagenesis, that antibody class switch recombination in activated B lymphocytes is targeted to distinct switch regions by transcription. His group contributed significantly to our current understanding of Th1 and Th2 cytokine memory, its imprinting and plasticity and, more recently, has identified critical molecular adaptations of Th effector memory cells to chronic inflammation. Radbruchs group developed the MACS technology and the cytometric secretion assay. Published online: September 5, 2013