Publications by authors named "Elena Ortona"

74 Publications

Long COVID: to investigate immunological mechanisms and sex/gender related aspects as fundamental steps for a tailored therapy.

Eur Respir J 2021 Sep 16. Epub 2021 Sep 16.

Center for Global Health, Università Cattolica del Sacro Cuore, Rome, Italy

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http://dx.doi.org/10.1183/13993003.02245-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462012PMC
September 2021

Sex-tailored pharmacology and COVID-19: Next steps towards appropriateness and health equity.

Pharmacol Res 2021 Aug 26;173:105848. Epub 2021 Aug 26.

Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy; Centro Studi Nazionale Salute e Medicina di Genere, Italy. Electronic address:

Making gender bias visible allows to fill the gaps in knowledge and understand health records and risks of women and men. The coronavirus disease 2019 (COVID-19) pandemic has shown a clear gender difference in health outcomes. The more severe symptoms and higher mortality in men as compared to women are likely due to sex and age differences in immune responses. Age-associated decline in sex steroid hormone levels may mediate proinflammatory reactions in older adults, thereby increasing their risk of adverse outcomes, whereas sex hormones and/or sex hormone receptor modulators may attenuate the inflammatory response and provide benefit to COVID-19 patients. While multiple pharmacological options including anticoagulants, glucocorticoids, antivirals, anti-inflammatory agents and traditional Chinese medicine preparations have been tested to treat COVID-19 patients with varied levels of evidence in terms of efficacy and safety, information on sex-targeted treatment strategies is currently limited. Women may have more benefit from COVID-19 vaccines than men, despite the occurrence of more frequent adverse effects, and long-term safety data with newly developed vectors are eagerly awaited. The prevalent inclusion of men in randomized clinical trials (RCTs) with subsequent extrapolation of results to women needs to be addressed, as reinforcing sex-neutral claims into COVID-19 research may insidiously lead to increased inequities in health care. The huge worldwide effort with over 3000 ongoing RCTs of pharmacological agents should focus on improving knowledge on sex, gender and age as pillars of individual variation in drug responses and enforce appropriateness.
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http://dx.doi.org/10.1016/j.phrs.2021.105848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387562PMC
August 2021

Chronic Isolation Stress Affects Central Neuroendocrine Signaling Leading to a Metabolically Active Microenvironment in a Mouse Model of Breast Cancer.

Front Behav Neurosci 2021 9;15:660738. Epub 2021 Jul 9.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.

Social isolation is a powerful stressor capable of affecting brain plasticity and function. In the case of breast cancer, previous data indicate that stressful experiences may contribute to a worse prognosis, activating neuroendocrine and metabolism pathways, although the mechanisms underlying these effects are still poorly understood. In this study, we tested the hypothesis that chronic isolation stress (IS) may boost hypothalamic-pituitary-adrenal (HPA) axis activity, leading to changes in the hypothalamic expression of genes modulating both mood and metabolism in an animal model of breast cancer. This centrally activated signaling cascade would, in turn, affect the mammary gland microenvironment specifically targeting fat metabolism, leading to accelerated tumor onset. MMTVNeuTg female mice (a model of breast cancer developing mammary hyperplasia at 5 months of age) were either group-housed (GH) or subjected to IS from weaning until 5 months of age. At this time, half of these subjects underwent acute restraint stress to assess corticosterone (CORT) levels, while the remaining subjects were characterized for their emotional profile in the forced swimming and saccharin preference tests. At the end of the procedures, all the mice were sacrificed to assess hypothalamic expression levels of Brain-derived neurotrophic factor (), Neuropeptide Y (), Agouti-Related Peptide (), and Serum/Glucocorticoid-Regulated Protein Kinase 1 (). Leptin and adiponectin expression levels, as well as the presence of brown adipose tissue (BAT), were assessed in mammary fat pads. The IS mice showed higher CORT levels following acute stress and decreased expression of , and , associated with greater behavioral despair in the forced swimming test. Furthermore, they were characterized by increased consumption of saccharin in a preference test, suggesting an enhanced hedonic profile. The IS mice also showed an earlier onset of breast lumps (assessed by palpation) accompanied by elevated levels of adipokines (leptin and adiponectin) and BAT in the mammary fat pads. Overall, these data point to IS as a pervasive stressor that is able to specifically target neuronal circuits, mastered by the hypothalamus, modulating mood, stress reactivity and energy homeostasis. The activation of such IS-driven machinery may hold main implications for the onset and maintenance of pro-tumorigenic environments.
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http://dx.doi.org/10.3389/fnbeh.2021.660738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298821PMC
July 2021

The Sex-Related Interplay between TME and Cancer: On the Critical Role of Estrogen, MicroRNAs and Autophagy.

Cancers (Basel) 2021 Jun 30;13(13). Epub 2021 Jun 30.

Center for Gender Specific Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.

The interplay between cancer cells and the tumor microenvironment (TME) has a fundamental role in tumor progression and response to therapy. The plethora of components constituting the TME, such as stroma, fibroblasts, endothelial and immune cells, as well as macromolecules, e.g., hormones and cytokines, and epigenetic factors, such as microRNAs, can modulate the survival or death of cancer cells. Actually, the TME can stimulate the genetically regulated programs that the cell puts in place under stress: apoptosis or, of interest here, autophagy. However, the implication of autophagy in tumor growth appears still undefined. Autophagy mainly represents a cyto-protective mechanism that allows cell survival but, in certain circumstances, also leads to the blocking of cell cycle progression, possibly leading to cell death. Since significant sex/gender differences in the incidence, progression and response to cancer therapy have been widely described in the literature, in this review, we analyzed the roles played by key components of the TME, e.g., estrogen and microRNAs, on autophagy regulation from a sex/gender-based perspective. We focused our attention on four paradigmatic and different forms of cancers-colon cancer, melanoma, lymphoma, and lung cancer-concluding that sex-specific differences may exert a significant impact on TME/cancer interaction and, thus, tumor growth.
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http://dx.doi.org/10.3390/cancers13133287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267629PMC
June 2021

Synergy Between Vitamin D and Sex Hormones in Respiratory Functionality of Patients Affected by COVID-19.

Front Pharmacol 2021 13;12:683529. Epub 2021 May 13.

Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy.

The outcome of COVID-19 appears to be influenced by vitamin D status of population. Although epidemiological data indicate that COVID-19 produces more severe symptoms and higher mortality in elderly in comparison to young patients and in men in comparison to women to date sex and age differences in vitamin D status in infected patients have not been evaluated yet. In this study we evaluated the levels of circulating 25(OH)D in patients hospitalized for COVID-19 divided accordingly to their sex and age. We also correlated 25(OH)D levels with patient's respiratory status (i.e., PaO2/FiO2 ratio) and with sex hormones plasma levels to analyze the potential relationship of these parameters. We found no significant differences in plasma levels of 25(OH)D between pre- and post-menopausal female patients and age matched male patients. Interestingly, the 25(OH)D plasma levels positively correlated to PaO2/FiO2 ratio only in young patients, regardless of their sex. We also found a significantly positive correlation between 17β-estradiol and 25(OH)D in elderly women and between testosterone and 25(OH)D in elderly men, supporting the role of sex hormones in maintaining 25(OH)D levels. In conclusion, we suggest that a synergy between vitamin D and sex hormones could contribute to the age-related outcome of COVID-19.
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http://dx.doi.org/10.3389/fphar.2021.683529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155348PMC
May 2021

A Sex Perspective in Neurodegenerative Diseases: microRNAs as Possible Peripheral Biomarkers.

Int J Mol Sci 2021 Apr 23;22(9). Epub 2021 Apr 23.

Department of Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

Sex is a significant variable in the prevalence and incidence of neurological disorders. Sex differences exist in neurodegenerative disorders (NDs), where sex dimorphisms play important roles in the development and progression of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In the last few years, some sex specific biomarkers for the identification of NDs have been described and recent studies have suggested that microRNA (miRNA) could be included among these, as influenced by the hormonal and genetic background. Failing to consider the possible differences between males and females in miRNA evaluation could introduce a sex bias in studies by not considering some of these sex-related biomarkers. In this review, we recapitulate what is known about the sex-specific differences in peripheral miRNA levels in neurodegenerative diseases. Several studies have reported sex-linked disparities, and from the literature analysis miR-206 particularly has been shown to have a sex-specific involvement. Hopefully, in the near future, patient stratification will provide important additional clues in diagnosis, prognosis, and tailoring of the best therapeutic approaches for each patient. Sex-specific biomarkers, such as miRNAs, could represent a useful tool for characterizing subgroups of patients.
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http://dx.doi.org/10.3390/ijms22094423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122918PMC
April 2021

Long COVID: an estrogen-associated autoimmune disease?

Cell Death Discov 2021 Apr 13;7(1):77. Epub 2021 Apr 13.

Center for Global Health, Università Cattolica del Sacro Cuiore, Rome, Italy.

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http://dx.doi.org/10.1038/s41420-021-00464-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042352PMC
April 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

The role of vitamin D in autoimmune diseases: could sex make the difference?

Biol Sex Differ 2021 01 12;12(1):12. Epub 2021 Jan 12.

Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy.

Over the last decades, a central role for vitamin D in immune modulation has been well established. The active form of vitamin D, i.e., 1,25-dihydroxyvitamin D, through the interaction with vitamin D receptor, exerts different activities on the innate and adaptive immune system, among which suppression of inflammation and promotion of tolerogenic responses. Vitamin D insufficiency has been linked to autoimmune disorders that commonly display significant differences between females and males due to genetic, epigenetic, hormonal, and environmental factors. Notably, a number of studies recently showed a cross-talk between vitamin D and the sex hormone estrogen. Estrogen-mediated effects on immune response may favor a Th1 profile or a Th2 profile, depending on hormone concentration. Thus, estrogen-mediated effects appear to be variable on autoimmunity depending on its concentration but also on the pathogenic mechanisms underlying the different autoimmune diseases (i.e., Th1- or Th2-mediated diseases). Notably, estrogen has been demonstrated to enhance vitamin D function favoring its accumulation, and increasing the expression of vitamin D receptor, thus resulting in a more potent anti-inflammatory response in females than males. On the other hand, vitamin D has been shown to downregulate in immune cells the expression of aromatase, which converts testosterone to estrogen, leading to a decrease in estrogen level. Overall, available data allow us to hypothesize a higher protective effect of vitamin D-based therapeutic approaches in women, at least in fertile age, than in men. Future studies are needed to expand current knowledge on the immunomodulatory role of vitamin D in a sex and gender perspective, paving the way to a more personalized therapeutic approach in autoimmune diseases.
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http://dx.doi.org/10.1186/s13293-021-00358-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802252PMC
January 2021

Vitamin D and Sex Differences in COVID-19.

Front Endocrinol (Lausanne) 2020 30;11:567824. Epub 2020 Sep 30.

Center for Gender Specific Medicine, Istituto Superiore di Sanità (ISS), Rome, Italy.

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http://dx.doi.org/10.3389/fendo.2020.567824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554594PMC
November 2020

Stress and coping in women with breast cancer:unravelling the mechanisms to improve resilience.

Neurosci Biobehav Rev 2020 12 18;119:406-421. Epub 2020 Oct 18.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy. Electronic address:

Breast cancer diagnosis, surgery, adjuvant therapies and survivorship can all be extremely stressful. In women, concerns about body image are common as a result of the disease and can affect interpersonal relationships, possibly leading to social isolation, increasing the likelihood for mood disorders. This is particularly relevant as women are at greater risk to develop anxiety and depressive symptoms in response to highly stressful situations. Here we address the mechanisms and the pathways activated as a result of stress and contributing to changes in the pathophysiology of breast cancer, as well as the potential of stress management factors and interventions in buffering the deleterious effects of chronic stress in a gender perspective. An improved understanding of the biological mechanisms linking stress-management resources to health-relevant biological processes in breast cancer patients could reveal novel therapeutic targets and help clarifying which psychosocial interventions can improve cancer outcomes, ultimately offering a unique opportunity to improve contemporary cancer treatments.
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http://dx.doi.org/10.1016/j.neubiorev.2020.10.011DOI Listing
December 2020

A Role for Estrogen Receptor alpha36 in Cancer Progression.

Front Endocrinol (Lausanne) 2020 31;11:506. Epub 2020 Jul 31.

Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy.

Estrogen receptor α (ERα) functions as a ligand dependent transcription factor that directly binds specific estrogen responsive elements, thus regulating the transcription of estrogen sensitive genes. ERα has also been shown to be associated with the plasma membrane (membrane associated ERα, mERα), concentrated in lipid rafts, plasma membrane microdomains with a distinct lipid composition, where it transduces membrane-initiated estrogen-dependent activation of the mitogen-activated protein (MAP) kinase signaling pathway. Two isoforms of ERα have been described: the "traditional" ERα66 (66 kDa) and a lower molecular weight variant: the ERα46 (46 kDa). More recently, a novel ERα variant with a molecular mass of 36 kDa (ERα36) has been discovered. Notably, ERα36 has been found expressed in different human tumor cells, including both ER- positive and ER- negative breast cancer cells. Estrogen signaling at the cell membrane via ERα36 appears as capable of activating multiple pathways of importance for cancer aggressiveness and metastatic potential. The presence of serum autoantibodies reacting with mERα (anti-ERα Abs) in a large percentage of patients with breast cancer has recently been reported by our group. These anti-ERα Abs seem to act as estrogen agonists rapidly triggering MAP kinase pathway activation thus inducing tumor cell proliferation and overcoming cell resistance to anti-estrogen drug tamoxifen. In this review, we describe the involvement of ERα36 in different tumors. We also report the potential pathogenetic activity of anti-ERα Abs and their implication in drug resistance.
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http://dx.doi.org/10.3389/fendo.2020.00506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411082PMC
June 2021

microRNAs as new possible actors in gender disparities of Covid-19 pandemic.

Acta Physiol (Oxf) 2020 09 30;230(1):e13538. Epub 2020 Jul 30.

Center for Gender-Specific Medicine, Istituto Superiore di Sanità, Rome, Italy.

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http://dx.doi.org/10.1111/apha.13538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404333PMC
September 2020

ACE2 expression and sex disparity in COVID-19.

Cell Death Discov 2020 26;6:37. Epub 2020 May 26.

Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy.

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http://dx.doi.org/10.1038/s41420-020-0276-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248455PMC
May 2020

Gender differences in patients with COVID-19: a narrative review.

Monaldi Arch Chest Dis 2020 May 25;90(2). Epub 2020 May 25.

President of GISeG, Italian Group for Health and Gender, Bari.

In December 2019 a novel coronavirus emerged in Wuhan, China causing many cases of severe pneumonia. World Health Organization (WHO) named this disease Coronavirus Disease 2019 (COVID-19). The infection has rapidly spread across China to many other countries, and on March 12, 2020 the WHO declared pandemic outbreak of COVID-19. As of May 16, 2020, COVID-19 has been diagnosed in more than 4,490,000 patients, associated to 305,976 deaths worldwide; in Italy 224,760 COVID-19 cases have been reported with 31,763 deaths. The main routes of transmission are respiratory droplets and direct contact with infected people, so numerous prevention strategies are employed to mitigate the spread of disease, including social distancing and isolation. The aim of this narrative review is to underline gender differences in epidemiology, etiopathogenesis, risk factors, clinical presentation, diagnosis, prognosis and mortality of patients infected with SARS-CoV-2. Currently data on the sex indicators for admitted or deceased patients are only available, but there is no analysis about other gender indicators. The data considered in our study are the only currently available in the literature, but it is appropriate to implement a specific analysis with all gender indicators to identify appropriate strategies. Moreover, the evaluation of a health service efficiency is a key element to define gender outcomes. Knowing the gender differences in COVID-19 outbreak would be a fundamental tool to understand the effects of a health emergency on individuals and communities as well as to carry out effective and equitable policies, public health measures and targeted solutions.
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http://dx.doi.org/10.4081/monaldi.2020.1389DOI Listing
May 2020

Autoantibodies Specific to ERα are Involved in Tamoxifen Resistance in Hormone Receptor Positive Breast Cancer.

Cells 2019 07 19;8(7). Epub 2019 Jul 19.

Center for Gender Specific Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.

Tamoxifen resistance is a major hurdle in the treatment of estrogen receptor (ER)-positive breast cancer. The mechanisms of tamoxifen resistance are not fully understood although several underlying molecular events have been suggested. Recently, we identified autoantibodies reacting with membrane-associated ERα (anti-ERα Abs) in sera of breast cancer patients, able to promote tumor growth. Here, we investigated whether anti-ERα Abs purified from sera of ER-positive breast cancer patients could contribute to tamoxifen resistance. Anti-ERα Abs inhibited tamoxifen-mediated effects on cell cycle and proliferation in MCF-7 cells. Moreover, anti-ERα Abs hampered the tamoxifen-mediated reduction of tumor growth in SCID mice xenografted with breast tumor. Notably, simvastatin-mediated disaggregation of lipid rafts, where membrane-associated ERα is embedded, restored tamoxifen sensitivity, preventing anti-ERα Abs effects. In conclusion, detection of serum anti-ERα Abs may help predict tamoxifen resistance and concur to appropriately inform therapeutic decisions concerning hormone therapy in ER-positive breast cancer patients.
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http://dx.doi.org/10.3390/cells8070750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678306PMC
July 2019

Functional Estrogen Receptors of Red Blood Cells. Do They Influence Intracellular Signaling?

Cell Physiol Biochem 2019 ;53(1):186-199

Center for Gender-Specific Medicine, Istituto Superiore di Sanità, Rome, Italy,

Background/aims: Estrogen could play a key role in the mechanisms underlying sex-related disparity in the incidence of thrombotic events. We investigated whether estrogen receptors (ERs) were expressed in human red blood cells (RBCs), and if they affected cell signaling of erythrocyte constitutive isoform of endothelial NO-synthase (eNOS) and nitric oxide (NO) release.

Methods: RBCs from 29 non-smoker volunteers (15 males and 14 females) aged between 20 and 40 years were analyzed by cytometry and western blot. In particular, content and distribution of ER-α and ER-β, tyrosine kinases and eNOS phosphorylation and NO release were analyzed.

Results: We demonstrated that: i) both ER-α and ER-β were expressed by RBCs; ii) they were both functionally active; and iii) ERs distribution and function were different in males and females. In particular, ERs modulated eNOS phosphorylation and NO release in RBCs from both sexes, but they induced the phosphorylation of specific tyrosine residues of kinases linked to eNOS activation and NO release in the RBCs from females only.

Conclusion: Collectively, these data suggest that ERs could play a critical role in RBC intracellular signaling. The possible implication of this signaling in sex-linked risk disparity in human cardiovascular diseases, e.g. in thrombotic events, may not be ruled out.
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http://dx.doi.org/10.33594/000000129DOI Listing
July 2019

Editorial: Sex Hormones and Gender Differences in Immune Responses.

Front Immunol 2019 9;10:1076. Epub 2019 May 9.

Department of Biology, Pittsburg State University, Pittsburg, KS, United States.

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http://dx.doi.org/10.3389/fimmu.2019.01076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530401PMC
June 2020

Sex Differences in Response to TNF-Inhibiting Drugs in Patients With Spondyloarthropathies or Inflammatory Bowel Diseases.

Front Pharmacol 2019 28;10:47. Epub 2019 Jan 28.

Rheumatology Unit, Nuovo Regina Margherita Hospital, Rome, Italy.

Spondyloarthritis (SpA) and inflammatory bowel diseases (IBD) are chronic inflammatory diseases characterized by an aberrant immune response and inflammation with a key role for TNF in their pathogenesis. Accordingly, TNF-inhibiting therapy (TNFi) has dramatically improved the management of these diseases. However, about 30% of patients discontinue TNFi for lack of response, loss of response, and side effects and/or adverse events. Thus, the possibility to identify in advance those patients who will have a good response to TNFi would be extremely beneficial. The aim of this study was to investigate differences between males and females with either SpA or IBD in response to TNFi molecules, i.e., infliximab (IFX) and adalimumab (ADA), considering the reasons for TNFi withdraw. Data of 594 patients, 349 with IBD (M/F: 194/155) and 245 with SpA (M/F: 123/122), previously unexposed to TNFi, were collected. In the IBD group, the rate of female patients discontinuing ADA was significantly higher than that of male patients ( = 0.03). No difference emerged according to the distribution of reason for discontinuation. Otherwise, a similar discontinuation rate between female and male patients receiving IFX therapy was observed. In the SpA group, the overall discontinuation rate was not different between males and females both for ADA and IFX. However, in patients treated with ADA, males interrupted therapy more frequently than females due to lack of response ( = 0.03). In conclusion, the assessment of sex differences in TNFi response could help physicians personalize the therapeutic approach in a sex-oriented perspective.
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http://dx.doi.org/10.3389/fphar.2019.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360251PMC
January 2019

The Natural Agonist of Estrogen Receptor β Silibinin Plays an Immunosuppressive Role Representing a Potential Therapeutic Tool in Rheumatoid Arthritis.

Front Immunol 2018 17;9:1903. Epub 2018 Aug 17.

Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy.

Estrogens, in particular 17β-estradiol (E2), have a strong influence on the immune system and also affect pathological conditions such as autoimmune diseases. The biological effects of E2 are mediated by two intracellular receptors, i.e., estrogen receptor (ER)α and ERβ, which function as ligand-activated nuclear transcription factors producing genomic effects. Immune cells express both ERα and ERβ that play a complex role in modulating inflammation. Phytoestrogens display estrogen-like effects. Among them, silibinin, the major active constituent of silymarin extracted by the milk thistle (), has been suggested to have an ERβ selective binding. Silibinin is known to have anti-inflammatory, hepatoprotective, and anticarcinogenic effects; however, the role of silibinin in modulating human immune responses and its impact on autoimmunity remains unclear. Aim of this study was to dissect the ability of the ERβ natural ligand silibinin to modulate T cell immunity, taking into account possible differences between females and males, and to define its possible role as therapeutic tool in immune-mediated diseases. To this purpose, female and age-matched male healthy subjects and patients with active rheumatoid arthritis (RA) were recruited. We evaluated the ability of silibinin to modulate ERβ expression in T lymphocytes and its effects on T cell functions (i.e., apoptosis, proliferation, and cytokine production). We also analyzed whether silibinin was able to modulate the expression of microRNA-155 (miR-155), which strongly contributes to the pathogenesis of RA driving aberrant activation of the immune system. We demonstrated that silibinin upregulated ERβ expression, induced apoptosis, inhibited proliferation, and reduced expression of the pro-inflammatory cytokines IL-17 and TNF-α, through ERβ binding, in T lymphocytes from female and male healthy donors. We obtained similar results in T lymphocytes from patients with active RA in term of apoptosis, proliferation, and cytokine production. In addition, we found that silibinin acted as an epigenetic modifier, down-modulating the expression of miR-155. In conclusion, our data demonstrated an immunosuppressive role of silibinin, supporting its application in the treatment of autoimmune diseases as drug, but also as dietary nutritional supplement, opening new perspective in the field of autoimmune disease management.
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http://dx.doi.org/10.3389/fimmu.2018.01903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107853PMC
September 2019

CD4 T lymphocyte autophagy is upregulated in the salivary glands of primary Sjögren's syndrome patients and correlates with focus score and disease activity.

Arthritis Res Ther 2017 07 25;19(1):178. Epub 2017 Jul 25.

Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy.

Background: Primary Sjögren's syndrome (pSS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands and peripheral lymphocyte perturbation. In the current study, we aimed to investigate the possible pathogenic implication of autophagy in T lymphocytes in patients with pSS.

Methods: Thirty consecutive pSS patients were recruited together with 20 patients affected by sicca syndrome and/or chronic sialoadenitis and 30 healthy controls. Disease activity and damage were evaluated according to SS disease activity index, EULAR SS disease activity index, and SS disease damage index. T lymphocytes were analyzed for the expression of autophagy-specific markers by biochemical, molecular, and histological assays in peripheral blood and labial gland biopsies. Serum interleukin (IL)-23 and IL-21 levels were quantified by enzyme-linked immunosorbent assay.

Results: Our study provides evidence for the first time that autophagy is upregulated in CD4 T lymphocyte salivary glands from pSS patients. Furthermore, a statistically significant correlation was detected between lymphocyte autophagy levels, disease activity, and damage indexes. We also found a positive correlation between autophagy enhancement and the increased salivary gland expression of IL-21 and IL-23, providing a further link between innate and adaptive immune responses in pSS.

Conclusions: These findings suggest that CD4 T lymphocyte autophagy could play a key role in pSS pathogenesis. Additionally, our data highlight the potential exploitation of T cell autophagy as a biomarker of disease activity and provide new ground to verify the therapeutic implications of autophagy as an innovative drug target in pSS.
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http://dx.doi.org/10.1186/s13075-017-1385-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526255PMC
July 2017

Anti-mutated citrullinated vimentin antibodies in antiphospholipid syndrome: diagnostic value and relationship with clinical features.

Immunol Res 2017 04;65(2):524-531

Lupus Clinic, Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Viale del Policlinico 155, 00161, Rome, Italy.

Antiphospholipid antibodies (aPLs) are a heterogeneous group of autoantibodies essential for the diagnosis of antiphospholipid syndrome (APS) but do not predict clinical manifestations or disease progression. Hence, the co-presence of other antibodies may prove useful. Autoimmunity directed toward vimentin and other citrullinated peptides was established in rheumatoid arthritis (RA) and in other autoimmune conditions including systemic lupus erythematosus (SLE). We have previously described the presence of autoantibodies directed against vimentin/cardiolipin complex in patients with antiphospholipid syndrome (APS), but there are no data on the role of citrullinated vimentin in APS. Thus, we evaluated the prevalence and clinical significance of anti-MCV in APS patients. The study group consisted of 79 unselected outpatients with APS. Control groups included 25 patients with SLE, 30 patients with RA, and 20 healthy subjects age- and sex-matched. To detect anti-MCV, anti-vimentin, anti-vimentin/cardiolipin, and anti-CCP2 antibodies, commercial or homemade enzyme-linked immunosorbent assays (ELISA) were performed. Anti-MCV antibodies were found in a high percentage of APS patients (26.6%). A significant correlation between anti-MCV and anti-vimentin/cardiolipin serum levels was observed (p = 0.029). Moreover, vimentin reactivity was increased by its citrullination or conjugation with cardiolipin (p = 0.01 and p < 0.001, respectively). Interestingly, anti-MCV was found associated with the presence of arthritis (p = 0.011) and anti-vimentin/cardiolipin was highly specific for the presence of arterial or venous thrombosis in APS (p = 0.003 and p = 0.002, respectively). The detection of additional autoantibodies may contribute to clinical assessment of APS patients. Citrullination may occur in APS and play a role in the pathogenesis of this condition.

Key Points: •Anti-MCV antibodies can be found in APS patients and are associated with the presence of arthritis. •Anti-vimentin/cardiolipin is strongly associated with the presence of thrombosis (both arterial and venous). •Citrullination occurs in APS, participate in disease pathogenesis, and influence clinical picture.
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http://dx.doi.org/10.1007/s12026-017-8899-xDOI Listing
April 2017

Estrogen receptor β ligation inhibits Hodgkin lymphoma growth by inducing autophagy.

Oncotarget 2017 Jan;8(5):8522-8535

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

Although Hodgkin lymphoma (HL) is curable with current therapy, at least 20% of patients relapse or fail to make complete remission. In addition, patients who achieve long-term disease-free survival frequently undergo infertility, secondary malignancies, and cardiac failure, which are related to chemotherapeutic agents and radiation therapies. Hence, new therapeutic strategies able to counteract the HL disease in this important patient population are still a matter of study. Estrogens, in particular 17β-estradiol (E2), have been suggested to play a role in lymphoma cell homeostasis by estrogen receptors (ER) β activation. On these bases, we investigated whether the ligation of ERβ by a selective agonist, the 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), could impact HL tumor growth. We found that DPN-mediated ERβ activation led to a reduction of in vitro cell proliferation and cell cycle progression by inducing autophagy. In nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice engrafted with HL cells, ERβ activation by DPN was able to reduce lymphoma growth up to 60% and this associated with the induction of tumor cell autophagy. Molecular characterization of ERβ-induced autophagy revealed an overexpression of damage-regulated autophagy modulator 2 (DRAM2) molecule, whose role in autophagy modulation is still debated. After ERβ activation, both DRAM2 and protein 1 light chain 3 (LC3), a key actor in the autophagosome formation, strictly interacted each other and localized at mitochondrial level.Altogether these results suggest that targeting ERβ with selective agonists might affect HL cell proliferation and tumor growth via a mechanism that brings into play DRAM2-dependent autophagic cascade.
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http://dx.doi.org/10.18632/oncotarget.14338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352419PMC
January 2017

Anti-GAPDH Autoantibodies as a Pathogenic Determinant and Potential Biomarker of Neuropsychiatric Diseases.

Arthritis Rheumatol 2016 11 9;68(11):2708-2716. Epub 2016 Oct 9.

Istituto Superiore di Sanità, Rome, Italy.

Objective: To investigate the potential role of circulating autoantibodies specific to neuronal cell surface antigens in the pathophysiology of neuropsychiatric disorders.

Methods: Two different kinds of immunoscreening approaches were used to identify autoantigens associated with neuropsychiatric disorders in the serum of patients with schizophrenia. The presence of autoantibodies specific to the identified autoantigens was then tested in patients with various psychiatric disorders and in patients with systemic lupus erythematosus (SLE) and concomitant neuropsychiatric manifestations. Furthermore, the potential pathogenic role of these autoantibodies was assessed both in vitro and in vivo.

Results: GAPDH was identified as a novel autoantigen associated with neuropsychiatric disorders. Serum anti-GAPDH IgG was detected in the serum of 51% of patients with schizophrenia and 50% of patients with major depression. Moreover, SLE patients with comorbid psychiatric manifestations presented significantly higher serum levels of anti-GAPDH antibodies than did SLE patients without psychiatric manifestations (P = 0.004 by chi-square test). Of note, a significant positive correlation (R = 0.48, P = 0.0049, by Spearman's rank correlation test) was found between the levels of serum anti-GAPDH antibodies and cognitive dysfunction in patients with SLE. In vitro analysis of the effects of purified human anti-GAPDH autoantibodies on SH-SY5Y cells showed an immediate neurite retraction. Finally, in vivo administration of anti-GAPDH autoantibodies in the right cerebral ventricle of C57BL/6J mice resulted in specific behavioral changes associated with a detrimental cognitive and emotional profile.

Conclusion: Overall, these data suggest that anti-GAPDH autoantibodies play a role in the pathogenesis of neuropsychiatric disorders, thus representing a potentially promising tool for the screening of individual vulnerability to these disabling conditions.
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http://dx.doi.org/10.1002/art.39750DOI Listing
November 2016

Organ transplantation and gender differences: a paradigmatic example of intertwining between biological and sociocultural determinants.

Biol Sex Differ 2016 28;7:35. Epub 2016 Jul 28.

Section of Gender Medicine, Istituto Superiore di Sanità, Rome, Italy.

Organ transplantation, e.g., of the heart, liver, or kidney, is nowadays a routine strategy to counteract several lethal human pathologies. From literature data and from data obtained in Italy, a striking scenario appears well evident: women are more often donors than recipients. On the other hand, recipients of organs are mainly males, probably reflecting a gender bias in the incidence of transplant-related pathologies. The impact of sex mismatch on transplant outcome remains debated, even though donor-recipient sex mismatch, due to biological matters, appears undesirable in female recipients. In our opinion, the analysis of how sex and gender can interact and affect grafting success could represent a mandatory task for the management of organ transplantation.
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http://dx.doi.org/10.1186/s13293-016-0088-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964018PMC
July 2016

Sex-based differences in autoimmune diseases.

Ann Ist Super Sanita 2016 Apr-Jun;52(2):205-12

Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center (affiliated to Tel-Aviv University), Tel-Hashomer, Israel.

Autoimmune diseases are characterized by an exaggerated immune response leading to damage and dysfunction of specific or multiple organs and tissues. Most autoimmune diseases are more prevalent in women than in men. Symptom severity, disease course, response to therapy and overall survival may also differ between males and females with autoimmune diseases. Sex hormones have a crucial role in this sex bias, with estrogens being potent stimulators of autoimmunity and androgens playing a protective role. Accumulating evidence indicates that genetic, epigenetic and environmental factors may also contribute to sex-related differences in risk and clinical course of autoimmune diseases. In this review, we discuss possible mechanisms for sex specific differences in autoimmunity with a special focus on three paradigmatic diseases: systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.
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http://dx.doi.org/10.4415/ANN_16_02_12DOI Listing
April 2017

A sex and gender perspective in medicine: a new mandatory challenge for human health. Preface.

Ann Ist Super Sanita 2016 Apr-Jun;52(2):146-8

Dipartimento del Farmaco, Istituto Superiore di Sanità, Rome, Italy.

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http://dx.doi.org/10.4415/ANN_16_02_02DOI Listing
April 2017

Autoantibodies specific to estrogen receptor alpha act as estrogen agonists and their levels correlate with breast cancer cell proliferation.

Oncoimmunology 2016 Feb 12;5(2):e1074375. Epub 2015 Aug 12.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy; San Raffaele Pisana Institute, Rome, Italy.

Estrogen receptors have recently been demonstrated at the cell surface. Unlike nuclear receptors, they are able to trigger rapid responses inside the cells. In this study, we evaluated the presence and the possible role of autoantibodies specific to estrogen receptor (anti-ER Abs) in the peripheral blood of breast cancer patients. Anti-ERα Abs were detectable in 22/48 (46%) patients' sera and their levels positively correlated with the percentage of Ki-67-positive breast cancer cells. Anti-ERα Abs purified from breast cancer patients' sera were able: (i) to recognize ERα epitopes expressed at the cell surface of ER-positive breast cancer cells, (ii) to trigger rapid extracellular signal-regulated kinase (ERK) phosphorylation, and (iii) to induce cell proliferation. Our results suggest that anti-ERα Abs can act as estrogen agonists playing a pathogenetic role as breast cancer-promoting factors. These autoantibodies could also be considered as possible peripheral blood biomarkers indicative of the breast cancer growth potential.
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http://dx.doi.org/10.1080/2162402X.2015.1074375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4801453PMC
February 2016

Low expression of estrogen receptor β in T lymphocytes and high serum levels of anti-estrogen receptor α antibodies impact disease activity in female patients with systemic lupus erythematosus.

Biol Sex Differ 2016 12;7. Epub 2016 Jan 12.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

Background: Current evidence indicates that estrogens, in particular 17β-estradiol (E2), play a crucial role in the gender bias of autoimmune diseases although the underlying molecular mechanisms have not yet been fully elucidated. Immune cells have estrogen receptors (ERs), i.e., ERα and ERβ, that play pro- and anti-inflammatory functions, respectively, and the presence of one estrogen receptor (ER) subtype over the other might change estrogen effects, promoting or dampening inflammation. In this study, we contributed to define the influences of E2 on T cells from female patients with systemic lupus erythematosus (SLE), a representative autoimmune disease characterized by a higher prevalence in women than in men (female/male ratio 9:1). Particularly, our aim was to evaluate whether alterations of ERα and ERβ expression in T cells from female SLE patients may impact lymphocyte sensitivity to E2 and anti-ERα antibody (anti-ERα Ab) stimulation interfering with cell signaling and display a direct clinical effect.

Methods: Sixty-one premenopausal female patients with SLE and 40 age-matched healthy donors were recruited. Patients were divided into two groups based on the SLE Disease Activity Index 2000 (SLEDAI-2K) (i.e., <6 and ≥6). ER expression was evaluated in T lymphocytes by flow cytometry, immunofluorescence, and Western blot analyses. Serum anti-ERα Ab levels were analyzed by enzyme-linked immunosorbent assay (ELISA). ER-dependent signaling pathways were measured by a phosphoprotein detection kit.

Results: Intracellular ERβ expression was significantly lower in T cells from patients with SLEDAI-2K ≥6 as compared with healthy donors and patients with SLEDAI-2K <6 and negatively correlated with disease activity. The expression of intracellular and membrane-associated-ERα was similar in SLE and control T cells. ER-dependent signaling pathways were activated in T cells from SLE patients with SLEDAI-2K ≥6, but not with SLEDAI-2K <6, when both membrane and intracellular ERs were stimulated by co-treatment with E2 and anti-ERα Abs.

Conclusions: Our results demonstrate an altered ER profile in SLE patients, possibly contributing to SLE pathogenesis and interfering with clinical activity, and highlight the potential exploitation of T cell-associated ERβ as a biomarker of disease activity.
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http://dx.doi.org/10.1186/s13293-016-0057-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709986PMC
January 2016
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