Human Monocyte-Derived Dendritic Cells Are the Pharmacological Target of the Immunosuppressant Flavonoid Silibinin.

Silibinin, a natural polyphenolic flavonoid, is known to possess anti-inflammatory, anticancer, antioxidant, and immunomodulatory properties. However, the effects of Silibinin on the maturation and immunostimulatory functions of human dendritic cells (DC) remain to be elucidated. In this study, we have attempted to ascertain whether Silibinin influences the maturation, cytokine production, and antigen-presenting capacity of human monocyte-derived DC. We show that Silibinin significantly suppresses the upregulation of costimulatory and MHC molecules in LPS-stimulated mature DC and inhibits lipopolysaccharide (LPS)-induced interleukin (IL)-12, IL-23, and TNF-α production. Furthermore, Silibinin impairs the proliferation response of the allogenic memory CD4 T lymphocytes elicited by LPS-matured DC and their Th1/Th17 profile. These findings demonstrate that Silibinin displays immunosuppressive activity by inhibiting the maturation and activation of human DC and support its potential application of adjuvant therapy in the treatment of autoimmune diseases.

Anti-Inflammatory Effects of 1,25(OH)2D/Calcitriol in T Cell Immunity: Does Sex Make a Difference?

Hypovitaminosis D is involved in various inflammatory, infectious and autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. Moreover, the active form of vitamin D, calcitriol, has been shown to modulate the immune response, playing an anti-inflammatory effect. However little is known about the mechanisms underlying this anti-inflammatory effect and the potential sex differences of calcitriol immune regulation. Hence, the aim of this study was to investigate whether calcitriol could act differently in modulating T cell immunity of age-matched male and female healthy donors. We analyzed the effects of calcitriol in T lymphocytes from healthy women and men on the expression levels of the vitamin D receptor (VDR) and pro- and anti-inflammatory cytokine production. We showed that a treatment with calcitriol induced a significant increase in the VDR expression levels of activated T lymphocytes from male and female healthy subjects. Moreover, we found that calcitriol significantly reduced the expression level of pro-inflammatory cytokines IL-17, INF-γ and TNF-α in the T lymphocytes of both sexes. Notably, we observed that calcitriol induced a significant increase in the expression level of anti-inflammatory cytokine IL-10 only in the T lymphocytes from female healthy donors. In conclusion, our study provides new insights regarding the sex-specific anti-inflammatory role of calcitriol in T cell immunity.

Hormonal Treatment Effect on Sexual Distress in Transgender Persons: 2-Year Follow-Up Data.

INTRODUCTION: As far as we know, no studies to date have investigated the psychobiological correlates of sexual distress (SD) nor the impact of hormonal treatment (HT) on SD in transgender persons. AIM: To evaluate the psychobiological correlates of SD and assess the effects of HT on SD in transgender persons without gender-affirming surgery. METHODS: A consecutive series of 301 transgender persons (160 transwomen and 141 transmen) was considered for the cross-sectional study, and a subset of 72 subjects was studied in a 2-year follow-up. A physical examination was performed. Blood samples were drawn for determination of cortisol levels. Subjects completed psychometric measures. During 2 years of HT, the evaluation of SD was prospectively repeated. MAIN OUTCOME MEASURE: Psychobiological correlates of SD in transgender population. Changes in SD during gender affirming hormonal treatment. CLINICAL IMPLICATIONS: Knowing how hormonal treatment influence SD will help care providers when counseling transgender people. STRENGTHS & LIMITATIONS: To the authors' knowledge, this is the first study prospectively evaluating the impact of gender affirming hormonal treatment on sexual distress in transgender individuals. The main limitations are represented by the small size of the sample and the use of questionnaires validated only in the cisgender population. RESULTS: SD showed a positive correlation with body uneasiness (P < .0001) and with dissatisfaction toward gender-related body parts or shapes (all P < .05). In addition, SD correlated positively with general psychopathology (P < .0001), alexithymia, social anxiety, and humiliation scales (all P < .05). In transmen, SD was positively associated with autism levels (P < .005), as well as with cortisol levels (P < .02). A significant correlation between SD and perceived discrimination was observed in transwomen (P < .05). In transwomen, SD was positively associated with hair density and negatively with breast growth (both P < .05). Finally, in transmen, a negative correlation was found between SD and hair density (P < .05). When the impact of HT on SD was evaluated, a significant reduction of SD was observed across time in both transwomen and transmen (P = .001 and P = .01, respectively). CONCLUSIONS: The present results support the efficacy of HT in reducing SD in transgender persons. Ristori J, Cocchetti C, Castellini G, et al. Hormonal Treatment Effect on Sexual Distress in Transgender Persons: 2-Year Follow-Up Data. J Sex Med 2020;17:142-151.

Membrane lipid rafts and estrogenic signalling: a functional role in the modulation of cell homeostasis.

It has become widely accepted that along with their ability to directly regulate gene expression, estrogens also influence cell signalling and cell function via rapid membrane-initiated events. Many of these signalling processes are dependent on estrogen receptors (ER) localized to the plasma membrane. However, the mechanisms by which ER are able to trigger cell signalling when targeted to the membrane surface have to be determined yet. Lipid rafts seem to be essential for the plasma membrane localization of ER and play a critical role in their membrane-initiated effects. In this review, we briefly recapitulate the localization and function of ER in different cell types and mostly discuss the possible role of lipid rafts in this context. Further studies in this field may disclose new promising therapeutic avenues by the disruption of lipid rafts in those diseases in which membrane ER activation has been demonstrated to play a pathogenetic role.

Autoantibodies specific to D4GDI modulate Rho GTPase mediated cytoskeleton remodeling and induce autophagy in T lymphocytes.

T lymphocytes from patients with Systemic Lupus Erythematosus (SLE) display multiple abnormalities, including increased cell activation, abnormal cell death by apoptosis and impairment of autophagy pathway. In the present study we report the presence of specific antibodies to D4GDI, a small GTPase family inhibitor, in a significant percentage (46%) of SLE patient sera. We also found a significant association between the presence of these autoantibodies and hematologic manifestations occurring in these patients. Investigating the possible implication of anti-D4GDI autoantibodies in SLE pathogenesis or progression, we found that these antibodies were capable of binding D4GDI expressed at the lymphocyte surface and triggering a series of subcellular events, including Rho GTPase activation. These antibodies were also able to induce autophagy in T cells from both healthy donors and SLE patients, but only those negative to these antibodies. We can conclude that anti-D4GDI autoantibodies could be capable of triggering important responses in T cells such as cytoskeleton remodeling and autophagy pathway and that, in SLE patients, the chronic exposure to these specific autoantibodies could lead to the selection of autophagy-resistant T cell clones contributing to the pathogenesis of the disease.

Autophagy as a pathogenic mechanism and drug target in lymphoproliferative disorders.

Autophagy represents a key mechanism of cytoprotection that can be activated by a variety of extracellular and intracellular stresses and allows the cell to sequester cytoplasmic components and damaged organelles, delivering them to lysosomes for degradation and recycling. However, the autophagy process has also been associated with the death of the cell. It has been demonstrated to be constitutive in some instances and inducible in others, and the idea that it could represent a pathogenetic determinant as well as a possible prognostic tool and a therapeutic target in a plethora of human diseases has recently been considered. Among these, cancer represents a major one. In this review, we recapitulate the critical implications of autophagy in the pathogenesis, progression, and treatment of lymphoproliferative disorders. Leukemias and lymphomas, in fact, represent paradigmatic human diseases in which advances have recently been made in this respect.

Autoantibodies specific to a peptide of ß2-glycoprotein I cross-react with TLR4, inducing a proinflammatory phenotype in endothelial cells and monocytes.

ß(2)-glycoprotein I (ß(2)GPI) is the major antigenic target for antiphospholipid Abs. Anti-ß(2)GPI Abs are a heterogeneous population of Igs targeting all domains of the molecule. Abs specific to ß(2)GPI domain I are strongly associated with thrombosis and obstetric complications. In the present study, we sought to understand the possible pathogenic mechanism for this subset of anti-ß(2)GPI Abs, investigating their potential cross-reactivity with other self-proteins involved in inflammatory or coagulant events. We compared the amino acid sequence of the ß(2)GPI domain I with human proteins in a protein databank and identified a peptide sharing 88% identity with an epitope of human TLR4. A high percentage of patients with antiphospholipid syndrome (41%) and systemic lupus erythematosus (50%) presented serum IgG specific to this peptide. Anti-ß(2)GPI peptide Abs binding the TLR4 were able to induce NF-κB activation in HEK293 cells that were stably transfected with the TLR4 gene. Anti-ß(2)GPI peptide Abs induced activation of TLR4 and triggered interleukin-1 receptor-associated kinase phosphorylation and NF-κB translocation, promoting VCAM expression on endothelial cells and TNF-α release by monocytes. In conclusion, our observations suggest a novel pathogenic mechanism in the TLR4 stimulation by anti-ß(2)GPI peptide Abs that links adaptive immune responses with innate immunity in antiphospholipid syndrome and systemic lupus erythematosus.

Diesel exhaust particle exposure in vitro impacts T lymphocyte phenotype and function.

BACKGROUND: Diesel exhaust particles (DEP) are major constituents of ambient air pollution and their adverse health effect is an area of intensive investigations. With respect to the immune system, DEP have attracted significant research attention as a factor that could influence allergic diseases interfering with cytokine production and chemokine expression. With this exception, scant data are available on the impact of DEP on lymphocyte homeostasis. Here, the effects of nanoparticles from Euro 4 (E4) and Euro 5 (E5) light duty diesel engines on the phenotype and function of T lymphocytes from healthy donors were evaluated. METHODS: T lymphocytes were isolated from peripheral blood obtained from healthy volunteers and subsequently stimulated with different concentration (from 0.15 to 60 µg/ml) and at different time points (from 24 h to 9 days) of either E4 or E5 particles. Immunological parameters, including apoptosis, autophagy, proliferation levels, mitochondrial function, expression of activation markers and cytokine production were evaluated by cellular and molecular analyses. RESULTS: DEP exposure caused a pronounced autophagic-lysosomal blockade, thus interfering with a key mechanism involved in the maintaining of T cell homeostasis. Moreover, DEP decreased mitochondrial membrane potential but, unexpectedly, this effect did not result in changes of the apoptosis and/or necrosis levels, as well as of intracellular content of adenosine triphosphate (ATP). Finally, a down-regulation of the expression of the alpha chain of the interleukin (IL)-2 receptor (i.e., the CD25 molecule) as well as an abnormal Th1 cytokine expression profile (i.e., a decrease of IL-2 and interferon (IFN)-γ production) were observed after DEP exposure. No differences between the two compounds were detected in all studied parameters. CONCLUSIONS: Overall, our data identify functional and phenotypic T lymphocyte parameters as relevant targets for DEP cytotoxicity, whose impairment could be detrimental, at least in the long run, for human health, favouring the development or the progression of diseases such as autoimmunity and cancer.

Evaluating the impact of distance learning on gender-affirming healthcare competence: knowledge acquisition and satisfaction among healthcare professionals in Italy.

Background: Transgender and gender diverse (TGD) individuals face significant healthcare barriers, with one of the most critical being the inadequate knowledge and skills of healthcare professionals (HCPs) in TGD health. To address this issue, we undertook a project to develop a distance learning course for all healthcare professions, encompassing a comprehensive range of topics related to TGD health issues. Objectives: This study aimed to evaluate the impact of a course on gender-affirming healthcare competence, with a focus on knowledge acquisition and satisfaction levels. The hypothesis was that participating in the course would enhance the participants' knowledge on the covered topics. Methods: A distance learning course, designed for all Continuing Medical Education professions, was conducted between March and September 2023. The course was structured according to the Problem-Based Learning methodology. We implemented a pre-test vs. post-test study design to evaluate the enhancement of knowledge, based on a set of Multiple Choice Questions (MCQs), and investigated users' satisfaction through the administration of a semi-structured questionnaire. We examined the pre- and post-course proportions of correct responses to questions, along with the mean score difference, categorized by learners' sex, age, and geographical area. Eventually, a Satisfaction Training Index was created. Results: The maximum capacity was reached, with 29,998 out of 30,000 available spots filled. Of those enrolled, 18,282 HCPs successfully completed the training. Post-test results revealed an increase in correct answers across all MCQs, with overall mean score rising from 48.8 to 68.0 (p < 0.001). Stratified analysis indicated improvements across all participant categories. A higher average increase among female (19.87) compared to male enrollees (17.06) was detected (p < 0.001). Both "over 55" and "46-55" age groups showed the greatest score increases compared to "35-46" and "under 35" groups, despite no significant differences in pre-test scores. Course satisfaction was high, averaging 4.38 out of 5. Top-rated aspects included "learning new concepts" (4.49), "accessibility" (4.46), and "platform functionality" (4.46). Conclusion: Our research hypothesis was confirmed by the significant increase in knowledge going from pre-test to post-test and by the high level of user satisfaction. The obtained results serve as a foundation for planning additional professional education in TGD health.

Back to the Future: Is GnRHa Treatment in Transgender and Gender Diverse Adolescents Only an Extended Evaluation Phase?

CONTEXT: The role of body modifications induced by gonadal suppression in transgender and gender diverse adolescents on psychological functioning has not yet been evaluated. OBJECTIVE: The main aim of the present study was to explore several hormone, physical and psychological functioning changes during gonadotropin-releasing hormone analog (GnRHa) treatment in transgender and gender diverse adolescents (TGDAs). The potential relationship between the physical and hormone effects of GnRHa and psychological well-being, along with its magnitude, was assessed for the first time. METHODS: This prospective multidisciplinary study included 36 TGDA (22 assigned female at birth, and 14 assigned male at birth) who received psychological assessment followed by triptorelin prescription after referring to the Florence Gender Clinic. This study consisted of 3 time points: first referral (T0), psychological assessment (T1); and treatment with intramuscular injections of triptorelin for 3 up to 12 months (T2). Psychometric questionnaires were administered at each time point, and clinical and biochemical evaluations were performed at T1 and T2. RESULTS: The following results were found: (1) GnRHa showed efficacy in inhibiting puberty progression in TGDAs; (2) an increase in psychopathology was observed before starting GnRHa (T1) compared with baseline levels; (3) during GnRHa treatment (T2), a significant improvement in psychological functioning, as well as decrease in suicidality, body uneasiness, depression, and anxiety levels were observed; (4) hormone and physical changes (in terms of gonadotropin and sex steroid levels, height and body mass index percentiles, waist-hip ratio, and acne severity) observed during triptorelin treatment significantly correlated with a reduction in suicidal ideation, anxiety, and body image concerns. CONCLUSION: Psychological improvement in TGDA on GnRHa seems to be related to the objective body changes induced by a GnRHa. Therefore, the rationale for treatment with a GnRHa may not only be considered an extension of the evaluation phase, but also the start of a medical (even if reversible) gender-affirming path, especially in TGDAs whose puberty has already progressed.

Dietary Habits, Physical Activity and Body Mass Index in Transgender and Gender Diverse Adults in Italy: A Voluntary Sampling Observational Study.

Transgender and gender-diverse (TGD) individuals continue to experience harassment and discrimination across various aspects of life, significantly impacting their physical and mental health. The scarcity of data on their general health, particularly regarding dietary habits, remains a challenge in developing effective healthcare strategies for this population. To address this gap, we analyzed selected dietary habits, physical activity (PA), and body mass index (BMI) among Italian TGD adults compared to the Italian general population (IGP). An online anonymous survey was conducted via the Computer Assisted Web Interviewing technique from June 2020 to June 2021. Participants were enrolled through clinical centers and TGD organizations. Data from 959 TGD adults were analyzed using chi-squared tests and logistic regression models. Key findings indicated that approximately 70% of TGD individuals consumed fewer servings of fruit and vegetables (FV) than recommended (five or more servings per day). Although red meat consumption was lower overall, a greater percentage of TGD individuals reported consuming more than three servings per week. Additionally, 58% of TGD participants indicated that they did not engage in any PA, compared to 36% of the IGP. Notably, significant differences in BMI were identified, with higher rates of overweight and obesity among TGD individuals assigned female at birth. These results underscore the urgent need for tailored nutritional guidelines and inclusive public health strategies to meet the specific health needs of the Italian TGD population. Expanding access to targeted interventions could contribute to improving overall well-being in this marginalized group.

Role of autophagy in immunity and autoimmunity, with a special focus on systemic lupus erythematosus.

Autophagy is a lysosome-mediated catabolic process that allows cells to degrade unwanted cytoplasmic constituents and to recycle nutrients. Autophagy is also involved in innate and adaptive immune responses, playing a key role in interactions against microbes, in antigen processing for major histocompatibility complex (MHC) presentation, and in lymphocyte development, survival, and proliferation. Over recent years, perturbations in autophagy have been implicated in a number of diseases, including autoimmunity. Systemic lupus erythematosus (SLE) is a multifactorial disease characterized by autoimmune responses against self-antigens generated by dying cells. Genome-wide association studies have linked several single-nucleotide polymorphisms (SNPs) in the autophagy-related gene Atg5 to SLE susceptibility. Loss of Atg5-dependent effects, including clearance of dying cells and cell antigen presentation, might contribute to the autoimmunity and inflammation associated with SLE. Moreover, activation of the mammalian target of rapamycin (mTOR), a key player in the autophagy regulation, has recently been demonstrated in SLE, confirming an altered autophagy pathway in this disease. In the present review, we summarize the autophagy mechanisms, their molecular regulation, and their relevance in immunity and autoimmunity. The potential of targeting autophagy pathway in SLE, by developing innovative therapeutic approaches, has finally been discussed.

T lymphocytes from patients with systemic lupus erythematosus are resistant to induction of autophagy.

Autophagy, the cytoprotection mechanism that takes place under metabolic impairment, has been implicated in the pathogenesis of autoimmunity. Here, we investigated the spontaneous and induced autophagic behavior of T lymphocytes from patients with systemic lupus erythematosus (SLE) compared with that of T lymphocytes from healthy donors by measuring the autophagy marker microtubule-associated protein 1 light chain 3 (LC3)-II. No significant differences in spontaneous autophagy were found between T lymphocytes from patients with SLE and from healthy donors, apart from CD4(+) naive T cells from patients with SLE in which constitutively higher levels of autophagy (P<0.001) were detected. At variance, whereas treatment of T lymphocytes from healthy donors with serum IgG from patients with SLE resulted in a 2-fold increase in LC3-II levels (P<0.001), T lymphocytes from SLE patients were resistant to autophagic induction and also displayed an up-regulation of genes negatively regulating autophagy, e.g., α-synuclein. These findings could open new perspectives in the search for pathogenetic determinants of SLE progression and in the development of therapeutic strategies aimed to recover T-cell compartment homeostasis by restoring autophagic susceptibility.

Autoantibodies to estrogen receptor α interfere with T lymphocyte homeostasis and are associated with disease activity in systemic lupus erythematosus.

OBJECTIVE: Estrogens influence many physiologic processes and are also implicated in the development or progression of numerous diseases, including autoimmune disorders. Aberrations of lymphocyte homeostasis that lead to the production of multiple pathogenic autoantibodies, including autoantibodies specific to estrogen receptor (ER), have been detected in the peripheral blood of patients with systemic lupus erythematosus (SLE). This study was undertaken to assess the presence of both anti-ERα and anti-ERß antibodies in sera from patients with SLE, to analyze the effect of these antibodies on peripheral blood T lymphocyte homeostasis, and to evaluate their role as determinants of disease pathogenesis and progression. METHODS: Anti-ER antibody serum immunoreactivity was analyzed by enzyme-linked immunosorbent assay in samples from 86 patients with SLE and 95 healthy donors. Phenotypic and functional analyses were performed by flow cytometry and Western blotting. RESULTS: Anti-ERα antibodies were present in 45% of the patients with SLE, whereas anti-ERß antibodies were undetectable. In healthy donors, anti-ERα antibodies induced cell activation and consequent apoptotic cell death in resting lymphocytes as well as proliferation of anti-CD3-stimulated T lymphocytes. A significant association between anti-ERα antibody values and clinical parameters, i.e., the SLE Disease Activity Index and arthritis, was found. CONCLUSION: Our data suggest that anti-ERα autoantibodies interfere with T lymphocyte homeostasis and are significantly associated with lupus disease activity.

Phase II study of sorafenib in patients with relapsed or refractory lymphoma.

The safety and activity of the multikinase inhibitor sorafenib were investigated in patients with relapsed or refractory lymphoproliferative disorders who received sorafenib (400 mg) twice daily until disease progression or appearance of significant clinical toxicity. The primary endpoint was overall response rate (ORR). Biomarkers of sorafenib activity were analysed at baseline and during treatment. Thirty patients (median age, 61 years; range, 18-74) received a median of 4 months of therapy. Grade 3-4 toxicities included hand/foot skin reactions (20%), infections (12%), neutropenia (20%) and thrombocytopenia (14%). Two patients achieved complete remission (CR), and two achieved partial remission (PR) for an ORR of 13%. Stable disease (SD) and progressive disease (PD) was observed in 15 (50%) and 11 patients (37%), respectively. The median overall survival (OS) for all patients was 16 months. For patients who achieved CR, PR and SD, the median time to progression and OS was 5 and 24 months, respectively. Compared with patients with PD, responsive patients had significantly higher baseline levels of extracellular signal-regulated kinase phosphorylation and autophagy and presented a significant reduction of these parameters after 1 month of therapy. Sorafenib was well tolerated and had a clinical activity that warrants development of combination regimens.

The Natural Estrogen Receptor Beta Agonist Silibinin as a Promising Therapeutic Tool in Diffuse Large B-cell Lymphoma.

BACKGROUND/AIM: About 40% of patients with diffuse large cell lymphoma (DLBCL) still have a poor prognosis. Additionally, DLBCL patients treated with doxorubicin are at risk of cardiac failure. Growing evidence suggests an antitumor and cardioprotective activity exerted by estrogen via its binding to estrogen receptor (ER) ß. The aim of this study was to evaluate the anticancer activity of the phytoestrogen silibinin, an ERß selective agonist, on DLBCL growth, and its potential cardioprotective effect. MATERIALS AND METHODS: DLBCL cell lines SUDHL-8, SUDHL-6, and RIVA were used. The anti-tumor activity of silibinin was also evaluated in vivo in NOD/SCID/IL2Rg-/- (NSG) xenografted mice. AC16 human ventricular cardiomyocytes were used to investigate the cardioprotective effects of silibinin. RESULTS: In vitro silibinin induced apoptosis and autophagy, and blocked tumor cell proliferation, also protecting AC16 cardiomyocytes from doxorubicin-induced toxicity. In vivo silibinin induced cell death and autophagy, and reduced tumor volume. CONCLUSION: Silibinin represents a promising therapeutic tool.

Prevalence and Correlates of Sexually Transmitted Infections in Transgender People: An Italian Multicentric Cross-Sectional Study.

The burden of sexually transmitted infections (STIs) in the transgender population remains an underestimated issue. The aims of the present study were to evaluate the prevalence of either self-reported and serological STIs and to describe socio-demographic and clinical characteristics of transgender individuals with STIs. A consecutive series of 705 transgender individuals (assigned-male at birth, AMAB n = 377; assigned-female at birth, AFAB n = 328) referring to six Italian gender clinics were included. Sociodemographic and clinical information was collected during the first visit. In a subsample of 126 individuals prevalence of STIs (human immunodeficiency virus, HIV; hepatitis C, HCV; hepatitis B, HBV; syphilis) were evaluated through serology tests. The self-reported prevalence of HIV, HBV, HCV and syphilis infection in the total sample were 3.4%, 1.6%, 2.6% and 2.0%, respectively. In the subsample who underwent serological tests, higher rates of serological prevalence were found (9.5%, 4.0%, 5.6% and 7.9% for HIV, HBV, HCV and syphilis, respectively). When comparing transgender people with or without self-reported STIs, unemployment, previous incarceration, justice problems and sex work resulted more frequent in the first group (p< 0.03 for all). Regarding health status, we observed higher rates of lifetime substance abuse and psychiatric morbidities in trans people with at least one reported STI (p < 0.05). The prevalence of STIs exceeded that reported in general population and STIs correlates underline the importance of stigma and discrimination as determinants of transgender health.

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

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.

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

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 17ß-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.