An Overview of Systematic Reviews of the Role of Vitamin D on Inflammation in Patients with Diabetes and the Potentiality of Its Application on Diabetic Patients with COVID-19.

Almost two years have passed since the outbreak reported for the first time in Wuhan of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome (SARS)-CoV-2 coronavirus, rapidly evolved into a pandemic. This infectious disease has stressed global health care systems. The mortality rate is higher, particularly in elderly population and in patients with comorbidities such as hypertension, diabetes mellitus, cardiovascular disease, chronic lung disease, chronic renal disease, and malignancy. Among them, subjects with diabetes have a high risk of developing severe form of COVID-19 and show increased mortality. How diabetes contributes to COVID-19 severity remains unclear. It has been hypothesized that it may be correlated with the effects of hyperglycemia on systemic inflammatory responses and immune system dysfunction. Vitamin D (VD) is a modulator of immune-response. Data from literature showed that vitamin D deficiency in COVID-19 patients increases COVID-19 severity, likely because of its negative impact on immune and inflammatory responses. Therefore, the use of vitamin D might play a role in some aspects of the infection, particularly the inflammatory state and the immune system function of patients. Moreover, a piece of evidence highlighted a link among vitamin D deficiency, obesity and diabetes, all factors associated with COVID-19 severity. Given this background, we performed an overview of the systematic reviews to assess the association between vitamin D supplementation and inflammatory markers in patients with diabetes; furthermore, vitamin D's possible role in COVID-19 patients was assessed as well. Three databases, namely MEDLINE, PubMed Central and the Cochrane Library of Systematic Reviews, were reviewed to retrieve the pertinent data. The aim of this review is to provide insight into the recent advances about the molecular basis of the relationship between vitamin D, immune response, inflammation, diabetes and COVID-19.

Vitamin D attenuates COVID-19 complications via modulation of proinflammatory cytokines, antiviral proteins, and autophagy.

INTRODUCTION: Global emergence of coronavirus disease-19 (COVID-19) has clearly shown variable severity, mortality, and frequency between and within populations worldwide. These striking differences have made many biological variables attractive for future investigations. One of these variables, vitamin D, has been implicated in COVID-19 with rapidly growing scientific evidence. AREAS COVERED: The review intended to systematically explore the sources, and immunomodulatory role of vitamin D in COVID-19. Search engines and data sources including Google Scholar, PubMed, NCBI, Scopus, and Web of Science were used for data collection. The search terms used were Vitamin D, COVID-19, immune system, and antiviral mechanism. Overall, 232 sources of information were collected and 188 were included in this review. EXPERT OPINION: Interaction of vitamin D and vitamin D receptor (VDR) triggers the cellular events to modulate the immune system by regulation of many genes. Vitamin D operates as a double-edged sword against COVID-19. First, in macrophages, it promotes the production of antimicrobial and antiviral proteins like ß-defensin 2 and cathelicidin, and these proteins inhibit the replication of viral particles and promote the clearance of virus from the cells by autophagy. Second, it suppresses cytokine storm and inflammatory processes in COVID-19.

Role of purinergic system and vitamin D in the anti-cancer immune response.

For several years, scientists have recognized that vitamin D plays an important role in mineral and bone homeostasis. It was mostly used to treat osteoporosis and rickets in the past decades. Vitamin D has also been discovered to be modulator of the immune system and may play a role in a variety of diseases, including autoimmune diseases, in recent years. Vitamin D interaction with the vitamin D receptor (VDR), which has transcriptional imparts and is displayed on a variety of cell types, including those of the immune system, appears to be accountable for the immune-modulating effects. The action of tumor cells and vitamin D were the first to be investigated, but the spotlight is now on immunologic and purinergic systems. We conducted a systematic search in Pub Med as well as Google scholar for studies written in English. Vitamin D, cancer, purinergic signaling, and immune response were among the search words. Vitamin D has the potential to be a useful coadjuvant in cancer therapy and the purinergic system may be a potential treatment target to cancer therapy, according to our findings.

Consumption of Food Supplements during the Three COVID-19 Waves in Poland-Focus on Zinc and Vitamin D.

Food supplements (FS) are a concentrated source of vitamins, minerals, or other ingredients with nutritional or other physiological effects. Due to their easy availability, widespread advertising, and sometimes low price, increased consumption of this group of preparations has been observed. Therefore, the aim of the study was to assess the knowledge and intake of FS during the COVID-19 pandemic in Poland, with particular reference to FS containing zinc and vitamin D. It was noted that both of the above ingredients were used significantly more often by people with higher education (59.0%), with a medical background or related working in the medical field (54.5%), and/or exercising at home (60.1%). Preparations containing vitamin D were used by 22.8% of the respondents in the first wave, 37.6% in the second wave, and 32.9% in the third wave. To sum up, we showed the highest consumption of vitamin and mineral supplements, and preparations containing zinc and vitamin D were taken significantly more often by people with higher medical and related education. This indicates a high awareness of health aspects and the need for preventive measures in these groups.

Regulation of innate immune responses in macrophages differentiated in the presence of vitamin D and infected with dengue virus 2.

A dysregulated or exacerbated inflammatory response is thought to be the key driver of the pathogenesis of severe disease caused by the mosquito-borne dengue virus (DENV). Compounds that restrict virus replication and modulate the inflammatory response could thus serve as promising therapeutics mitigating the disease pathogenesis. We and others have previously shown that macrophages, which are important cellular targets for DENV replication, differentiated in the presence of bioactive vitamin D (VitD3) are less permissive to viral replication, and produce lower levels of pro-inflammatory cytokines. Therefore, we here evaluated the extent and kinetics of innate immune responses of DENV-2 infected monocytes differentiated into macrophages in the presence (D3-MDMs) or absence of VitD3 (MDMs). We found that D3-MDMs expressed lower levels of RIG I, Toll-like receptor (TLR)3, and TLR7, as well as higher levels of SOCS-1 in response to DENV-2 infection. D3-MDMs produced lower levels of reactive oxygen species, related to a lower expression of TLR9. Moreover, although VitD3 treatment did not modulate either the expression of IFN-α or IFN-ß, higher expression of protein kinase R (PKR) and 2'-5'-oligoadenylate synthetase 1 (OAS1) mRNA were found in D3-MDMs. Importantly, the observed effects were independent of reduced infection, highlighting the intrinsic differences between D3-MDMs and MDMs. Taken together, our results suggest that differentiation of MDMs in the presence of VitD3 modulates innate immunity in responses to DENV-2 infection.

Vitamin D-independent benefits of safe sunlight exposure.

This review examines the beneficial effects of ultraviolet radiation on systemic autoimmune diseases, including multiple sclerosis and type I diabetes, where the epidemiological evidence for the vitamin D-independent effects of sunlight is most apparent. Ultraviolet radiation, in addition to its role in the synthesis of vitamin D, stimulates anti-inflammatory pathways, alters the composition of dendritic cells, T cells, and T regulatory cells, and induces nitric oxide synthase and heme oxygenase metabolic pathways, which may directly or indirectly mitigate disease progression and susceptibility. Recent work has also explored how the immune-modulating functions of ultraviolet radiation affect type II diabetes, cancer, and the current global pandemic caused by SARS-CoV-2. These diseases are particularly important amidst global changes in lifestyle that result in unhealthy eating, increased sedentary habits, and alcohol and tobacco consumption. Compelling epidemiological data shows increased ultraviolet radiation associated with reduced rates of certain cancers, such as colorectal cancer, breast cancer, non-Hodgkins lymphoma, and ultraviolet radiation exposure correlated with susceptibility and mortality rates of COVID-19. Therefore, understanding the effects of ultraviolet radiation on both vitamin D-dependent and -independent pathways is necessary to understand how they influence the course of many human diseases.

Celiac Disease and the Thyroid: Highlighting the Roles of Vitamin D and Iron.

Celiac disease (CD) and autoimmune thyroid diseases (AITD) like Hashimoto's thyroiditis (HT) and Graves' disease (GD) frequently coexist, entailing numerous potential impacts on diagnostic and therapeutic approaches. Possible correlations might exist through gut microbiota, regulating the immune system and inflammatory responses, promoting autoimmune diseases, as well as shared cytokines in pathogenesis pathways, cross-reacting antibodies or malabsorption of micronutrients that are essential for the thyroid like iron or vitamin D. Vitamin D deficiency is a common finding in patients with AITD, but might protect from autoimmunity by wielding immunoregulatory and tolerogenic impacts. Additionally, vitamin D is assumed to be involved in the onset and progression of CD, presumably plays a substantial protective role for intestinal mucosa and affects the thyroid via its immunomodulatory effects. Iron is an essential micronutrient for the thyroid gland needed for effective iodine utilization by the iron-dependent enzyme thyroid iodine peroxidase (TPO). Despite being crucial for thyroid hormone synthesis, iron deficiency (ID) is a common finding in patients with hypothyroidism like HT and is frequently found in patients with CD. A literature research was conducted to examine the interplay between CD, AITD, vitamin D and iron deficiency. This narrative review highlights the relevant correlation of the two disease entities CD and AITD, their reciprocal impact and possible therapeutic options that should be further explored by future studies.

Immunomodulation of T Helper Cells by Tumor Microenvironment in Oral Cancer Is Associated With CCR8 Expression and Rapid Membrane Vitamin D Signaling Pathway.

The immune system plays a key role in the protective response against oral cancer; however, the tumor microenvironment (TME) impairs this anti-cancer response by modulating T helper (Th) responses and promoting an anti-inflammatory environment. Regulatory T cells (Tregs) and Th2 effector cells (Teff) are associated with poor prognosis in oral squamous cell carcinoma (OSCC). However, the main immunomodulatory mechanisms associated with the enrichment of these subsets in OSCC remain unknown. We characterized Th-like lineages in Tregs and Teff and evaluated immunomodulatory changes induced by the TME in OSCC. Our phenotypic data revealed a higher distribution of tumour-infiltrating CCR8+ and Th2-like Treg in OSCC compared with non-malignant samples, whereas the percentages of Th1 cells were reduced in cancer. We then analyzed the direct effect of the TME by exposing T cell subsets to cancer secretomes and observed the OSCC secretome induced CCR8 expression and reduced cytokine production from both subsets. Transcriptomic analysis showed that the co-culture with OSCC secretome induced several gene changes associated with the vitamin D (VitD) signaling pathway in T cells. In addition, proteomic analysis identified the presence of several proteins associated with prostaglandin E2 (PGE2) production by rapid membrane VitD signaling and a reduced presence of the VitD binding protein. Thus, we analyzed the effect of VitD and PGE2 and observed that VitD promotes a regulatory Th2-like response with CCR8 expression whilst PGE2 also modulated CCR8 but inhibited cytokine production in combination with VitD. Finally, we evaluated the presence of CCR8 ligand in OSCC and observed increased chemokine CCL18, which was also able to upregulate CCR8 in activated Th cells. Overall, our data showed the immunomodulatory changes induced by the TME involving CCR8 expression and regulatory Th2 phenotypes, which are associated with PGE2 mediated VitD signaling pathway and CCL18 expression in OSCC.

Inhibitory effects of Vitamin D on inflammation and IL-6 release. A further support for COVID-19 management?

The ongoing worldwide pandemic of Coronavirus disease 2019 (COVID-19), raised the urgency to address knowledge gaps and to establish evidence for improving management and control of this viral infection. Throughout a keen analysis of the World Health Organization (WHO) most updated data, a gender-specific difference in the occurrence of infection was determined, which seems to correlate with patient's vitamin D status. Therefore, our purpose is to provide insights into the nutritional importance of vitamin D for its immunomodulatory effect, in order to help counteracting the COVID-19 pandemic. Novel interesting findings suggest that vitamin D, by inducing progesterone-induced blocking factor (PIBF), might regulate the immune response and also modulate cytokine IL-6, which appears to be increased in COVID-19 infections. Therefore, in addition to the standard recommendations to prevent the infection, supplementation of vitamin D might be considered an approach to help counteracting this global epidemic.

Importancia de la Vitamina D en la época del COVID-19 / Importance of Vitamin D in the time of COVID-19

"Los coronavirus pertenecen a una gran familia de virus (Coronaviridae) que infectan aves y varios mamíferos. El coronavirus actualmente denominado SARS-CoV-2, fue descubierto en diciembre de 2019 en Wuhan, provincia de Hubei, China, y es el agente causal de la epidemia de neumonía atípica actual" (COVID-19; Coronavirus Disease 2019). Los casos más graves presentan un síndrome de dificultad respiratoria aguda que puede conducir a la muerte. La vitamina D (VD), además del efecto bien conocido y positivo sobre la salud ósea y la homeostasis del calcio, tiene efecto pleiotrópico en varios órganos, con distribución casi universal del receptor de VD y de las enzimas de metabolización de 25 hidroxivitamina D (25OHD) en las células del organismo. Estas acciones extraesqueléticas dependen de la síntesis en dichas células del metabolito activo 1,25 dihidroxivitamina D por regulación paracrina y autocrina, dependiente de niveles circulantes óptimos de 25OHD. Por sus acciones inmunomoduladora, antiinflamatoria, antimicrobiana, reguladora del sistema renina-angiotensina-aldosterona, favorecedora de la indemnidad del epitelio respiratorio y la homeostasis redox celular, la VD podría tener efecto protector en la infección por COVID-19. Entre los grupos de riesgo para COVID-19 figuran los adultos mayores, obesos, diabéticos, hipertensos, con afecciones cardiovasculares, patologías con mayor incidencia en individuos con hipovitaminosis VD. La suplementación con VD, para alcanzar niveles óptimos de 25OHD de 40-60 ng/ml, podría reducir la incidencia, severidad y riesgo de muerte en la actual pandemia por COVID-19, como medida complementaria mientras se desarrollan la vacuna y otras medicaciones específicas. (AU)

Coronaviruses belong to a large family of viruses (Coronaviridae) that infect birds and various mammals. The novel coronavirus currently known as SARS-CoV-2 was discovered in December 2019 in Wuhan, Hubei province, China and is the causal agent of the current atypical pneumonia epidemic (COVID-19: Coronavirus Disease 2019); The most severe cases present with acute respiratory distress syndrome that can lead to death. Vitamin D (VD) has a pleiotropic effect on several organs, in addition to its wellknown and positive effect on bone health and calcium homeostasis, with an almost universal distribution of the VD receptor and the metabolites of 25hydroxyvitamin D (25OHD) in all cells of the body. These extra-skeletal actions depend on the synthesis of the active metabolite 1,25dihydroxyvitamin D in the cells depending on the optimal circulating levels of 25OHD and though paracrine and autocrine regulation. Due to its immunomodulatory, anti-inflammatory, antimicrobial, and regulatory actions on the renin angiotensin aldosterone system, which favors the compensation of the respiratory epithelium and cellular redox homeostasis, the VD could have a protective effect on COVID-19 infection. Among the risk groups for COVID-19 are obese, diabetic, and hypertensive patients, subjects with cardiovascular conditions, and elderly people. All these pathologies show a higher incidence in individuals with VD hypovitaminosis. VD supplementation, to achieve optimal 25OHD levels of 40-60 ng/ml, could reduce the incidence, severity, and risk of death in the current COVID-19 pandemic, as a complementary measure while the vaccine and other specific therapies are being developed. (AU)

Nuclear Receptors, Ligands and the Mammalian B Cell.

Questions concerning the influences of nuclear receptors and their ligands on mammalian B cells are vast in number. Here, we briefly review the effects of nuclear receptor ligands, including estrogen and vitamins, on immunoglobulin production and protection from infectious diseases. We describe nuclear receptor interactions with the B cell genome and the potential mechanisms of gene regulation. Attention to the nuclear receptor/ligand regulation of B cell function may help optimize B cell responses, improve pathogen clearance, and prevent damaging responses toward inert- and self-antigens.

Insights Into the Role of Vitamin D as a Biomarker in Stem Cell Transplantation.

Vitamin D was discovered 100 years ago and since then multiple studies have consistently proved its effect on bone health and mineral metabolism. Further research has also explored its so-called "non-classical" biological effects, encompassing immune regulation and control of cell proliferation and differentiation. Vitamin D downregulates pro-inflammatory immune cells and subsequently their cytokine production, while enhancing the anti-inflammatory subsets, thus mediating inflammation and fostering a more tolerogenic environment. Its biological action is exerted through the vitamin D receptor, a nuclear receptor that mediates gene transcription and is expressed in most cells from the innate and adaptive immunity. Owing to its immune-modulatory properties, its role in cancer pathophysiology, hematology disorders and stem cell transplantation has also been investigated. Vitamin D deficiency causes immune imbalance and cytokine dysregulation, contributing to some autoimmune diseases. In the hematopoietic stem cell transplant setting this could lead to complications such as acute and chronic graft-versus-host disease, ultimately impacting transplant outcomes. Other factors have also been linked to this, including specific polymorphisms of the vitamin D receptor in both stem cell donors and recipients. Nevertheless, studies thus far have shown conflicting results and the use of vitamin D or its receptor as biomarkers has not been validated yet, therefore there are no evidence-based consensus guidelines to guide clinicians in their day-to-day practice. To gain more insight in this topic, we have reviewed the existent literature and gathered the current evidence. This is an overview of the role of serum vitamin D and its receptor as biomarkers for clinical outcomes in patients undergoing hematopoietic stem cell transplantation. Further prospective studies with larger cohorts are warranted to validate the viability of using serum vitamin D, and its receptor, as biomarkers in potential stem cell donors and patients, to identify those at risk of post-transplant complications and enable early therapeutic interventions.

Arsenic exposure associated T cell proliferation, smoking, and vitamin D in Bangladeshi men and women.

There are limited data examining the consequences of environmental exposure to arsenic on the immune system in adults, particularly among smokers. Smoking has been shown to exacerbate or contribute to impaired immune function in men chronically exposed to arsenic. In contrast, vitamin D (VitD) is known to have a positive influence on innate and adaptive immune responses. The effect of circulating VitD on arsenic-associated immune dysfunction is not known. Here we examine the relationship of arsenic exposure and T cell proliferation (TCP), a measure of immune responsiveness, and circulating VitD among adult men and women in Bangladesh. Arsenic exposure was assessed using total urinary arsenic as well as urinary arsenic metabolites all adjusted for urinary creatinine. TCP was measured ex vivo in cryopreserved peripheral blood mononuclear cells from 614 adult participants enrolled in the Bangladesh Health Effects of Arsenic Longitudinal Study; serum VitD was also evaluated. The influence of cigarette smoking on arsenic-induced TCP modulation was assessed only in males as there was an inadequate number of female smokers. These studies show that arsenic suppressed TCP in males. The association was significantly strong in male smokers and to a lesser extent in male non-smokers. Interestingly, we found a strong protective effect of high/sufficient serum VitD levels on TCP among non-smoking males. Furthermore, among male smokers with low serum VitD (⊔20 ng/ml), we found a strong suppression of TCP by arsenic. On the other hand, high VitD (>20 ng/ml) was found to attenuate effects of arsenic on TCP among male-smokers. Overall, we found a strong protective effect of VitD, when serum levels were >20 ng/ml, on arsenic-induced inhibition of TCP in men, irrespective of smoking status. To our knowledge this is the first large study of immune function in healthy adult males and females with a history of chronic arsenic exposure.

Vitamin D Effects on the Immune System from Periconception through Pregnancy.

Vitamin D is a well-known secosteroid and guardian of bone health and calcium homeostasis. Studies on its role in immunomodulatory functions have expanded its field in recent years. In addition to its impact on human physiology, vitamin D influences the differentiation and proliferation of immune system modulators, interleukin expression and antimicrobial responses. Furthermore, it has been shown that vitamin D is synthesized in female reproductive tissues and, by modulating the immune system, affects the periconception period and reproductive outcomes. B cells, T cells, macrophages and dendritic cells can all synthesize active vitamin D and are involved in processes which occur from fertilization, implantation and maintenance of pregnancy. Components of vitamin D synthesis are expressed in the ovary, decidua, endometrium and placenta. An inadequate vitamin D level has been associated with recurrent implantation failure and pregnancy loss and is associated with pregnancy-related disorders like preeclampsia. This paper reviews the most important data on immunomodulatory vitamin D effects in relation to the immune system from periconception to pregnancy and provides an insight into the possible consequences of vitamin D deficiency before and during pregnancy.

Immunomodulatory Effects of Vitamin D in Thyroid Diseases.

Vitamin D is a secosteroid with a pleiotropic role in multiple physiological processes. Besides the well-known activity on bone homeostasis, recent studies suggested a peculiar role of vitamin D in different non-skeletal pathways, including a key role in the modulation of immune responses. Recent evidences demonstrated that vitamin D acts on innate and adaptative immunity and seems to exert an immunomodulating action on autoimmune diseases and cancers. Several studies demonstrated a relationship between vitamin D deficiency, autoimmune thyroid disorders, and thyroid cancer. This review aims to summarize the evidences on the immunomodulatory effect of vitamin D on thyroid diseases.

Impact of Epigenetics on Complications of Fanconi Anemia: The Role of Vitamin D-Modulated Immunity.

Fanconi anemia (FA) is a rare disorder with the clinical characteristics of (i) specific malformations at birth, (ii) progressive bone marrow failure already during early childhood and (iii) dramatically increased risk of developing cancer in early age, such as acute myeloid leukemia and squamous cell carcinoma. Patients with FA show DNA fragility due to a defect in the DNA repair machinery based on predominately recessive mutations in 23 genes. Interestingly, patients originating from the same family and sharing an identical mutation, frequently show significant differences in their clinical presentation. This implies that epigenetics plays an important role in the manifestation of the disease. The biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 controls cellular growth, differentiation and apoptosis via the modulation of the immune system. The nuclear hormone activates the transcription factor vitamin D receptor that affects, via fine-tuning of the epigenome, the transcription of >1000 human genes. In this review, we discuss that changes in the epigenome, in particular in immune cells, may be central for the clinical manifestation of FA. These epigenetic changes can be modulated by vitamin D suggesting that the individual FA patient's vitamin D status and responsiveness are of critical importance for disease progression.

Potential impact of maternal vitamin D status on peripheral blood and endometrium cellular immunity in women with recurrent implantation failure.

PROBLEM: This study aims to evaluate the modulatory effects of vitamin D on peripheral blood and endometrial cellular immunity in women with recurrent implantation failure (RIF). METHOD OF STUDY: One hundred and fifty-four women with RIF were identified at a fertility center from January 2018 and March 2019. Blood and endometrium samples were collected during the mid-luteal phase before IVF treatment or pregnancy. The serum vitamin D status, NK cell cytotoxicity, Th1 cytokine production, and endometrial immune cells were detected before and after vitamin D supplementation. RESULTS: The NK cell cytotoxicity at an effector:target (E:T) ratio of 50:1 or 25:1 was significantly higher in vitamin D insufficiency group (VDI) than those in vitamin D normal group (VDN) (P < .05 each). The percentage of IFN-γ- or TNF-α-producing Th cells was significantly increased in VDI or vitamin D deficiency group (VDD) when compared with VDN (P < .05 each). The percentage of CD68+ macrophages on all endometrial cells in VDI and VDD was significantly higher than in VDN (P < .05 each), while no significant differences in the percentage of other endometrial immune cells among the three groups were observed. This dysregulation was significantly reduced with vitamin D supplementation. CONCLUSION: Our findings highlighted that vitamin D may have an important role in the regulation of not only systemic but also local immune response for optimization of maternal tolerance for implantation in women with RIF. Pre-conception optimization of vitamin D status should be considered in women with RIF.

Vitamin D deficiency and thyroid autoantibody fluctuations in patients with Graves' disease - A mere coincidence or a real relationship?

PURPOSE: The aim of this study was to evaluate the association between vitamin D (vitD) and changes in the titers of anti-TSH receptor (TSHR-Abs), antithyroglobulin (Tg-Abs), and antiperoxidase (TPO-Abs) autoantibodies. MATERIALS/METHODS: The study involved 269 patients with Graves' disease (GD), divided into four subgroups (1-4), i.e. 65 smokers treated with vitD(+) (1), 76 smokers not treated with vitD(-) (2), 61 non-smokers treated with vitD(+) (3) and 67 non-smokers with vitD(-) (4). All thyroid parameters were analyzed at entry and 1, 3, 6, 9 and 12 months later. RESULTS: The titer of TSHR-Abs in group 3 was significantly lower than in groups 1 and 2 across all time points. At 3, 6 and 12 months, the titers of TSHR-Abs were also lower in group 4 compared to groups 1 and 2. At 9 months, the titers in group 3 were lower than in all other groups. There was a significant inverse correlation between baseline levels of vitD and baseline titers of Tg-Abs (in group 1 only), Tg-Abs after 12 months (in group 1 only), TPO-Abs after 12 months (in groups 1 and 3), fT4 (in group 4 only), and a significant positive correlation with TPO-Abs (in group 2 only). VitD levels at 12 months were inversely correlated with Tg-Abs in group 1. CONCLUSIONS: VitD measurements in patients with GD, especially smokers with an increased TSHR-Ab titers before 131I therapy, are recommended. Immunological remission is more likely in patients with GD who receive vitD, particularly smokers.

Poor ovarian response is associated with serum vitamin D levels and pro-inflammatory immune responses in women undergoing in-vitro fertilization.

Poor ovarian response (POR1) limits the success of infertility treatment modality. In this study, we aim to investigate if POR is associated with serum 25(OH) vitamin D (VD2) levels and pro-inflammatory immune responses in infertile women with a history of in-vitro fertilization and embryo transfer failures. A retrospective cross-sectional study included 157 women with IVF failures. Study patients were divided into four groups based on serum 25(OH)VD level and ovarian responses during the most recent IVF cycle; low VD (LVD3) with POR, LVD with normal ovarian response (NOR4), normal VD (NVD5) with POR, and NVD with NOR. Serum 25(OH)VD level, cellular- and auto-immunity, and metabolic parameters, including homocysteine and plasminogen activator inhibitor-1 were investigated. Peripheral blood CD56+ NK cell levels (%) and NK cytotoxicity were significantly higher in POR-LVD when compared to the other groups (P < 0.05, respectively). CD19 + B and CD19+/5+ B-1 cell levels were significantly higher in women with POR-LVD as compared with those of NOR-LVD and POR-NVD (P < 0.05, respectively). TNF-α/IL-10 producing Th1/Th2 cell ratio of POR-LVD was significantly higher than those of POR-NVD and NOR-NVD (P < 0.05 respectively). Peripheral blood homocysteine level of POR-LVD was significantly higher than those of NOR-LVD and POR-NVD (P < 0.05 respectively). We conclude that assessment of cellular and autoimmune abnormalities and metabolic factors, such as homocysteine should be considered in women with POR and LVD. VD and folic acid supplementation may be explored further as a possible therapeutic option for POR with immune and metabolic etiologies.