Tγδ LGLL identifies a subset with more symptomatic disease: analysis of an international cohort of 137 patients.

Tγδ large granular lymphocyte leukemia (LGLL) is a rare variant of T-cell LGLL (T-LGLL) that has been less investigated as compared with the more frequent Tαß LGLL, particularly in terms of frequency of STAT3 and STAT5b mutations. In this study, we characterized the clinical and biological features of 137 patients affected by Tγδ LGLL; data were retrospectively collected from 1997 to 2020 at 8 referral centers. Neutropenia and anemia were the most relevant clinical features, being present in 54.2% and 49.6% of cases, respectively, including severe neutropenia and anemia in ∼20% of cases each. Among the various treatments, cyclosporine A was shown to provide the best response rates. DNA samples of 97 and 94 cases were available for STAT3 and STAT5b mutation analysis, with 38.1% and 4.2% of cases being mutated, respectively. Clinical and biological features of our series of Tγδ cases were also compared with a recently published Tαß cohort including 129 cases. Though no differences in STAT3 and STAT5b mutational frequency were found, Tγδ cases more frequently presented with neutropenia (P = .0161), anemia (P < .0001), severe anemia (P = .0065), and thrombocytopenia (P = .0187). Moreover, Vδ2- cases displayed higher frequency of symptomatic disease. Overall, Tγδ cases displayed reduced survival with respect to Tαß cases (P = .0017). Although there was no difference in STAT3 mutation frequency, our results showed that Tγδ LGLL represents a subset of T-LGLL characterized by more frequent symptoms and reduced survival as compared with Tαß LGLL.

Effects of Supplementation with NAD + Precursors on Metabolic Syndrome Parameters: A Systematic Review and Meta-Analysis.

Intracellular levels of NAD + regulate metabolism, among other ways, through enzymes that use NAD + as a substrate, capable of inducing catabolic processes, such as lipid oxidation, glucose uptake, and mitochondrial activity. In several model organisms, administering precursor compounds for NAD + synthesis increases its levels, improves lipid and glucose homeostasis, and reduces weight gain. However, evidence of the effects of these precursors on human patients needs to be better evaluated. Therefore, we carried out a systematic review and meta-analysis of randomized clinical trials that assessed the effects of NAD + precursors on Metabolic Syndrome parameters in humans. We based our methods on PRISMA 2020. Our search retrieved 429 articles, and 19 randomized controlled trials were included in the meta-analysis. We assessed the risk of bias with the Rob 2 algorithm and summarized the quality of evidence with the GRADE algorithm. Supplementation with NAD + precursors reduced plasma levels of total cholesterol and triglycerides in volunteers, but the intervention did not significantly affect the other outcomes analyzed. Three of the included articles presented a high risk of bias. The quality of evidence varied between very low and low due to the risk of bias, imprecision, and indirectness. The number of participants in outcomes other than lipidemia is still generally tiny; therefore, more clinical trials evaluating these parameters will increase the quality of the evidence. On the other hand, quality randomized studies are essential to assess better the effects of NAD + precursors on lipidemia.

Improved Sézary cell detection and novel insights into immunophenotypic and molecular heterogeneity in Sézary syndrome.

Sézary syndrome (SS) is an aggressive leukemic form of cutaneous T-cell lymphoma with neoplastic CD4+ T cells present in skin, lymph nodes, and blood. Despite advances in therapy, prognosis remains poor, with a 5-year overall survival of 30%. The immunophenotype of Sézary cells is diverse, which hampers efficient diagnosis, sensitive disease monitoring, and accurate assessment of treatment response. Comprehensive immunophenotypic profiling of Sézary cells with an in-depth analysis of maturation and functional subsets has not been performed thus far. We immunophenotypically profiled 24 patients with SS using standardized and sensitive EuroFlow-based multiparameter flow cytometry. We accurately identified and quantified Sézary cells in blood and performed an in-depth assessment of their phenotypic characteristics in comparison with their normal counterparts in the blood CD4+ T-cell compartment. We observed inter- and intrapatient heterogeneity and phenotypic changes over time. Sézary cells exhibited phenotypes corresponding with classical and nonclassical T helper subsets with different maturation phenotypes. We combined multiparameter flow cytometry analyses with fluorescence-activated cell sorting and performed RNA sequencing studies on purified subsets of malignant Sézary cells and normal CD4+ T cells of the same patients. We confirmed pure monoclonality in Sézary subsets, compared transcriptomes of phenotypically distinct Sézary subsets, and identified novel downregulated genes, most remarkably THEMIS and LAIR1, which discriminate Sézary cells from normal residual CD4+ T cells. Together, these findings further unravel the heterogeneity of Sézary cell subpopulations within and between patients. These new data will support improved blood staging and more accurate disease monitoring.

Immune cell kinetics and antibody response in COVID-19 patients with low-count monoclonal B-cell lymphocytosis.

Low-count monoclonal B-cell lymphocytosis (MBLlo ) has been associated with an underlying immunodeficiency and has recently emerged as a new risk factor for severe COVID-19. Here, we investigated the kinetics of immune cell and antibody responses in blood during COVID-19 of MBLlo versus non-MBL patients. For this study, we analyzed the kinetics of immune cells in blood of 336 COVID-19 patients (74 MBLlo and 262 non-MBL), who had not been vaccinated against SARS-CoV-2, over a period of 43 weeks since the onset of infection, using high-sensitivity flow cytometry. Plasma levels of anti-SARS-CoV-2 antibodies were measured in parallel by ELISA. Overall, early after the onset of symptoms, MBLlo COVID-19 patients showed increased neutrophil, monocyte, and particularly, plasma cell (PC) counts, whereas eosinophil, dendritic cell, basophil, and lymphocyte counts were markedly decreased in blood of a variable percentage of samples, and with a tendency toward normal levels from week +5 of infection onward. Compared with non-MBL patients, MBLlo COVID-19 patients presented higher neutrophil counts, together with decreased pre-GC B-cell, dendritic cell, and innate-like T-cell counts. Higher PC levels, together with a delayed PC peak and greater plasma levels of anti-SARS-CoV-2-specific antibodies (at week +2 to week +4) were also observed in MBLlo patients. In summary, MBLlo COVID-19 patients share immune profiles previously described for patients with severe SARS-CoV-2 infection, associated with a delayed but more pronounced PC and antibody humoral response once compared with non-MBL patients.

Low-count monoclonal B-cell lymphocytosis persists after seven years of follow up and is associated with a poorer outcome.

Low-count monoclonal B-cell lymphocytosis is defined by the presence of very low numbers of circulating clonal B cells, usually phenotypically similar to chronic lymphocytic leukemia cells, whose biological and clinical significance remains elusive. Herein, we re-evaluated 65/91 low-count monoclonal B-cell lymphocytosis cases (54 chronic lymphocytic leukemia-like and 11 non-chronic lymphocytic leukemia-like) followed-up for a median of seven years, using high-sensitivity flow cytometry and interphase fluorescence in situ hybridization. Overall, the clone size significantly increased in 69% of low-count monoclonal B-cell lymphocytosis cases, but only one subject progressed to high-count monoclonal B-cell lymphocytosis. In parallel, the frequency of cytogenetic alterations increased over time (32% vs 61% of cases, respectively). The absolute number of the major T-cell and natural killer cell populations also increased, but only among chronic lymphocytic leukemia-like cases with increased clone size vs age- and sex-matched controls. Although progression to chronic lymphocytic leukemia was not observed, the overall survival of low-count monoclonal B-cell lymphocytosis individuals was significantly reduced vs non-monoclonal B-cell lymphocytosis controls (P=0.03) plus the general population from the same region (P≤0.001), particularly among females (P=0.01); infection and cancer were the main causes of death in low-count monoclonal B-cell lymphocytosis. In summary, despite the fact that mid-term progression from low-count monoclonal B-cell lymphocytosis to high-count monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia appears to be unlikely, these clones persist at increased numbers, usually carrying more genetic alterations, and might thus be a marker of an impaired immune system indirectly associated with a poorer outcome, particularly among females.

Neurological manifestations of congenital Zika virus infection.

INTRODUCTION: In 2015, it was observed a rise in the number of microcephalic newborns associated with a history of non-specific febrile sickness and rash during pregnancy in Brazil. Since then, microcephaly has emerged as a public health concern. A few months after, the causal relation between congenital microcephaly and the Zika virus was discovered. Zika virus, an arbovirus, is a new TORCH member that leads to congenital infection through vertical transmission and harms the developing brain, disrupting synaptogenesis, and causing other central nervous system lesions. OBJECTIVE: The purpose of this article is to report the congenital Zika syndrome (CZS) and to emphasize the need for follow-up of the affected children to better know the evolutionary history of this new agent and to optimize the provision of healthcare and improve the quality of life of these patients. METHODS: We review the most relevant literature about clinical manifestations and neuroimaging findings related to neurotropism of Zika virus to characterize the congenital Zika syndrome and suggest the systematization of some exams and procedures to evaluate children exposed to ZIKV with or without microcephaly, according to the author's own experience. CONCLUSIONS: Vertical ZIKV infection can cause a wide spectrum of neurological manifestations that go beyond microcephaly, and even the non-microcephalic child should be followed during the first years of life, because infection may be asymptomatic or lead to neuropsicomotor delay, epilepsy, and visual abnormalities. The appropriate prospective multidisciplinary follow-up of these patients aims to understand the natural history of this new agent and to provide a better development and quality of life for them and their families.

Host virus and pneumococcus-specific immune responses in high-count monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia: implications for disease progression.

Patients diagnosed with chronic lymphocytic leukemia (CLL) display a high incidence of infections due to an associated immunodeficiency that includes hypogammaglobulinemia. A higher risk of infections has also been recently reported for high-count monoclonal B-cell lymphocytosis, while no information is available in low-count monoclonal B-cell lymphocytosis. Here, we evaluated the status of the humoral immune system in patients with chronic lymphocytic leukemia (n=58), as well as in low- (n=71) and high- (n=29) count monoclonal B-cell lymphocytosis versus healthy donors (n=91). Total free plasma immunoglobulin titers and specific levels of antibodies against cytomegalovirus, Epstein-Barr virus, influenza and S.pneumoniae were measured by nephelometry and ELISA-based techniques, respectively. Overall, our results show that both CLL and high-count monoclonal B-cell lymphocytosis patients, but not low-count monoclonal B-cell lymphocytosis subjects, present with relatively high levels of antibodies specific for the latent viruses investigated, associated with progressively lower levels of S.pneumoniae-specific immunoglobulins. These findings probably reflect asymptomatic chronic reactivation of humoral immune responses against host viruses associated with expanded virus-specific antibody levels and progressively decreased protection against other micro-organisms, denoting a severe humoral immunodeficiency state not reflected by the overall plasma immunoglobulin levels. Alternatively, these results could reflect a potential role of ubiquitous viruses in the pathogenesis of the disease. Further analyses are necessary to establish the relevance of such asymptomatic humoral immune responses against host viruses in the expansion of the tumor B-cell clone and progression from monoclonal B-cell lymphocytosis to CLL.

Multipronged functional proteomics approaches for global identification of altered cell signalling pathways in B-cell chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is a malignant B cell disorder characterized by its high heterogeneity. Although genomic alterations have been broadly reported, protein studies are still in their early stages. Herein, a 224-antibody microarray has been employed to study the intracellular signalling pathways in a cohort of 14 newly diagnosed B-CLL patients as a preliminary study for further investigations. Several protein profiles were differentially identified across the cytogenetic and molecular alterations presented in the samples (deletion 13q14 and 17p13.1, trisomy 12, and NOTCH1 mutations) by a combination of affinity and MS/MS proteomics approaches. Among others altered cell signalling pathways, PKC family members were identified as down-regulated in nearly 75% of the samples tested with the antibody arrays. This might explain the rapid progression of the disease when showing p53, Rb1, or NOTCH1 mutations due to PKC-proteins family plays a critical role favouring the slowly progressive indolent behaviour of CLL. Additionally, the antibody microarray results were validated by a LC-MS/MS quantification strategy and compared to a transcriptomic CLL database. In summary, this research displays the usefulness of proteomic strategies to globally evaluate the protein alterations in CLL cells and select the possible biomarkers to be further studied with larger sample sizes.

Effect of mTORC1/mTORC2 inhibition on T cell function: potential role in graft-versus-host disease control.

The mechanistic target of rapamycin (mTOR) pathway is crucial for the activation and function of T cells, which play an essential role in the development of graft-versus-host disease (GvHD). Despite its partial ability to block mTOR pathway, the mTORC1 inhibitor rapamycin has shown encouraging results in the control of GvHD. Therefore, we considered that simultaneous targeting of both mTORC1 and mTORC2 complexes could exert a more potent inhibition of T cell activation and, thus, could have utility in GvHD control. To assess this assumption, we have used the dual mTORC1/mTORC2 inhibitors CC214-1 and CC214-2. In vitro studies confirmed the superior ability of CC214-1 versus rapamycin to block mTORC1 and mTORC2 activity and to reduce T cell proliferation. Both drugs induced a similar decrease in Th1/Th2 cytokine secretion, but CC214-1 was more efficient in inhibiting naïve T cell activation and the expression of T-cell activation markers. In addition, CC214-1 induced specific tolerance against alloantigens, while preserving anti-cytomegalovirus response. Finally, in a mouse model of GvHD, the administration of CC214-2 significantly improved mice survival and decreased GvHD-induced damages. In conclusion, the current study shows, for the first time, the immunosuppressive ability of CC214-1 on T lymphocytes and illustrates the role of CC214-2 in the allogeneic transplantation setting as a possible GvHD prophylaxis agent.

Contribution of cerebrospinal fluid sCD19 levels to the detection of CNS lymphoma and its impact on disease outcome.

Flow cytometry (FCM) is more sensitive than conventional cytology for detection of occult leptomeningeal lymphoma; however, some FCM-negative patients show central nervous system (CNS) recurrence. Here, we evaluated the cerebrospinal fluid (CSF) levels of 13 B-cell-associated markers and their contribution to the diagnosis of CNS lymphoma in 91 diffuse large B-cell lymphomas (DLBCL) and 22 Burkitt lymphomas (BLs). From all markers tested, CD19 was the most informative. Thus, higher soluble CD19 (sCD19) levels were associated with a greater frequency of neurological symptoms in DLBCL and BL and with parenchymal CNS lymphoma in DLBCL; sCD19 emerged as a powerful predictor of event-free and overall survival in DLBCL and BL, particularly when combined with FCM detection of CNS disease. These results support the utility of combined FCM detection of lymphoma cells and assessment of sCD19 levels in CSF, for more accurate identification of CNS disease in DLBCL and BL patients.

Subjects with chronic lymphocytic leukaemia-like B-cell clones with stereotyped B-cell receptors frequently show MDS-associated phenotypes on myeloid cells.

An increasing body of evidence suggests the potential occurrence of antigen encounter by the cell of origin in chronic lymphocytic leukaemia (CLL) and CLL-like monoclonal B-cell lymphocytosis (MBL). However, the scenario in which this event might occur remains unknown. In order to gain insight into this scenario we investigated the molecular, cytogenetic and haematological features of 223 CLL-like (n = 84) and CLL (n = 139) clones with stereotyped (n = 32) versus non-stereotyped (n = 191) immunoglobulin heavy chain variable region (IGHV) amino acid sequences. Overall, stereotyped CLL-like MBL and CLL clones showed a unique IGHV profile, associated with higher IGHV1 and lower IGHV3 gene family usage (P = 0·03), longer IGHV complementary determining region 3 (HCDR3) sequences (P = 0·007) and unmutated IGHV (P < 0·001) versus non-stereotyped clones. Whilst the overall size of the stereotyped B-cell clones in peripheral blood did not appear to be associated with the CLL-related cytogenetic profile of B-cells (P > 0·05), it did show a significant association with the presence of myelodysplastic syndrome (MDS)-associated immunophenotypes on peripheral blood neutrophils and/or monocytes (P = 0·01). Altogether our results point to the potential involvement of different selection forces in the expansion of stereotyped vs. non-stereotyped CLL and CLL-like MBL clones, the former being potentially favoured by an underlying altered haematopoiesis.

Immunogenetics shows that not all MBL are equal: the larger the clone, the more similar to CLL.

Chronic lymphocytic leukemia (CLL) -like monoclonal B-cell lymphocytosis (MBL) shares common immunophenotype and cytogenetic abnormalities with CLL, from which it is discriminated by a cutoff value of 5 × 10(9)/L circulating clonal B cells. However, the clonal size in MBL is extremely variable and allows discrimination of two distinct entities (high-count [HC] and low-count [LC]-MBL) based on a cutoff value of 0.5 × 10(9)/L clonal B cells. HC-MBL is associated with lymphocytosis and progresses to CLL requiring treatment at a rate of 1.1% per year, whereas LC-MBL is found in the general population only through high-sensitivity techniques and carries limited, if any, risk of progression. We performed an immunogenetic profiling of 333 cases with CLL-like MBL supplemented by detailed comparisons with CLL, focusing especially on CLL Rai stage 0 (CLL-0). LC- and HC-MBL had similar somatic hypermutation status, yet different IGHV gene repertoires and frequencies of B-cell receptor (BcR) stereotypy. In particular, stereotyped BcRs were infrequent in LC-MBL and were often not CLL specific. In contrast, HC-MBL exhibited clear immunogenetic similarities to CLL-0. These findings indicate that LC-MBL may not represent a true preleukemic condition, thus differing from HC-MBL/CLL-0 in which the identification of factors endowing malignant potential is strongly warranted.

Altered Distribution of Peripheral Blood Maturation-Associated B-Cell Subsets in Chronic Alcoholism.

BACKGROUND: Although decreased counts of peripheral blood (PB) B cells-associated with an apparently contradictory polyclonal hypergammaglobulinemia-have been reported in chronic alcoholism, no information exists about the specific subsets of circulating B cells altered and their relationship with antibody production. Here, we analyzed for the first time the distribution of multiple maturation-associated subpopulations of PB B cells in alcoholism and its potential relationship with the onset of liver disease. METHODS: PB samples from 35 male patients-20 had alcoholic hepatitis (AH) and 15 chronic alcoholism without liver disease (AWLD)-were studied, in parallel to 19 male healthy donors (controls). The distribution of PB B-cell subsets (immature/regulatory, naïve, CD27(-) and CD27(+) memory B lymphocytes, and circulating plasmablasts of distinct immunoglobulin-Ig-isotypes) was analyzed by flow cytometry. RESULTS: Patients with AH showed significantly decreased numbers of total PB B lymphocytes (vs. controls and AWLD), at the expense of immature, memory, and, to a lesser extent, also naïve B cells. AWLD showed reduced numbers of immature and naïve B cells (vs. controls), but higher PB counts of plasmablasts (vs. the other 2 groups). Although PB memory B cells were reduced among the patients, the percentage of surface (s)IgA(+) cells (particularly CD27(-) /sIgA(+) cells) was increased in AH, whereas both sIgG(+) and sIgA(+) memory B cells were significantly overrepresented in AWLD versus healthy donors. Regarding circulating plasmablasts, patients with AH only showed significantly reduced counts of sIgG(+) cells versus controls. In contrast, the proportion of both sIgA(+) and sIgG(+) plasmablasts-from all plasmablasts-was reduced in AH and increased in AWLD (vs. the other 2 groups). CONCLUSIONS: AH and AWLD patients display a significantly reduced PB B-cell count, at the expense of decreased numbers of recently produced immature/regulatory B cells and naïve B cells, together with an increase in Ig-switched memory B lymphocytes and plasmablasts, particularly of IgA(+) cells.

Resin-based luting agents and color stability of bonded ceramic veneers.

STATEMENT OF PROBLEM: The type of resin-based luting agent might influence the color stability of ceramic veneers. PURPOSE: The purpose of this study was to investigate the effects of resin-based agents and aging on the color stability of ceramic veneers bonded to enamel. MATERIAL AND METHODS: Ceramic disks were cemented to bovine enamel disks with 4 resin-based luting agents (n=10): dual-polymerizing cement (RelyX ARC), light-polymerizing cement (RelyX Veneer), flowable composite resin (Filtek Z350 Flow), or composite resin preheated for 30 minutes at 60°C (Filtek Z350 XT). CIE L*, a*, and b* color coordinates were measured 24 hours after cementation (baseline) with a color spectrophotometer and reevaluated after 10,000 and 20,000 thermal cycles. Color variation was calculated by using CIELab (ΔE*(ab)) and CIEDE2000 (ΔE00) methods. Then 95% confidence intervals were calculated for color variation means between baseline and 10,000 thermal cycles and between 10,000 and 20,000 thermal cycles. The 95% confidence intervals were also calculated for the means of individual color coordinates (L*, a*, and b*). RESULTS: The dual-polymerizing cement had the highest color variation among all luting agents. No significant differences were found in color variation among the light-polymerizing materials. All agents showed ΔE*(ab)>3.46 and ΔE00>2.25 after 20,000 thermal cycles. Variations in L*, a*, and b* coordinates were material dependent. The dual-polymerizing agent was yellowish and reddish after aging. CONCLUSIONS: The dual-polymerizing cement had higher color variation than the light-polymerized materials when used for bonding ceramic veneers to enamel. Flowable and preheated composite resins had similar color stability to that of light-polymerizing resin-based cement.

Molecular and cytogenetic characterization of expanded B-cell clones from multiclonal versus monoclonal B-cell chronic lymphoproliferative disorders.

Chronic antigen-stimulation has been recurrently involved in the earlier stages of monoclonal B-cell lymphocytosis, chronic lymphocytic leukemia and other B-cell chronic lymphoproliferative disorders. The expansion of two or more B-cell clones has frequently been reported in individuals with these conditions; potentially, such coexisting clones have a greater probability of interaction with common immunological determinants. Here, we analyzed the B-cell receptor repertoire and molecular profile, as well as the phenotypic, cytogenetic and hematologic features, of 228 chronic lymphocytic leukemia-like and non-chronic lymphocytic leukemia-like clones comparing multiclonal (n=85 clones from 41 cases) versus monoclonal (n=143 clones) monoclonal B-cell lymphocytosis, chronic lymphocytic leukemia and other B-cell chronic lymphoproliferative disorders. The B-cell receptor of B-cell clones from multiclonal cases showed a slightly higher degree of HCDR3 homology than B-cell clones from mono clonal cases, in association with unique hematologic (e.g. lower B-lymphocyte counts) and cytogenetic (e.g. lower frequency of cytogenetically altered clones) features usually related to earlier stages of the disease. Moreover, a subgroup of coexisting B-cell clones from individual multiclonal cases which were found to be phylogenetically related showed unique molecular and cytogenetic features: they more frequently shared IGHV3 gene usage, shorter HCDR3 sequences with a greater proportion of IGHV mutations and del(13q14.3), than other unrelated B-cell clones. These results would support the antigen-driven nature of such multiclonal B-cell expansions, with potential involvement of multiple antigens/epitopes.

Circulating clonotypic B cells in multiple myeloma and monoclonal gammopathy of undetermined significance.

The B-cell compartment in which multiple myeloma stem cells reside remains unclear. We investigated the potential presence of mature, surface-membrane immunoglobulin-positive B lymphocytes clonally related to the tumor bone marrow plasma cells among different subsets of peripheral blood B cells from ten patients (7 with multiple myeloma and 3 with monoclonal gammopathies of undetermined significance). The presence of clonotypic immunoglobulin heavy chain gene rearrangements was determined in multiple highly-purified fractions of peripheral blood B-lymphocytes including surface-membrane IgM(+) CD27(-) naïve B-lymphocytes, plus surface-membrane IgG(+), IgA(+) and IgM(+) memory CD27(+) B cells, and normal circulating plasma cells, in addition to (mono)clonal plasma cells, by a highly-specific and sensitive allele-specific oligonucleotide polymerase chain reaction directed to the CDR3 sequence of the rearranged IGH gene of tumor plasma cells from individual patients. Our results showed systematic absence of clonotypic rearrangements in all the different B-cell subsets analyzed, including M-component isotype-matched memory B-lymphocytes, at frequencies <0.03 cells/µL (range: 0.0003-0.08 cells/µL); the only exception were the myeloma plasma cells detected and purified from the peripheral blood of four of the seven myeloma patients. These results indicate that circulating B cells from patients with multiple myeloma and monoclonal gammopathies of undetermined significance are usually devoid of clonotypic B cells while the presence of immunophenotypically aberrant myeloma plasma cells in peripheral blood of myeloma patients is a relatively frequent finding.

Effects of vitamin D supplementation on metabolic syndrome parameters in patients with obesity or diabetes in Brazil, Europe, and the United States: A systematic review and meta-analysis.

Plasma 25-dihydroxyvitamin D levels appear reduced in patients with obesity or type 2 diabetes, as reported in several observational studies. However, the association between these reduced hormone levels and metabolic parameters is unclear. In any case, vitamin D supplementation in patients with Metabolic Syndrome is standard. Still, the impacts of this supplementation on conditions such as glycemia, blood pressure, and lipidemia are debatable. Based on this question, we carried out a systematic review and meta-analysis of randomized clinical trials in Brazil, Europe, and the United States that analyzed the effects of vitamin D supplementation on Metabolic Syndrome parameters in patients with obesity or type 2 diabetes. Our search yielded 519 articles and included 12 randomized controlled trials in the meta-analysis. Vitamin D supplementation had no effect on any of the outcomes analyzed (fasting blood glucose and insulinemia, glycated hemoglobin, HOMA index, systolic and diastolic blood pressure, weight, waist circumference, total cholesterol, LDL and HDL, and triglycerides). However, subgroup analyses indicated that using vitamin D up to 2000 IU daily reduced participants' fasting blood glucose and glycated hemoglobin. Furthermore, the intervention reduced diastolic blood pressure only in participants with vitamin D deficiency. At least two studies showed a high risk of bias using the Rob2 protocol. According to the GRADE protocol, the evidence quality varied from moderate to very low. These results indicate that vitamin D supplementation does not improve patients' metabolic parameters and that the association between plasma 25-dihydroxyvitamin D levels and Metabolic Syndrome may not be causal but caused by other confounding characteristics. However, in any case, the quality of evidence is still low, and more randomized clinical trials are essential to clarify these relationships.