Correction to: Prevalence of vitamin D deficiency and its predictors in the Portuguese population: a nationwide population-based study.

The original version of this article, published on 02 March 2020, unfortunately contained an error on "Fig. 3 Prevalence of Vitamin D Levels by NUTSII."

Prevalence of vitamin D deficiency and its predictors in the Portuguese population: a nationwide population-based study.

Vitamin D deficiency is prevalent worldwide, but its prevalence is unknown in adult Portuguese population. In Portugal, 66% of adults present Vitamin D insufficiency/deficiency. Winter, living in Azores, older age, and obesity were the most important risk factors. It highlights the need of strategies to prevent vitamin D deficiency in Portugal. OBJECTIVE: To estimate the prevalence and risk factors of vitamin D deficiency in the adult Portuguese population. METHODS: Adults (≥ 18 years old) from the EpiReumaPt Study (2011-2013) were included. Standardized questionnaires on socio-demographic and lifestyle features were obtained. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were evaluated using ADVIA Centaur VitD competitive immunoassay (Siemens Healthineers) in 2015-2017 as 25 (OH)D Level 0: ≤ 10 ng/mL; Level 1: 11-19 ng/mL; Level 2: 20-29 ng/mL, and Level 3: ≥ 30 ng/mL. Weighted multinomial regression analysis was conducted to evaluate the association between socio-demographic and lifestyle variables and vitamin D status. RESULTS: Based on weighted analysis, the estimated prevalence of levels of 25(OH)D ≤ 10, < 20, and < 30 ng/mL was 21.2, 66.6, and 96.4%, respectively. The strongest independent predictors of serum 25 (OH)D ≤ 10 ng/mL were living in the Azores archipelagos (OR 9.39; 95%CI 1.27-69.6) and having the blood sample collection in winter (OR 18.53; 95%CI 7.83-43.87) or spring (11.55; 95%CI 5.18-25.74). Other significant predictors included older age (OR 5.65, 95%CI 2.08-15.35), obesity (OR 2.61; 95%CI 1.35-5.08), current smoking (OR 2.33; 95%CI 1.23-4.43), and female gender (OR 1.9, 95%CI 1.1-3.28). Conversely, physical exercise (OR 0.48, 95%CI 0.28-0.81) and occasional alcohol intake (OR 0.48, 95%CI 0.29-0.81) were associated with a lower risk of 25(OH)D ≤ 10 ng/mL. CONCLUSION: Vitamin D deficiency/insufficiency [25(OH)D < 20 ng/ml] is highly prevalent in Portugal, affecting > 60% of all Portuguese adults, with strong geographical and seasonal variation. This study highlights the need to critically assess the relevance of vitamin D deficiency as a public health problem and the urgent need for a wide and scientifically robust debate about the most appropriate interventions at the individual and societal levels.

CD8+ T cell profiles in patients with rheumatoid arthritis and their relationship to disease activity.

OBJECTIVE: CD8+ T cells are abundant in rheumatoid arthritis (RA). However, their role in disease pathogenesis is poorly defined. This study was undertaken to investigate the relationship between disease activity and CD8+ T cell phenotypes, production of cytokines, and production of cytotoxic molecules in the peripheral blood (PB) and synovial fluid (SF) of patients with RA. METHODS: CD8+ T cell phenotypes were determined in 96 patients with RA (44 with disease in remission, 34 with active disease, 18 with low disease activity) and in 64 sex- and age-matched healthy controls. Ten paired PB and SF samples from patients with active RA were analyzed. The expression of surface markers, cytokines, and proteolytic enzymes in CD8+ T cells was evaluated using flow cytometry. RESULTS: PB CD8+ T cells from RA patients with active disease exhibited an effector (CD27-CD62L-) phenotype (P = 0.005), with elevated expression of proinflammatory cytokines (tumor necrosis factor α [TNFα], interferon-γ [IFNγ], interleukin-6 [IL-6], IL-17A) when compared to healthy controls. In a state of remission, the same phenotype observed in patients with active disease persisted, including a significant increase in the frequency of CD69 (P < 0.001), but lower cytokine production was observed. SF CD8+ T cells from RA patients expressed more robust effector memory (CD27+CD62L-) and activated (CD69+) profiles compared to the T cell subsets in paired PB samples. Production of cytokines (IL-6, IL-17A, and IFNγ) by CD8+ T cells from RA PB was positively correlated within individual donors. Moreover, production of cytokines (TNFα, IFNγ, and IL-17A) by CD8+ T cells from RA PB positively correlated with the Disease Activity Score in 28 joints. CONCLUSION: The activation status and proinflammatory potential of CD8+ T cell subsets observed in the RA patients in this study strongly suggest that a phenotype of local and systemic cytotoxic effector T cells plays a role in this disease.

Deficient production of reactive oxygen species leads to severe chronic DSS-induced colitis in Ncf1/p47phox-mutant mice.

BACKGROUND: Colitis is a common clinical complication in chronic granulomatous disease (CGD), a primary immunodeficiency caused by impaired oxidative burst. Existing experimental data from NADPH-oxidase knockout mice propose contradictory roles for the involvement of reactive oxygen species in colitis chronicity and severity. Since genetically controlled mice with a point-mutation in the Ncf1 gene are susceptible to chronic inflammation and autoimmunity, we tested whether they presented increased predisposition to develop chronic colitis. METHODS: Colitis was induced in Ncf1-mutant and wild-type mice by a 1st 7-days cycle of dextran sulfate sodium (DSS), intercalated by a 7-days resting period followed by a 2nd 7-days DSS-cycle. Cytokines were quantified locally in the colon inflammatory infiltrates and in the serum. Leukocyte infiltration and morphological alterations of the colon mucosa were assessed by immunohistochemistry. RESULTS: Clinical scores demonstrated a more severe colitis in Ncf1-mutant mice than controls, with no recovery during the resting period and a severe chronic colitis after the 2nd cycle, confirmed by histopathology and presence of infiltrating neutrophils, macrophages, plasmocytes and lymphocytes in the colon. Severe colitis was mediated by increased local expression of cytokines (IL-6, IL-10, TNF-α, IFN-γ and IL-17A) and phosphorylation of Leucine-rich repeat kinase 2 (LRRK2). Serological cytokine titers of those inflammatory cytokines were more elevated in Ncf1-mutant than control mice, and were accompanied by systemic changes in functional subsets of monocytes, CD4+ T and B cells. CONCLUSION: This suggests that an ineffective oxidative burst leads to severe chronic colitis through local accumulation of peroxynitrites, pro-inflammatory cytokines and lymphocytes and systemic immune deregulation similar to CGD.

Alterations in the peripheral blood B cell subpopulations of multidrug-resistant tuberculosis patients.

The function of B cells in the immune response against Mycobacterium tuberculosis (Mtb) is still regarded as secondary, although major findings in mouse models of tuberculosis (TB) support their participation as regulators and antibody producers. However, studies in cohorts of TB or multidrug-resistant TB (MDR-TB) patients have failed to clearly identify changes in the circulating B cell pool. Therefore, in the present study we aimed at identifying alterations in the different B cell subpopulations in peripheral blood samples of HIV-negative pulmonary MDR-TB patients when compared to healthy donors. The data show, for the first time, that MDR-TB patients, similarly to what has been observed in other chronic inflammatory diseases, have a much lower frequency of peripheral blood unswitched IgD(+)CD27(+) memory B cells. Equally novel are the findings that in MDR-TB patients there is a reduction in the circulating plasma cell pool and that in MDR-TB there is an increased frequency of circulating type 1 transitional IgD(+)CD38(++), CD69(+) and TLR9(+) B cells. These results document disease-related shifts in peripheral blood B cell subsets in MDR-TB and suggest that such changes should be taken into account when designing new strategies to boost the cellular and humoral immune response against Mtb.

Potential roles for CD8(+) T cells in rheumatoid arthritis.

CD8(+) T cells have long been suggested to play a role in rheumatoid arthritis (RA). The current paradigm on the pathogenesis and maintenance of the disease would endorse these cells with predominantly protective and minor influences. However, several animal studies suggest that these cells may have a predominantly proinflammatory (cytotoxic) effect in the disease. Other studies claim otherwise, that they have a mainly regulatory role in inflammatory joints. The evidence in human disease is remarkably scarce. Studies in human samples indicate that CD8(+) T cells play an important role in the establishment of germinal centers observed in nearly 50% of RA patients, which may have a decisive role in the initiation and maintenance of the disease process. The conflicting results of experimental studies, the scarcity of data and the complexity of research needed to unravel these complex interactions may explain the relative oblivion of CD8 cells in the field of arthritis over recent decades. Is this a wise decision or may we run the risk of not finding the key to RA because we search for it where there is light as opposed to its probable location? The present review brings together available data on the potential role of CD8(+) T cells in inflammation, with emphasis on rheumatoid arthritis, hoping to foster interest and fresh research in this area.

Monoclonal anti-CD8 therapy induces disease amelioration in the K/BxN mouse model of spontaneous chronic polyarthritis.

OBJECTIVE: CD8+ T cells are part of the T cell pool infiltrating the synovium in rheumatoid arthritis (RA). However, their role in the pathogenesis of RA has not been fully delineated. Using the K/BxN mouse model of spontaneous chronic arthritis, which shares many similarities with RA, we studied the potential of CD8+ T cell depletion with monoclonal antibodies (mAb) to stop and reverse the progression of experimental arthritis. METHODS: CD8+ T cells from the blood and articular infiltrate of K/BxN mice were characterized for cell surface phenotypic markers and for cytokine production. Additionally, mice were treated with specific anti-CD8 mAb (YTS105 and YTS169.4), with and without thymectomy. RESULTS: CD8+ T cells from the peripheral blood and joints of K/BxN mice were mainly CD69+ and CD62L-CD27+ T cells expressing proinflammatory cytokines (interferon-γ [IFNγ], tumor necrosis factor α [TNFα], interleukin-17a [IL-17A], and IL-4), and granzyme B. In mice receiving anti-CD8 mAb, the arthritis score improved 5 days after treatment. Recovery of the CD8+ T cells was associated with a new increase in the arthritis score after 20 days. In thymectomized and anti-CD8 mAb-treated mice, the arthritis score improved permanently. Histologic analysis showed an absence of inflammatory infiltrate in the anti-CD8 mAb-treated mice. In anti-CD8 mAb-treated mice, the serologic levels of TNFα, IFNγ, IL-6, and IL-5 normalized. The levels of the disease-related anti-glucose-6-phosphate isomerase antibodies did not change. CONCLUSION: These results indicate that synovial activated effector CD8+ T cells locally synthesize proinflammatory cytokines (IFNγ, TNFα, IL-17, IL-6) and granzyme B in the arthritic joint, thus playing a pivotal role in maintaining chronic synovitis in the K/BxN mouse model of arthritis.

CXCL12/CXCR4 promotes motility and proliferation of glioma cells.

Glioblastoma (GBM) is the most aggressive and malignant brain tumor. Recent studies indicated that glioma samples are characterized by increased expression of CXCR4, the CXCL12/SDF-1 chemokine receptor. To better understand the role of CXCR4 in GBM biology we performed an integrated study where we simultaneously evaluate the contribution of the CXCR4/CXCL12 signaling pathway to the proliferation, survival and motility of a human GBM cell line. Our results indicated that CXCR4/CXCL12 axis induced an increase in cell proliferation and in cell motility. The blockage of CXCR4 induced a significant increase of apoptosis. Together, our results indicated that CXCR4/CXCL12 signalling pathway may contribute to GBM development and emphasize the therapeutic potential of this pathway in patients with GBM.