Publications by authors named "Ricardo Paiva"

14 Publications

  • Page 1 of 1

Peptidylprolyl isomerase C (Ppic) regulates invariant Natural Killer T cell (iNKT) differentiation in mice.

Eur J Immunol 2021 Aug 5;51(8):1968-1979. Epub 2021 May 5.

Lymphocyte Development and Leukemogenesis Laboratory, Instituto Gulbenkian de Ciência, Calouste Gulbenkian Foundation, Oeiras, Portugal.

Peptidyl-prolyl cis-trans isomerase C (Ppic) is expressed in several bone marrow (BM) hematopoietic progenitors and in T-cell precursors. Since the expression profile of Ppic in the hematoimmune system was suggestive that it could play a role in hematopoiesis and/or T lymphocyte differentiation, we sought to test that hypothesis in vivo. Specifically, we generated a Ppic-deficient mouse model by targeting the endogenous locus by CRISPR/Cas9 and tested the requirement of Ppic in hematopoiesis. Several immune cell lineages covering BM progenitors, lymphocyte precursors, as well as mature cells at the periphery were analyzed. While most lineages were unaffected, invariant NKT (iNKT) cells were reduced in percentage and absolute cell numbers in the Ppic-deficient thymus. This affected the most mature stages in the thymus, S2 and S3, and the phenotype was maintained at the periphery. Additionally, immature transitional T1 and T2 B lymphocytes were increased in the Ppic-deficient spleen, but the phenotype was lost in mature B lymphocytes. In sum, our data show that Ppic is dispensable for myeloid cells, platelets, erythrocytes, αβ, and γδ T lymphocytes in vivo in the steady state, while being involved in B- and iNKT cell differentiation.
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http://dx.doi.org/10.1002/eji.202048924DOI Listing
August 2021

The fermented soy beverage Q-CAN® plus induces beneficial changes in the oral and intestinal microbiome.

BMC Nutr 2021 Mar 4;7(1). Epub 2021 Mar 4.

Department of Pediatrics (General Pediatrics), Yale University School of Medicine, New Haven, USA.

Background: Soy products are associated with many beneficial health consequences, but their effects on the human intestinal microbiome are poorly characterized.

Objectives: To identify the changes in the oral and fecal microbiome in lean and obese participants due to consumption of Q-CAN®, and to assess the expected consequences of these changes based on the published literature.

Methods: Prospective study of lean (10) and obese (9) participants consuming Q-CAN® twice daily for 4 weeks with 8 weeks follow-up. Microbial DNA was extracted from saliva and stool samples, amplified against the V4 region of the 16S ribosomal RNA gene and data analyzed using QIIME 1.9.1 bioinformatics. Four hundred forty-four samples were collected in total, 424 of which were productive and yielded good quality data.

Results: STOOL. In the lean population Bifidobacteria and Blautia show a significant increase while taking Q-CAN®, and there was a trend for this in the obese population. ORAL. There were relatively fewer major changes in the oral microbiome with an increase in the family Veillonellaceae in the lean population while on Q-CAN®.

Conclusion: Q-CAN® consumption induced a number of significant changes in the fecal and oral microbiome. Most notably an increase in the stool microbiome of Bifidobacteria and Blautia, both of which are associated with positive health benefits, and in the saliva an increase in Veillonellaceae.

Trial Registration: This trial was registered with Clinicaltrials.gov on January 14th 2016. ClinicalTrials.gov Identifier: NCT02656056.
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http://dx.doi.org/10.1186/s40795-021-00408-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931600PMC
March 2021

Fermented Soy Beverage Q-CAN Plus Consumption Improves Serum Cholesterol and Cytokines.

J Med Food 2020 May 22;23(5):560-563. Epub 2019 Nov 22.

Department of Pediatrics (General Pediatrics), Yale University School of Medicine, New Haven, Connecticut, USA.

Soy-based beverages are well recognized for their rich nutritional contents and positive health benefits. However, there is little information regarding the composition of various commercially available soy-based beverages and uncertainty among patients regarding the utility of fermented soy products. Current study evaluates the health benefits of QCAN Plus-an easily available fermented soy drink. This study was performed in lean ( = 10) and obese ( = 10) subjects. The subjects were observed during pre-soy (weeks -2, -1, and 0), on-soy (weeks 1, 2, 3, and 4), and post-soy (weeks 6, 8, 10, and 12) periods. The serum samples during these visits were subjected to lipid profile analysis and multiplex assay for cytokines. The results revealed that total cholesterol and low-density lipoprotein (LDL) cholesterol levels were significantly reduced in both lean and obese individuals during on-soy ( ≤ .05). Furthermore, cytokines such as platelet-derived growth factor (PDGF) AA and AB/BB were significantly lowered on-soy compared with pre-soy ( ≤ .05) in lean subjects and PDGF AA, IL-1RA, and GMCSF were significantly reduced on-soy ( ≤ .05) in obese subjects. In addition, a qualitative and quantitative analysis of the Q-CAN Plus by a third-party laboratory confirmed its chemical and microbial safety. Our preliminary study on Q-CAN Plus ensures its safety for consumption and highlights its hypolipidemic and suppressive effect on certain cytokines. These observations and relevant studies in future might guide clinicians in future to consider Q-CAN Plus as a therapeutic nutritional supplement.
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http://dx.doi.org/10.1089/jmf.2019.0116DOI Listing
May 2020

Harnessing the power of regulatory T-cells to control autoimmune diabetes: overview and perspective.

Immunology 2018 02 11;153(2):161-170. Epub 2017 Dec 11.

Department of Immunobiology, Yale University, New Haven, CT, USA.

Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease resulting in islet β-cell destruction, hypoinsulinaemia and severely altered glucose homeostasis. Although the mechanisms that initiate T1D still remain elusive, a breakdown of immune tolerance between effector T-cells (T ) and regulatory T-cells (T ) is considered to be the crucial component leading to autoimmunity. As such, strategies have been developed to boost the number and/or function of T in the hope of specifically hampering the pathogenic T activity. In this review, we will summarize the current understanding of biomarkers and functions of both forkhead box protein 3 (FoxP3) T and type 1 regulatory T (Tr1) cells in health and in T1D, examine the outcome of experimental therapies in both animal models and humans via manipulation of T responses and also provide an outlook on the potential of T -based immunotherapies in the prevention and treatment of this disease. Discussed immunotherapies include adoptive transfer of ex-vivo expanded FoxP3 T , manipulation of T cells via the interleukin (IL)-2/IL-2R pathway and induction of T by tolerogenic peptides, tolerogenic dendritic cells or altered gut microbiota.
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http://dx.doi.org/10.1111/imm.12867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765377PMC
February 2018

A new species of Dolicholana Bruce, 1986 (Isopoda, Cymothoidea, Cirolanidae), the first record of the genus from the Atlantic Ocean.

Zootaxa 2015 Nov 5;4039(2):276-88. Epub 2015 Nov 5.

Universidade Federal de Pernambuco, Museu de Oceanografia Prof. Petrônio Alves Coelho, Laboratório de Carcinologia, Avenida Arquitetura, s/n, Cidade Universitária, CEP 50740-550, Recife, Pernambuco, Brazil.; Email:

The isopod genus Dolicholana Bruce, 1986, previously known only from the Indo-West Pacific, is recorded for the first time from the Atlantic Ocean. A new species, Dolicholana brucei sp. nov., is described from the northeastern Brazilian coast, and is the first record of the genus Dolicholana Bruce, 1986 for the Atlantic Ocean. The material was collected from the upper part of the continental slope off Rio Grande do Norte (150 m depth). The new species is characterized by pereopod 1 propodal palm being crenulate, ischium of pereopod 1 and 2 with a plumose seta on the anterior margin, peduncle of pleopods 3-5 bearing an accessory lobe acute on the distolateral angle, pleotelson posterior margin being rounded, and the uropodal endopod and the exopod apices distally being rounded. A revised key to the genus is provided.
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http://dx.doi.org/10.11646/zootaxa.4039.2.4DOI Listing
November 2015

Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation.

Nature 2015 Jul 29;523(7559):221-5. Epub 2015 Apr 29.

1] Department of Immunobiology, School of Medicine, Yale University, New Haven, 06520, USA [2] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

Inflammation is a beneficial host response to infection but can contribute to inflammatory disease if unregulated. The Th17 lineage of T helper (Th) cells can cause severe human inflammatory diseases. These cells exhibit both instability (they can cease to express their signature cytokine, IL-17A) and plasticity (they can start expressing cytokines typical of other lineages) upon in vitro re-stimulation. However, technical limitations have prevented the transcriptional profiling of pre- and post-conversion Th17 cells ex vivo during immune responses. Thus, it is unknown whether Th17 cell plasticity merely reflects change in expression of a few cytokines, or if Th17 cells physiologically undergo global genetic reprogramming driving their conversion from one T helper cell type to another, a process known as transdifferentiation. Furthermore, although Th17 cell instability/plasticity has been associated with pathogenicity, it is unknown whether this could present a therapeutic opportunity, whereby formerly pathogenic Th17 cells could adopt an anti-inflammatory fate. Here we used two new fate-mapping mouse models to track Th17 cells during immune responses to show that CD4(+) T cells that formerly expressed IL-17A go on to acquire an anti-inflammatory phenotype. The transdifferentiation of Th17 into regulatory T cells was illustrated by a change in their signature transcriptional profile and the acquisition of potent regulatory capacity. Comparisons of the transcriptional profiles of pre- and post-conversion Th17 cells also revealed a role for canonical TGF-β signalling and consequently for the aryl hydrocarbon receptor (AhR) in conversion. Thus, Th17 cells transdifferentiate into regulatory cells, and contribute to the resolution of inflammation. Our data suggest that Th17 cell instability and plasticity is a therapeutic opportunity for inflammatory diseases.
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http://dx.doi.org/10.1038/nature14452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498984PMC
July 2015

Analysis of the sensitivity and specificity of noninvasive imaging tests for the diagnosis of renal artery stenosis.

Arq Bras Cardiol 2013 Nov 24;101(5):423-33. Epub 2013 Sep 24.

Background: Aging and atherosclerosis are related to renovascular hypertension in elderly individuals. Regardless of comorbidities, renal artery stenosis is itself an important cause of cardiovascular morbidity and mortality.

Objective: To define the sensitivity, specificity, positive predictive value, and negative predictive value of noninvasive imaging tests used in the diagnosis of renal artery stenosis.

Methods: In a group of 61 patients recruited, 122 arteries were analized, thus permitting the definition of sensitivity, specificity, and the relative contribution of each imaging study performed (Doppler, scintigraphy and computed tomographic angiography in comparison to renal arteriography).

Results: The mean age was 65.43 years (standard deviation: 8.7). Of the variables related to the study population that were compared to arteriography, two correlated with renal artery stenosis, renal dysfunction and triglycerides. The median glomerular filtration rate was 52.8 mL/min/m². Doppler showed sensitivity of 82.90%, specificity of 70%, a positive predictive value of 85% and negative predictive value of 66.70%. For tomography, sensitivity was 66.70%, specificity 80%, positive predictive value 87.50% and negative predictive value 55.20%. With these findings, we could identify the imaging tests that best detected stenosis.

Conclusion: Tomography and Doppler showed good quality and efficacy in the diagnosis of renal artery stenosis, with Doppler having the advantage of not requiring the use of contrast medium for the assessment of a disease that is common in diabetics and is associated with renal dysfunction and severe left ventricular dysfunction.
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http://dx.doi.org/10.5935/abc.20130191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081166PMC
November 2013

Recent thymic emigrants are the preferential precursors of regulatory T cells differentiated in the periphery.

Proc Natl Acad Sci U S A 2013 Apr 1;110(16):6494-9. Epub 2013 Apr 1.

Instituto Gulbenkian de Ciência, 2780-901 Oeiras, Portugal.

Most Forkhead box P3(+) (Foxp3(+)) CD4 regulatory T cell (Treg) precursors are newly formed thymocytes that acquire Foxp3 expression on antigen encounter in the thymus. Differentiation of Treg, however, can also occur in the periphery. What limits this second layer of self- and nonself-reactive Treg production in physiological conditions remains to be understood. In this work, we tested the hypothesis that, similarly to thymic Treg, the precursors of peripheral Treg are immature T cells. We show that CD4(+)CD8(-)Foxp3(-) thymocytes and recent thymic emigrants (RTEs), contrarily to peripheral naïve mature cells, efficiently differentiate into Treg on transfer into lymphopenic mice. By varying donor and recipient mice and conducting ex vivo assays, we document that the preferential conversion of newly formed T cells does not require intrathymic preactivation, is cell-intrinsic, and correlates with low and high sensitivity to natural inhibitors and inducers of Foxp3 expression, such as IL-6, T-cell receptor triggering, and TGF-β. Finally, ex vivo analysis of human thymocytes and peripheral blood T cells revealed that human RTE and newly developed T cells share an increased potential to acquire a FOXP3(bright)CD25(high) Treg phenotype. Our findings indicating that RTEs are the precursors of Tregs differentiated in the periphery should guide the design of Treg-based therapies.
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http://dx.doi.org/10.1073/pnas.1221955110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631617PMC
April 2013

Sub-optimal CD4+ T-cell activation triggers autonomous TGF-β-dependent conversion to Foxp3+ regulatory T cells.

Eur J Immunol 2011 May;41(5):1249-55

Instituto de Medicina Molecular, Medical School of University of Lisbon, Lisbon, Portugal.

Classical in vitro Treg conversion assays, which rely on optimal T-cell activation in the presence of exogenous TGF-β, induce Foxp3 expression at a frequency far above that which is observed in vivo in Treg-dependent models of oral or transplantation tolerance. We have found that suboptimal murine T-cell activation in vitro results in induction of Foxp3 expression, in the absence of exogenous TGF-β, at a frequency similar to that which we found in vivo upon anti-CD4-induced transplantation tolerance. We show that TCR triggering with either low-dose anti-CD3 or low-dose agonist peptide, as well as down-modulation of the TCR signal with non-depleting anti-CD4, promotes TGF-β production by T cells, an event that precedes Foxp3 expression and is Foxp3 independent. These findings support the view that sub-immunogenic regimens lead to dominant tolerance as a result of T-cell intrinsic properties.
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http://dx.doi.org/10.1002/eji.201040896DOI Listing
May 2011

Cutting edge: Intrathymic differentiation of adaptive Foxp3+ regulatory T cells upon peripheral proinflammatory immunization.

J Immunol 2010 Oct 3;185(7):3829-33. Epub 2010 Sep 3.

Instituto Gulbenkian de Ciência, Oeiras, Portugal.

Thymocytes differentiate into CD4(+) Foxp3(+) regulatory T cells (T(R)) upon interaction between their TCR and peptide-MHC II complexes locally expressed in the thymus. Conversion of naive CD4(+) T cells into T(R) can additionally take place in the periphery under noninflammatory conditions of Ag encounter. In this study, making use of TCR transgenic models naturally devoid of Foxp3(+) cells, we report de novo generation of T(R) upon a single footpad injection of Ag mixed with a classic proinflammatory adjuvant. Abrupt T(R) differentiation upon immunization occurred intrathymically and was essential for robust tolerance induction in a mouse model of spontaneous encephalomyelitis. This phenomenon could be attributed to a specific feature of thymocytes, which, in contrast to mature peripheral CD4(+) T cells, were insensitive to the inhibitory effects of IL-6 on the induction of Foxp3 expression. Our findings uncover a pathway for T(R) generation with major implications for immunity and tolerance induction.
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http://dx.doi.org/10.4049/jimmunol.1001281DOI Listing
October 2010

Validation of cytopathology as a technique for analysis of epithelial cell maturation in oral mucosa of smokers and nonsmokers.

Anal Quant Cytol Histol 2009 Apr;31(2):96-100

Graduate Program in Dentistry, School of Dentistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.

Objective: To validate quantitative analysis of epithelial cells in oral mucosa smears of smokers and nonsmokers.

Study Design: Sixty samples from the oral mucosa of 10 smokers and 10 nonsmokers were collected from the anatomic sites more frequently affected by oral cancer: lower lip, border of the tongue and floor of the mouth. Slides were stained using Papanicolau and Traut techniques; anucleated squamous, nucleated superficial and intermediate cells were counted.

Results: The first 50, the first 100 and all nonoverlapping cells on the slide were counted. To compare percentages of cell types, Pearson's correlation coefficient was used. In the first 50 cells analyzed, there was no significant correlation for anucleated cells in lower lip samples of smokers and border of the tongue samples of nonsmokers; for the other types of cells, a significant correlation was found. For the first 100 cells analyzed, all types of cells in the 3 anatomic sites showed a significant correlation, both in smokers and nonsmokers.

Conclusion: The quantification of the first 100 cells proved to be sufficient to evaluate the epithelial maturation pattern in smears of the lower lip, border of the tongue and floor of the mouth of smokers and nonsmokers.
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April 2009

Tooth fragments lodged in the lower lip after traumatic dental injury: a case report.

Dent Traumatol 2008 Aug;24(4):487-9

Pontifical Catholic University of The State of Rio Grande do Sul, Porto Alegre, Brazil.

Dental fractures are common trauma complications in the oral cavity. The efficient diagnosis and treatment of dental injury are important elements in clinical dentistry. This article describes a case study of trauma in central maxillary incisors with tooth fragments lodged in the lower lip. Radiographs of the soft structures proved themselves as an important tool in the detection and identification of occult tooth fragments, and play an important role in the establishment of the treatment to be adopted. Also, case follow-up is of fundamental significance in the preservation and maintenance of compromised structures.
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http://dx.doi.org/10.1111/j.1600-9657.2008.00565.xDOI Listing
August 2008

Assessment of micronucleus frequency in normal oral mucosa of patients exposed to carcinogens.

Acta Cytol 2005 May-Jun;49(3):265-72

Graduate Program in Dentistry, School of Dentistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Objective: To assess the presence of micronuclei in exfoliated oral mucosal cells collected from 3 anatomic sites in patients exposed to tobacco and alcohol.

Study Design: Smears were prepared with normal oral mucosal cells obtained from the lower lip, tongue border and floor of the mouth of 21 controls, 28 tobacco users and 19 tobacco/alcohol users. Slides were stained with Feulgen stain for quantification of micronucleated cells, karyorrhexis and "broken eggs."

Results: The groups were similar in terms of the mean number of micronucleated cells and cells undergoing karyorrhexis. In the comparison of anatomic sites, the mean number of cells undergoing karyorrhexis was higher on the lower lip than on the tongue border or floor of the mouth (all groups). A significantly higher number of broken eggs was observed in the control group when compared to the tobacco and tobacco/alcohol groups at all anatomic sites.

Conclusion: The higher number of broken eggs in patients not exposed to tobacco and/or alcohol suggests that this nuclear alteration may be associated with DNA repair or a healthy mucosa. A trend toward an increased number of micronucleated cells was observed for tobacco and/or alcohol users at all anatomic sites.
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http://dx.doi.org/10.1159/000326148DOI Listing
July 2005

AgNOR quantification in cells of normal oral mucosa exposed to smoking and alcohol. A cytopathologic study.

Anal Quant Cytol Histol 2004 Jun;26(3):175-80

Department of Oral Pathology, School of Dentistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Objective: To evaluate cell proliferative activity by counting and measuring argyrophilic nucleolar organizer regions (AgNORs) per nucleus in cell smears from mucosa clinically exposed to smoking and alcohol.

Study Design: Group 1 (control) consisted 17 patients, group 2 (smoking) of 25 and group 3 (smoking and alcohol) of 18. Cell smears collected from the mucosa of the lower lip, border of the tongue and floor of the mouth underwent AgNOR staining. Mean number and mean area of AgNORs per nucleus were calculated for the first 50 cells in each smear. ANOVA and the Tukey test were used for statistical analyses at a 5% significance level.

Results: Statistical analyses revealed a greater mean number and larger mean area of AgNORs per nucleus in groups 2 (smoking) and 3 (smoking and alcohol). Samples from the border of the tongue had the lowest mean values for number and area of AgNORs per nucleus in comparison with samples from the lower lip and floor of the mouth in the 3 groups.

Conclusion: Anatomic sites exposed to smoking or to smoking and alcohol had increased cellular proliferative activity.
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June 2004
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