KARINA INACIO LADISLAU DE CARVALHO SALMAZI
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- Microbial Translocation Is Associated with Extensive Immune Activation in Dengue Virus Infected Patients with Severe Disease(2013) WEG, Cornelia A. M. van de; PANNUTI, Claudio S.; ARAUJO, Evaldo S. A. de; HAM, Henk-Jan van den; ANDEWEG, Arno C.; BOAS, Lucy S. V.; FELIX, Alvina C.; CARVALHO, Karina I.; MATOS, Andreia M. de; LEVI, Jose E.; ROMANO, Camila M.; CENTRONE, Cristiane C.; RODRIGUES, Celia L. de Lima; LUNA, Expedito; GORP, Eric C. M. van; OSTERHAUS, Albert D. M. E.; MARTINA, Byron E. E.; KALLAS, Esper G.Background: Severe dengue virus (DENV) disease is associated with extensive immune activation, characterized by a cytokine storm. Previously, elevated lipopolysaccharide (LPS) levels in dengue were found to correlate with clinical disease severity. In the present cross-sectional study we identified markers of microbial translocation and immune activation, which are associated with severe manifestations of DENV infection. Methods: Serum samples from DENV-infected patients were collected during the outbreak in 2010 in the State of Sao Paulo, Brazil. Levels of LPS, lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14) and IgM and IgG endotoxin core antibodies were determined by ELISA. Thirty cytokines were quantified using a multiplex luminex system. Patients were classified according to the 2009 WHO classification and the occurrence of plasma leakage/shock and hemorrhage. Moreover, a (non-supervised) cluster analysis based on the expression of the quantified cytokines was applied to identify groups of patients with similar cytokine profiles. Markers of microbial translocation were linked to groups with similar clinical disease severity and clusters with similar cytokine profiles. Results: Cluster analysis indicated that LPS levels were significantly increased in patients with a profound pro-inflammatory cytokine profile. LBP and sCD14 showed significantly increased levels in patients with severe disease in the clinical classification and in patients with severe inflammation in the cluster analysis. With both the clinical classification and the cluster analysis, levels of IL-6, IL-8, sIL-2R, MCP-1, RANTES, HGF, G-CSF and EGF were associated with severe disease. Conclusions: The present study provides evidence that both microbial translocation and extensive immune activation occur during severe DENV infection and may play an important role in the pathogenesis.
- Dysregulated CD1 profile in myeloid dendritic cells in CVID is normalized by IVIg treatment(2013) PAQUIN-PROULX, Dominic; SANTOS, Bianca A. N.; CARVALHO, Karina I.; TOLEDO-BARROS, Myrthes; OLIVEIRA, Ana Karolina Barreto de; KOKRON, Cristina M.; KALIL, Jorge; MOLL, Markus; KALLAS, Esper G.; SANDBERG, Johan K.
- Tooth Tissue Engineering: The Influence of Hydrophilic Surface on Nanocrystalline Diamond Films for Human Dental Stem Cells(2013) DUAILIBI, Silvio Eduardo; DUAILIBI, Monica Talarico; FERREIRA, Lydia Masako; SALMAZI, Karina Inacio Ladislau Carvalho; SALVADORI, Maria Cecilia; TEIXEIRA, Fernanda de Sa; PASQUARELLI, Alberto; VACANTI, Joseph Phillip; YELICK, Pamela CrottyNew techniques for tissue engineering (TE) are rapidly emerging. The basic concept of autologous TE is to isolate cells from small biopsy specimens, and to expand these cells in culture for subsequent seeding onto biodegradable scaffolds. Nanocrystalline diamond films have attracted the attention of researchers from a variety of different areas in recent years, due to their unique and exceptional properties. In this approach, human dental stem cells (hDSCs) were characterized by flow cytometry and grown on diamond films with hydrogen (H)-terminated and oxygen (O)-terminated surfaces for 28 days, and then removed by lysis and washing with distilled water. Energy dispersive spectroscopy analysis was performed, showing that the regions with O-terminated surfaces contained much higher levels of deposited calcium, oxygen, and phosphorus. These results suggest that the extracellular matrix was considerably more developed in the O-terminated regions, as compared with the H-terminated regions. In addition, optical microscopy of hDSCs cultured on the diamond substrate with H- and O-terminated surfaces, before washing with distilled water, showed preferential directions of the cells arrangement, where orthogonal lines suggest that the cells appeared to be following the O-terminated regions or hydrophilic surface. These findings suggest that O-terminated diamond surfaces prepared on biodegradable scaffolds can be useful for mineralized dental tissue formation.
- Early immunologic and virologic predictors of clinical HIV-1 disease progression(2013) MAHNKE, Yolanda D.; SONG, Kaimei; SAUER, Mariana M.; NASON, Martha C.; GIRET, Maria Teresa M.; CARVALHO, Karina I.; COSTA, Priscilla R.; ROEDERER, Mario; KALLAS, Esper G.Objective: To identify early determinants of HIV-1 disease progression, which could potentially enable individualized patient treatment, and provide correlates of progression applicable as reference phenotypes to evaluate breakthrough infections in vaccine development. Design: High-throughput technologies were employed to interrogate multiple parameters on cryopreserved, retrospective peripheral blood mononuclear cell (PBMC) samples from 51 individuals from Sao Paulo, Brazil, obtained within 1 year of diagnosing early Clade B HIV-1 infection. Fast Progressors, Slow Progressors, and Controllers were identified based on a 2-year clinical follow-up. Methods: Phenotypic and functional T-cell parameters were tested by flow cytometry and qPCR to identify potential early determinants of subsequent HIV-1 disease progression. Results: Major differences were observed between Controllers and Progressors, especially in cell-associated viral load (CAVL), the differentiation pattern and CD38 expression of CD8(+) T cells, and the cytokine pattern and activation phenotype of HIV-1-specific CD8(+) T cells. Despite remarkably few other differences between the two Progressor groups, the CAVL had predictive power independent of plasma viral load. Conclusion: Analysis of three parameters (% CD38(+)CD8(+) T cells, total CAVL,% CCR5(+) CD8(+) T cells) was sufficient to predict subsequent disease progression (P < 0.001). Use of such prognostic correlates may be crucial when early CD4(+) T-cell counts and plasma viral load levels fail to discriminate among groups with differing subsequent clinical progression. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins AIDS 2013, 27:697-706
- HCV Viremia Drives an Increment of CD86 Expression by Myeloid Dendritic Cells(2013) MALTA, F. M.; BRUNO, F. R.; CARVALHO, K. I.; NASTRI, A. C. S. S.; KALIL, J.; CARRILHO, F. J.; KALLAS, E. G.; PINHO, J. R. R.The host immune response, including innate and adaptive immunity, plays a critical role in determining the outcome of viral infection. Nevertheless, little is known about the exact reasons for the failure of the host immune system in controlling hepatitis C virus (HCV) infection. Impairment of dendritic cells (DCs) function is probably one of the mechanisms responsible for immune evasion of HCV. In this study, the frequency and phenotype of DCs subsets were analyzed in three groups: HCV-infected individuals who developed viral persistence (1), HCV-infected individuals who spontaneously cleared the virus (2) and HCV-seronegative uninfected subjects (3). The results showed that the frequency of DCs subsets was not statistically significant between groups. Plasmacytoid DCs circulating exhibited an immature phenotype characterized by low expression of CD86. On the other hand, CD86 expression in myeloid DCs was significantly higher in chronic infected individuals compared to healthy controls (P=0.037). A positive correlation was observed between CD86(+) myeloid DC (mDC) and HCV viral load (r=0.4121, P=0.0263). These results suggest that HCV did not have an inhibitory effect on mDC maturation and the HCV viremia drives the increase of CD86 expression in mDC. The regulation of DCs maturation and migration lies at the level of intracellular signaling. HCV can activate or block intracellular signaling pathways and alter DC function. In conclusion, the present study suggests that imbalance of DC maturation by the virus represents a mechanism of evasion of the immune system despite the fact that HCV viremia appears to exert a stimulatory effect on cell-surface immune phenotype. J Med. Virol. 85:1919-1924, 2013. (c) 2013 Wiley Periodicals, Inc.
- Variability of HIV-1 Genomes among Children and Adolescents from Sao Paulo, Brazil(2013) SANABANI, Sabri Saeed; PESSOA, Rodrigo; OLIVEIRA, Ana Carolina Soares de; MARTINEZ, Vanessa Pouza; GIRET, Maria Teresa Maidana; SUCCI, Regina Celia de Menezes; CARVALHO, Karina; TOMIYAMA, Claudia Satiko; NIXON, Douglas F.; SABINO, Ester Cerdeira; KALLAS, Esper GeorgesBackground: Genetic variability is a major feature of the human immunodeficiency virus type 1 (HIV-1) and considered the key factor to frustrating efforts to halt the virus epidemic. In this study, we aimed to investigate the genetic variability of HIV-1 strains among children and adolescents born from 1992 to 2009 in the state of Sao Paulo, Brazil. Methodology: Plasma and peripheral blood mononuclear cells (PBMC) were collected from 51 HIV-1-positive children and adolescents on ART followed between September 1992 and July 2009. After extraction, the genetic materials were used in a polymerase chain reaction (PCR) to amplify the viral near full length genomes (NFLGs) from 5 overlapped fragments. NFLGs and partial amplicons were directly sequenced and data were phylogenetically inferred. Results: Of the 51 samples studied, the NFLGs and partial fragments of HIV-1 from 42 PBMCs and 25 plasma were successfully subtyped. Results based on proviral DNA revealed that 22 (52.4%) patients were infected with subtype B, 16 (38.1%) were infected with BF1 mosaic variants and 4 (9.5%) were infected with sub-subtype F1. All the BF1 recombinants were unique and distinct from any previously identified unique or circulating recombinant forms in South America. Evidence of dual infections was detected in 3 patients coinfected with the same or distinct HIV-1 subtypes. Ten of the 31 (32.2%) and 12 of the 21 (57.1%) subjects with recovered proviral and plasma, respectively, protease sequences were infected with major mutants resistant to protease inhibitors. The V3 sequences of 14 patients with available sequences from PBMC/or plasma were predicted to be R5-tropic virus except for two patients who harbored an X4 strain. Conclusions: The high proportion of HIV-1 BF1 recombinant, coinfection rate and vertical transmission in Brazil merits urgent attention and effective measures to reduce the transmission of HIV among spouses and sex partners.
- IVIg Immune Reconstitution Treatment Alleviates the State of Persistent Immune Activation and Suppressed CD4 T Cell Counts in CVID(2013) PAQUIN-PROULX, Dominic; SANTOS, Bianca A. N.; CARVALHO, Karina I.; TOLEDO-BARROS, Myrthes; OLIVEIRA, Ana Karolina Barreto de; KOKRON, Cristina M.; KALIL, Jorge; MOLL, Markus; KALLAS, Esper G.; SANDBERG, Johan K.Common variable immunodeficiency (CVID) is characterized by defective B cell function, impaired antibody production, and increased susceptibility to bacterial infections. Here, we addressed the hypothesis that poor antibody-mediated immune control of infections may result in substantial perturbations in the T cell compartment. Newly diagnosed CVID patients were sampled before, and 6-12 months after, initiation of intravenous immunoglobulin (IVIg) therapy. Treatment-naive CVID patients displayed suppressed CD4 T cell counts and myeloid dendritic cell (mDC) levels, as well as high levels of immune activation in CD8 T cells, CD4 T cells, and invariant natural killer T (iNKT) cells. Expression of co-stimulatory receptors CD80 and CD83 was elevated in mDCs and correlated with T cell activation. Levels of both FoxP3+ T regulatory (Treg) cells and iNKT cells were low, whereas soluble CD14 (sCD14), indicative of monocyte activation, was elevated. Importantly, immune reconstitution treatment with IVIg partially restored the CD4 T cell and mDC compartments. Treatment furthermore reduced the levels of CD8 T cell activation and mDC activation, whereas levels of Treg cells and iNKT cells remained low. Thus, primary deficiency in humoral immunity with impaired control of microbial infections is associated with significant pathological changes in cell-mediated immunity. Furthermore, therapeutic enhancement of humoral immunity with IVIg infusions alleviates several of these defects, indicating a relationship between poor antibody-mediated immune control of infections and the occurrence of abnormalities in the T cell and mDC compartments. These findings help our understanding of the immunopathogenesis of primary immunodeficiency, as well as acquired immunodeficiency caused by HIV-1 infection.
- Chemokines in the pathogenesis of endometriosis and infertility(2013) BORRELLI, G. M.; CARVALHO, K. I.; KALLAS, E. G.; MECHSNER, S.; BARACAT, E. C.; ABRAO, M. S.Endometriosis is a chronic benign disease that affects women of reproductive age causing abdominal pain and infertility. Its pathogenesis remains obscure despite all the research conducted over the past 100 years. However, there is a consensus among the specialists that the basis of its pathophysiology would be multifactorial. Many publications have demonstrated that chemokines are somehow associated with the development of endometriosis and infertility. In this study, we reviewed all PubMed literature using MeSH terms ""chemokines"" and ""endometriosis"" as well as ""chemokines"" and ""female infertility"" to establish what we know and what we do not yet know about this relationship.
- Expansion in CD39(+) CD4(+) Immunoregulatory T Cells and Rarity of Th17 Cells in HTLV-1 Infected Patients Is Associated with Neurological Complications(2013) LEAL, Fabio E.; NDHLOVU, Lishomwa C.; HASENKRUG, Aaron M.; BRUNO, Fernanda R.; CARVALHO, Karina I.; WYNN-WILLIAMS, Harry; NETO, Walter K.; SANABANI, Sabri S.; SEGURADO, Aluisio C.; NIXON, Douglas F.; KALLAS, Esper G.HTLV-1 infection is associated with several inflammatory disorders, including the neurodegenerative condition HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is unclear why a minority of infected subjects develops HAM/TSP. CD4(+) T cells are the main target of infection and play a pivotal role in regulating immunity to HTLV and are hypothesized to participate in the pathogenesis of HAM/TSP. The CD39 ectonucleotidase receptor is expressed on CD4(+) T cells and based on co-expression with CD25, marks T cells with distinct regulatory (CD39(+)CD25(+)) and effector (CD39(+)CD25(-)) function. Here, we investigated the expression of CD39 on CD4(+) T cells from a cohort of HAM/TSP patients, HTLV-1 asymptomatic carriers (AC), and matched uninfected controls. The frequency of CD39(+)CD4(+) T cells was increased in HTLV-1 infected patients, regardless of clinical status. More importantly, the proportion of the immunostimulatory CD39(+)CD25(-) CD4+ T-cell subset was significantly elevated in HAM/TSP patients as compared to AC and phenotypically had lower levels of the immunoinhibitory receptor, PD-1. We saw no difference in the frequency of CD39(+)CD25(+) regulatory (Treg) cells between AC and HAM/TSP patients. However, these cells transition from being anergic to displaying a polyfunctional cytokine response following HTLV-1 infection. CD39(-)CD25(+) T cell subsets predominantly secreted the inflammatory cytokine IL-17. We found that HAM/TSP patients had significantly fewer numbers of IL-17 secreting CD4(+) T cells compared to uninfected controls. Taken together, we show that the expression of CD39 is upregulated on CD4(+) T cells HAM/TSP patients. This upregulation may play a role in the development of the proinflammatory milieu through pathways both distinct and separate among the different CD39 T cell subsets. CD39 upregulation may therefore serve as a surrogate diagnostic marker of progression and could potentially be a target for interventions to reduce the development of HAM/TSP.