JEFFERSON RUSSO VICTOR
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/56 - Laboratório de Investigação em Dermatologia e Imunodeficiências, Hospital das Clínicas, Faculdade de Medicina
LIM/56 - Laboratório de Investigação em Dermatologia e Imunodeficiências, Hospital das Clínicas, Faculdade de Medicina
5 resultados
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- IgG from Adult Atopic Dermatitis (AD) Patients Induces Nonatopic Neonatal Thymic Gamma-Delta T Cells (gamma delta T) to Acquire IL-22/IL-17 Secretion Profile with Skin-Homing Properties and Epigenetic Implications Mediated by miRNA(2022) FAGUNDES, Beatriz Oliveira; SOUSA, Thamires Rodrigues de; NASCIMENTO, Andrezza; FERNANDES, Lorena Abreu; SGNOTTO, Fabio da Ressureicao; ORFALI, Raquel Leao; AOKI, Valeria; DUARTE, Alberto Jose da Silva; SANABANI, Sabri Saeed; VICTOR, Jefferson Russogamma delta T cells mature in the human thymus, and mainly produce IL-17A or IFN-gamma, but can also produce IL-22 and modulate a variety of immune responses. Here, we aimed to evaluate whether IgG from AD patients (AD IgG) can functionally modulate thymic nonatopic gamma delta T cells. Thymic tissues were obtained from 12 infants who had not had an atopic history. Thymocytes were cultured in mock condition, or in the presence of either AD IgG or therapeutic intravenous IgG (IVIg). Following these treatments, intracellular cytokine production, phenotype, and microRNA expression profiles were investigated. AD IgG could downregulate alpha 4 beta 7, upregulate CLA, and induce the production of IFN-gamma, IL-17, and IL-22 in gamma delta T cells. Although both AD IgG and IVIg could directly interact with gamma delta T cell membranes, AD IgG could reduce gamma delta T cell apoptosis. AD IgG could upregulate nine miRNAs compared to IVIg, and six when compared to the mock condition. In parallel, some miRNAs were downregulated. Target gene prediction and functional analysis indicated that some target genes were enriched in the negative regulation of cellular transcription. This study shows that AD IgG influences the production of IL-17 and IL-22 by intrathymic nonatopic gamma delta T cells, and demonstrates epigenetic implications mediated by miRNAs.
- IgG from atopic dermatitis patients induces non-atopic infant thymic invariant natural killer T (iNKT) cells to produce IL-4, IL-17, and IL-10(2020) SANTOS, Ludimila S.; SGNOTTO, Fabio da Ressureicao; SOUSA, Thamires R.; ORFALI, Raquel L.; AOKI, Valeria; DUARTE, Alberto Jose da Silva; VICTOR, Jefferson R.Background Atopic dermatitis (AD) pathogenesis still needs to be elucidated, but invariant natural killer T (iNKT) cell involvement was already described by several groups. Our group has demonstrated that IgG antibodies purified from AD patients can modulate cytokine production by thymic T cells. Here we aimed to investigate if IgG from AD patients can modulate infant non-atopic thymic iNKT cells cytokine production in order to collaborate with the elucidation of AD development in infancy. Methods Thymic tissues were obtained from children from non-atopic mothers, and IgG was purified from AD patients diagnosed as moderate or severe and, as controls, from subjects clinically classified as non-atopic individuals. PBMCs from non-atopic individuals were also used in this study. Results Our results demonstrated that IgG from AD patients could induce non-atopic children thymic iNKT cells to produce higher levels of intracellular IL-4, IL-10, and IL-17 when compared to all control conditions. No effect was observed in non-atopic adults peripheral iNKT. We also observed that IgG from AD patients induces an increase in the expression of CD4 and Ror gamma t transcription factor in non-atopic children thymic iNKT cells compared to the condition of all controls. Conclusions These observations suggest that IgG from AD patients can induce a cytokine profile by thymic iNKT cells from non-atopic infants compatible with the observations in AD development, which can collaborate with the elucidation of AD pathogenesis.
conferenceObject IgG from atopic dermatitis patients induces IL-17 and IL-10 production in infant intra-thymic TCD4 and TCD8 cells(2018) SGNOTTO, F. R.; OLIVEIRA, M. G.; LIRA, A. A. L.; INOUE, A. H. S.; TITZ, T. O.; ORFALI, R. L.; BENTO-DE-SOUZA, L.; SATO, M. N.; AOKI, V.; DUARTE, A. J. S.; VICTOR, J. R.- IgG from Adult Atopic Dermatitis (AD) Patients Induces Thymic IL-22 Production and CLA Expression on CD4+T Cells: Possible Epigenetic Implications Mediated by miRNA(2022) SOUSA, Thamires Rodrigues de; FAGUNDES, Beatriz Oliveira; NASCIMENTO, Andrezza; FERNANDES, Lorena Abreu; SGNOTTO, Fabio da Ressureicao; ORFALI, Raquel Leao; AOKI, Valeria; DUARTE, Alberto Jose da Silva; SANABANI, Sabri Saeed; VICTOR, Jefferson RussoAtopic dermatitis (AD) is a common relapsing inflammatory skin disorder characterized by immune-mediated inflammation and epidermal barrier dysfunction. The pathogenesis of AD is multifactorial and has not been fully elucidated to date. This study aimed to evaluate whether serum IgG from adult AD patients could modulate the thymic maturation of IL-22-producing T cells and CLA+ T cells of non-atopic infants. Given that miRNAs regulate immune response genes, we evaluated whether miRNA expression is also altered in cultured thymocytes. Thymocytes were cultured with purified IgG from AD patients or control conditions (mock, Intravenous-IgG (IVIg), non-atopic IgG, or atopic non-AD IgG). Using flow cytometry analysis, we assessed the expression of CLA and intracellular levels of IL-4, IFN-gamma, and IL-22 on double-positive T cells (DP T), CD4 T cells, or CD8 T cells. We also investigated the frequency of IgG isotypes and their direct interaction with the thymic T cells membrane. The miRNA profiles were evaluated by the Illumina small RNA-seq approach. MiRNA target gene prediction and enrichment analyses were performed using bioinformatics. Increased frequencies of IL-22 and CLA+ producing CD4+ T cells cultured with IgG of AD patients was seen in non-atopic infant thymocytes compared to all control conditions. No alterations were observed in the frequency of IgG isotypes among evaluated IgG pools. Evidence for a direct interaction between IgG and thymic DP T, CD4 T, and CD8 T cells is presented. The small RNA-seq analysis identified ten mature miRNAs that were modulated by AD IgG compared to mock condition (miR-181b-5p, hsa-miR-130b-3p, hsa-miR-26a-5p, hsa-miR-4497, has-miR-146a, hsa-let-7i-5p, hsa-miR-342-3p, has-miR-148a-3p, has-miR-92a and has-miR-4492). The prediction of the targetome of the seven dysregulated miRNAs between AD and mock control revealed 122 putative targets, and functional and pathway enrichment analyses were performed. Our results enhance our understanding of the mechanism by which IgG can collaborate in thymic T cells in the setting of infant AD.
- IgG from atopic dermatitis patients induces IL-17 and IL-10 production in infant intrathymic TCD4 and TCD8 cells(2018) SGNOTTO, Fabio D. R.; OLIVEIRA, Marilia G. de; LIRA, Aline A. L.; INOUE, Amanda H. S.; TITZ, Tiago O.; ORFALI, Raquel L.; BENTO-DE-SOUZA, Luciana; SATO, Maria N.; AOKI, Valeria; DUARTE, Alberto J. S.; VICTOR, Jefferson R.IntroductionOur group recently demonstrated that IgG modulates T cell cytokine production during the maturation process in the human thymus. The effects of this modulation are IgG repertoire dependent and can exert a systemic and long-term impact. ObjectiveTo investigate whether IgG from atopic dermatitis (AD) patients can modulate cytokine production of infant intrathymic TCD4 and TCD8 cells in vitro. MethodsThymic tissues were obtained from newborn children from nonatopic mothers, and thymocytes were cultured for 6 days with purified IgG from AD patients or with intravenous immunoglobulin (IVIG) or mock conditions as controls. Cells were gated as double positive T cells (TDP(-)CD4(+)CD8(+)), TCD4 cells (CD4(+)CD8(-)), or TCD8 cells (CD4(-)CD8(+)), and intracellular levels of IL-17A, IFN-, TNF-, IL-4, IL-10, and TGF- were evaluated by flow cytometry. ResultsCompared to mock and IVIG culture conditions, IgG of AD individuals induced in vitro intracellular production of IL-17 and IL-10 by intrathymic TDP, TCD4, and TCD8 cells of infants. TGF- was also detected at a higher frequency in response to AD IgG in TDP and TCD8 cells compared to mock and IVIG cultured conditions. An opposite effect was detected upon IFN- production in TCD4 cells, such that AD IgG reduced IFN- production compared to production under mock conditions but not under IVIG conditions. ConclusionIgG of AD patients can stimulate cytokine production in infant thymocytes and thus resembles the peripheral profile observed in adults. These findings suggest a novel mechanism that can contribute to AD pathogenesis.