MARIA NOTOMI SATO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Dermatologia, Faculdade de Medicina - Docente
LIM/56 - Laboratório de Investigação em Dermatologia e Imunodeficiências, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/56 - Laboratório de Investigação em Dermatologia e Imunodeficiências, Hospital das Clínicas, Faculdade de Medicina - Líder
38 resultados
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- Evidence of regulatory myeloid dendritic cells and circulating inflammatory epidermal dendritic cells-like modulated by Toll-like receptors 2 and 7/8 in adults with atopic dermatitis(2017) SANTOS, Vanessa G. dos; ORFALI, Raquel L.; TITZ, Tiago de Oliveira; DUARTE, Alberto J. da Silva; SATO, Maria N.; AOKI, ValeriaBackgroud Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense pruritus and xerosis. Dendritic cells (DC) play an essential role in tissue inflammation in atopic dermatitis (AD) skin, especially the inflammatory epidermal dendritic cells (IDEC), a particular subset of myeloid dendritic cells (mDC). The aim of the present study was to assess the phenotype and function of mDC and circulating IDEC-like in peripheral blood mononuclear cells (PBMC) of adults with AD. Methods We selected 21 AD patients and 21 non-AD controls, age and gender matched. Expressions of Fc epsilon RI, CD36, TNF, IFN-gamma , and IL-10 in mDC were analyzed by flow cytometry under various stimuli, such as staphylococcal enterotoxin B (SEB), TLR2 (Pam3CSK4), TLR4 (LPS), and TLR7/8 (CL097) agonists. Results The most prominent findings in AD patients were: (i) enhanced frequency of IL-10 under TLR4 (LPS), and decreased frequency of IFN-gamma and TNF under TLR2 (Pam3CSK4) and 7/8 (CL097) stimulation in classic mDC; (ii) elevation of circulating IDEC-like frequency with TLR2 (Pam3CSK4) stimuli, augmented frequency of IFN-gamma in nonstimulated condition, and of IL-10 under TLR7/8 (CL097) stimuli in IDEC-like population. Conclusions In AD individuals, classic mDC showed an immunomodulatory profile, favoring tolerance in a combined action with IDEC-like, and inducing Th1 polarization. Our findings indicate a potential role of IDEC-like in the maintenance of inflammation in atopic dermatitis patients; moreover, IDEC-like may exert a regulatory impact on T cells of AD individuals through IL-10, often induced by agonist mimicking single stranded RNA virus.
- Activation of myeloid dendritic cells, effector cells and regulatory T cells in lichen planus(2016) DOMINGUES, Rosana; CARVALHO, Gabriel Costa de; AOKI, Valeria; DUARTE, Alberto Jose da Silva; SATO, Maria NotomiBackground: Lichen planus (LP) is a chronic mucocutaneous inflammatory disease. Evaluating the balance between regulatory T cells and effector T cells could be useful for monitoring the proinflammatory profile of LP. Therefore, this study aimed to assess populations of dendritic cells (DCs) and regulatory and effector T cells in peripheral blood samples collected from patients with LP to evaluate the polyfunctionality of T cells upon toll-like receptor (TLR) activation. Methods: Peripheral blood mononuclear cells collected from 18 patients with LP and 22 healthy control subjects were stimulated with agonists of TLR4, TLR7, TLR7/TLR8 or TLR9. Frequencies of circulating IFN-alpha(+) plasmacytoid DCs (pDCs); TNF-alpha(+) myeloid DCs (mDCs); regulatory T cells (Tregs); and IL-17-, IL-10-, IL-22-, TNF-, and IFN-gamma-secreting T cells were assessed via flow cytometry. Results: The frequencies of regulatory CD4(+) and CD8(+)CD25(+)Foxp3(+)CD127(low/-)T cells and TNF-alpha(+) mDCs were induced following activation with TLR4, TLR7 and TLR8 agonists in the LP group. Moreover, increased baseline frequencies of CD4(+)IL-10(+) T cells and CD8(+)IL-22(+) or IFN-gamma(+) T cells were found. In the LP group, TLR4 activation induced an increased frequency of CD4(+) IFN-gamma(+) T cells, while TLR7/8 and staphylococcal enterotoxin B (SEB) activation induced an increased frequency of CD8(+)IL-22(+) T cells. An increased frequency of polyfunctional CD4(+) T cells that simultaneously secreted 3 of the evaluated cytokines (not including IL-10) was verified upon TLR7/8/9 activation, while polyfunctional CD8(+) T cells were already detectable at baseline. Conclusions: TLR-mediated activation of the innate immune response induced the production of proinflammatory mDCs, Tregs and polyfunctional T cells in patients with LP. Therefore, TLR activation has an adjuvant role in inducing both innate and adaptive immune responses.
- Outlining the skin-homing and circulating CLA+NK cells in patients with severe atopic dermatitis(2024) LIMA, Josenilson Feitosa de; TEIXEIRA, Franciane Mouradian Emidio; RAMOS, Yasmim alefe Leuzzi; CARVALHO, Gabriel Costa de; BRANCO, Anna Claudia Calvielli Castelo; PEREIRA, Naiura Vieira; SOTTO, Mirian Nacagami; AOKI, Valeria; SATO, Maria Notomi; ORFALI, Raquel LeaoAtopic dermatitis (AD) is a complex, multifactorial skin disease, characterized by pruritus and predominant Th2 inflammation. Innate immune cells may play a role in AD development and are composed of granulocytes, macrophages, innate-like T cells, and innate lymphoid cells. This study investigates the phenotypic and functional profile of circulating CLA(+) natural killer (NK) cells and its role in the skin-homing to NK cells infiltrated in adults' skin with AD. We selected 44 AD patients and 27 non-AD volunteers for the study. The results showed increased frequencies of both CLA(+)CD56(bright) and CLA(+)CD56(dim) NK cell populations in the peripheral blood, mainly in severe AD patients. Upon SEB stimulation, we observed an augmented percentage of CLA(+)CD56(dim) NK cells expressing CD107a, IFN-gamma, IL-10, and TNF, reinforcing the role of staphylococcal enterotoxins in AD pathogenesis. Additionally, we demonstrated increased dermal expression of both NK cell markers NCAM-1/CD56 and pan-granzyme, corroborating the skin-homing, mostly in severe AD. Further studies are necessary to elucidate the potential role of NK cells in the chronification of the inflammatory process in AD skin, as well as their possible relationship with staphylococcal enterotoxins, and as practicable therapeutic targets.
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.conferenceObject Atopic dermatitis in adults: Augmented circulating IgG4 and IgE antibodies against Staphylococcus aureus enterotoxin B(2013) ORFALI, R. L.; SATO, M. N.; SANTOS, V. G. Dos; TITZ, T. O.; DUARTE, A. S.; TAKAOKA, R.; AOKI, V.The aim of this study was to evaluate the profile of anti-Staphylococcus aureus enterotoxin B (SEB) antibody (Ab) response in adults with AD. We selected 38 patients diagnosed as AD (Hanifin & Rajka's criteria), aged between 18 and 65, and 26 healthy controls (HC), aged between 20 and 47 years. Severity of the disease was established according to EASI (Eczema Area and Severity Index) and patients were graded as mild (28%), moderate (58%) and severe (14%). Sera were assessed for IgG subclasses, IgA, IgM and IgE against SEB by ELISA. The humoral response in AD patients to SEB showed elevated circulating IgE and IgG4 levels (p < 0.05 and p δ 0.001, respectively), and decreased IgA and IgM levels (p < 0.05). Severity of atopic dermatitis was related with low IgG1 and IgG3 levels (p < 0.05), and high IgE antibody response (p < 0.05) to SEB. Interestingly, absence of IgE and IgG1 response to SEB was seen in some AD patients (26.3% and 18.4% respectively). In AD, the immunoglobulin-related subtype Th2 lymphocytes, such as IgE and IgG4, appear to be relevant in the response to superantigens. These results emphasize an altered pattern of Ab response to SEB in AD, which is impaired according the disease severity.- Staphylococcal enterotoxins modulate the effector CD4(+)T cell response by reshaping the gene expression profile in adults with atopic dermatitis(2019) ORFALI, Raquel Leao; YOSHIKAWA, Fabio Seiti Yamada; OLIVEIRA, Luanda Mara da Silva; PEREIRA, Natalli Zanete; LIMA, Josenilson Feitosa de; RAMOS, Yasmim Alefe Leuzzi; DUARTE, Alberto Jose da Silva; SATO, Maria Notomi; AOKI, ValeriaStaphylococcus aureus colonizes the skin of atopic dermatitis (AD) individuals, but the impact of its enterotoxins on the chronic activation of CD4(+)T cells demands further analysis. We aimed to analyze the CD4(+)T cell anergy profile and their phenotypic and functional features through differential expression of cellular activation markers, cytokine production and response to staphylococcal enterotoxin A (SEA). A panel of 84 genes relevant to T cell anergy was assessed by PCR array in FACS-sorted CD4(+)T cells, and the most prominent genes were validated by RT-qPCR. We evaluated frequencies of circulating CD4(+)T cells secreting single or multiple (polyfunctional) cytokines (IL-17A, IL-22, TNF, IFN-gamma, and MIP-1 beta) and expression of activation marker CD38 in response to SEA stimulation by flow cytometry. Our main findings indicated upregulation of anergy-related genes (EGR2 and IL13) promoted by SEA in AD patients, associated to a compromised polyfunctional response particularly in CD4(+)CD38(+)T cells in response to antigen stimulation. The pathogenic role of staphylococcal enterotoxins in adult AD can be explained by their ability to downmodulate the activated effector T cell response, altering gene expression profile such as EGR2 induction, and may contribute to negative regulation of polyfunctional CD4(+)T cells in these patients.
- Methotrexate for refractory adult atopic dermatitis leads to alterations in cutaneous IL-31 and IL-31RA expression(2024) SAMORANO, Luciana Paula; MANFRERE, Kelly Cristina Gomes; PEREIRA, Naiura Vieira; TAKAOKA, Roberto; VALENTE, Neusa Yuriko Sakai; SOTTO, Mirian Nacagami; SILVA, Luiz Fernando Ferraz; SATO, Maria Notomi; AOKI, ValeriaBackground: Methotrexate (MTX) is an alternative treatment for patients with moderate/severe atopic dermatitis (AD). Objective: The authors evaluated the effect of MTX on the cutaneous expression of cytokines and chemokines that are involved in the inflammatory response in adult AD patients who received treatment with methotrexate for 24 weeks. Methods: The authors conducted a prospective single-institution cohort study with 12 adults with moderate/severe AD who received oral MTX (15 mg/wk for 24 wks) and 10 non-atopic matched controls. The comparison was made of skin biopsies of lesional and non-lesional skin, pre- and post MTX treatment. The authors analyzed mean epidermal thickness and expression of IL-31, IL-31RA, OSMR, TSLP, Ki67, IL-4 mRNA, IL-6, IL-10, TNF-alpha, IFN-gamma, TARC, and CCL-22. Results: There was a reduction in mean epidermal thickness (p = 0.021), an increase in IL-31RA expression (immunohistochemistry) in the epidermis (p = 0.016) and a decrease in IL-31 gene expression (p = 0.019) on lesional AD skin post-MTX treatment. No significant changes in the cutaneous expression of the other evaluated markers were identified. Study limitations: Small sample size and limited length of follow-up. Conclusions: Treatment with MTX in adults with moderate/severe AD reduced epidermal hyperplasia and changed the cutaneous expression of inflammatory cytokines and receptors that are mainly related to pruritus, including IL-31 and IL-31RA. (c) 2023 Published by Elsevier Espana, S.L.U. on behalf of Sociedade Brasileira de Dermatologia. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
- Human endogenous retrovirus expression is inversely related with the up-regulation of interferon-inducible genes in the skin of patients with lichen planus(2015) NOGUEIRA, Marcelle Almeida de Sousa; GAVIOLI, Camila Fatima Biancardi; PEREIRA, Natalli Zanete; CARVALHO, Gabriel Costa de; DOMINGUES, Rosana; AOKI, Valeria; SATO, Maria NotomiLichen planus (LP) is a common inflammatory skin disease of unknown etiology. Reports of a common transactivation of quiescent human endogenous retroviruses (HERVs) support the connection of viruses to the disease. HERVs are ancient retroviral sequences in the human genome and their transcription is often deregulated in cancer and autoimmune diseases. We explored the transcriptional activity of HERV sequences as well as the antiviral restriction factor and interferon-inducible genes in the skin from LP patients and healthy control (HC) donors. The study included 13 skin biopsies from patients with LP and 12 controls. Real-time PCR assay identified significant decrease in the HERV-K gag and env mRNA expression levels in LP subjects, when compared to control group. The expressions of HERV-K18 and HERV-W env were also inhibited in the skin of LP patients. We observed a strong correlation between HERV-K gag with other HERV sequences, regardless the down-modulation of transcripts levels in LP group. In contrast, a significant up-regulation of the cytidine deaminase APOBEC 3G (apolipoprotein B mRNA-editing), and the GTPase MxA (Myxovirus resistance A) mRNA expression level was identified in the LP skin specimens. Other transcript expressions, such as the master regulator of type I interferon-dependent immune responses, STING (stimulator of interferon genes) and IRF-7 (interferon regulatory factor 7), IFN-beta and the inflammassome NALP3, had increased levels in LP, when compared to HC group. Our study suggests that interferon-inducible factors, in addition to their role in innate immunity against exogenous pathogens, contribute to the immune control of HERVs. Evaluation of the balance between HERV and interferon-inducible factor expression could possibly contribute to surveillance of inflammatory/malignant status of skin diseases.
conferenceObject Staphylococcus aureus enterotoxins modulate IL-22-secreting cells in adults with atopic dermatitis(2018) ORFALI, R. L.; OLIVEIRA, L. M. S.; LIMA, J. F.; CARVALHO, G. C.; RAMOS, Y. A. L.; PEREIRA, N. Z.; VIEIRA, N. P.; ZANIBONI, M. C.; SATO, M. N.; AOKI, V.- Generation of Cytotoxic T Cells and Dysfunctional CD8 T Cells in Severe COVID-19 Patients(2022) GOZZI-SILVA, Sarah Cristina; OLIVEIRA, Luana de Mendonca; ALBERCA, Ricardo Wesley; PEREIRA, Natalli Zanete; YOSHIKAWA, Fabio Seiti; PIETROBON, Anna Julia; YENDO, Tatiana Mina; ANDRADE, Milena Mary de Souza; RAMOS, Yasmim Alefe Leuzzi; BRITO, Cyro Alves; OLIVEIRA, Emily Araujo; BESERRA, Danielle Rosa; ORFALI, Raquel Leao; AOKI, Valeria; DUARTE, Alberto Jose da Silva; SATO, Maria NotomiCOVID-19, the infectious disease caused by SARS-CoV-2, has spread on a pandemic scale. The viral infection can evolve asymptomatically or can generate severe symptoms, influenced by the presence of comorbidities. Lymphopenia based on the severity of symptoms in patients affected with COVID-19 is frequent. However, the profiles of CD4+ and CD8+ T cells regarding cytotoxicity and antiviral factor expression have not yet been completely elucidated in acute SARS-CoV-2 infections. The purpose of this study was to evaluate the phenotypic and functional profile of T lymphocytes in patients with moderate and severe/critical COVID-19. During the pandemic period, we analyzed a cohort of 62 confirmed patients with SARS-CoV-2 (22 moderate cases and 40 severe/critical cases). Notwithstanding lymphopenia, we observed an increase in the expression of CD28, a co-stimulator molecule, and activation markers (CD38 and HLA-DR) in T lymphocytes as well as an increase in the frequency of CD4+ T cells, CD8+ T cells, and NK cells that express the immunological checkpoint protein PD-1 in patients with a severe/critical condition compared to healthy controls. Regarding the cytotoxic profile of peripheral blood mononuclear cells, an increase in the response of CD4+ T cells was already observed at the baseline level and scarcely changed upon PMA and Ionomycin stimulation. Meanwhile, CD8+ T lymphocytes decreased the cytotoxic response, evidencing a profile of exhaustion in patients with severe COVID-19. As observed by t-SNE, there were CD4+ T-cytotoxic and CD8+ T with low granzyme production, evidencing their dysfunction in severe/critical conditions. In addition, purified CD8+ T lymphocytes from patients with severe COVID-19 showed increased constitutive expression of differentially expressed genes associated with the caspase pathway, inflammasome, and antiviral factors, and, curiously, had reduced expression of TNF-alpha. The cytotoxic profile of CD4+ T cells may compensate for the dysfunction/exhaustion of TCD8+ in acute SARS-CoV-2 infection. These findings may provide an understanding of the interplay of cytotoxicity between CD4+ T cells and CD8+ T cells in the severity of acute COVID-19 infection.