LUIZA GUILHERME GUGLIELMI
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina - Líder
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- Sickening or Healing the Heart? The Association of Ficolin-1 and Rheumatic Fever(2018) CATARINO, Sandra Jeremias; ANDRADE, Fabiana Antunes; BOLDT, Angelica Beate Winter; GUILHERME, Luiza; MESSIAS-REASON, Iara JoseRheumatic fever (RF) and its subsequent progression to rheumatic heart disease (RHD) are chronic inflammatory disorders prevalent in children and adolescents in underdeveloped countries, and a contributing factor for highmorbidity andmortality rates worldwide. Their primary cause is oropharynx infection by Streptococcus pyogenes, whose acetylated residues are recognized by ficolin-1. This is the onlymembrane-bound, as well as soluble activator molecule of the complement lectin pathway (LP). Although LP genetic polymorphisms are associated with RF, FCN1 gene's role remains unknown. To understand this role, we haplotyped five FCN1 promoter polymorphisms by sequence-specific amplification in 193 patients (138 with RHD and 55, RF only) and 193 controls, measuring ficolin-1 serum concentrations in 78 patients and 86 controls, using enzyme-linked immunosorbent assay (ELISA). Patients presented lower ficolin-1 serum levels (p < 0.0001), but did not differ according to cardiac commitment. Control's genotype distribution was in the Hardy-Weinberg equilibrium. Four alleles (rs2989727: c.-1981A, rs10120023: c.-542A, rs10117466: c.-144A, and rs10858293: c. 33T), all associated with increased FCN1 gene expression in whole blood or adipose subcutaneous tissue (p = 0.000001), were also associated with increased protection against the disease. They occur within the *3C2 haplotype, associated with an increased protection against RF (OR = 0.41, p < 0.0001) and with higher ficolin-1 levels in patient serum (p = 0.03). In addition, major alleles of these same polymorphisms comprehend the most primitive *1 haplotype, associated with increased susceptibility to RF (OR = 1.76, p < 0.0001). Nevertheless, instead of having a clear-cut protective role, theminor c.-1981A and c.-144A alleles were also associated with additive susceptibility to valvar stenosis and mitral insufficiency (OR = 3.75, p = 0.009 and OR = 3.37, p = 0.027, respectively). All associations were independent of age, sex or ethnicity. Thus, minor FCN1 promoter variants may play a protective role against RF, by encouraging bacteria elimination as well as increasing gene expression and protein levels. On the other hand, theymay also predispose the patients to RHD symptoms, by probably contributing to chronic inflammation and tissue injury, thus emphasizing the dual importance of ficolin-1 in both conditions.
- Rheumatic heart disease: molecules involved in valve tissue inflammation leading to the autoimmune process and anti-S. pyogenes vaccine(2013) GUILHERME, Luiza; KALIL, JorgeThe major events leading to both rheumatic fever (RE) and rheumatic heart disease (RHD) are reviewed. Several genes are involved in the development of RE and RHD. The inflammatory process that results from S. pyogenes infection involves the activation of several molecules such as VCAM and ICAM, which play a role in the migration of leukocytes to the heart, particularly to the valves. Specific chemokines, such as CXCL3/MIP1a as well as CCL1/I-309 and CXCL9/Mig, attractT cells to the myocardium and valves, respectively. The autoimmune reactions are mediated by both the B- and T-cell responses that begin at the periphery, followed by the migration of T cell clones to the heart and the infiltration of heart lesions in RHD patients. These cells recognize streptococcal antigens and humantissue proteins. Molecular mimicry between streptococcal M protein and human proteins has been proposed as the triggering factor leading to autoimmunity in RE and RHD. The production of cytokines from peripheral and heart-infiltrating mononuclear cells suggests that T helper 1 and Th17 cytokines are the mediators of RHD heart lesions. The low numbers of 1154 producing cells in the valvular tissue might contribute to the maintenance and progression of the valve lesions. The identification of a vaccine epitope opens a perspective of development of an effective and safe vaccine to prevent S. pyogenes infections, consequently RE and RHD.
- Thymopoiesis in Pre- and Post-Hematopoietic Stem Cell Transplantation(2018) ROCHA, Luis Klaus A. da; BARROS, Samar Freschi de; BANDEIRA, Francine; BOLLINI, Alexia; TESTA, Lucia Helena de A.; SIMIONE, Anderson Joao; SOUZA, Marina de O. e; ZANETTI, Lilian P.; OLIVEIRA, Leila Cibele S. de; SANTOS, Ana Claudia F. dos; SOUZA, Mair Pedro de; COLTURADO, Vergilio Antonio R.; KALIL, Jorge; MACHADO, Clarisse M.; GUILHERME, LuizaHematopoietic stem cell transplantation (HSCT) is an important therapeutic option for some hematological diseases. However, patients who undergo HSCT acquire a state of immunodeficiency that causes significant mortality. Reconstitution of thymic function is needed to support the immune system. One way to measure thymic function is through T-cell receptor excision circle (TREC) quantification. TRECs are generated by T-cell receptor gene rearrangements during T-cell maturation in the thymus and represent a reliable marker for thymic output. In this study, we aimed to assess aging and malignant hematological diseases as two important factors that may influence thymic output before HSCT. We observed that patients before HSCT presented signal joint TREC (sjTREC) numbers lower than 606.55 copies/mu g DNA (low values) compared with healthy individuals, with an odds ratio (OR) of 12.88 [95% confidence interval (CI): 5.26-31.53; p < 0.001]. Our results showed that a group of older individuals (>= 50 years old), comprising both healthy individuals and patients, had an OR of 10.07 (95% CI: 2.80-36.20) for low sjTREC values compared with younger individuals (<= 24 years old; p < 0.001). Multiple logistic regression analysis confirmed that both older age (>= 50 years old) and malignant hematological diseases and their treatments were important and independent risk factors related to thymic function impairment (p < 0.001). The median sjTREC value for patients of all ages was significantly lower than the sjTREC median for the subgroup of older healthy individuals (>= 50 years old; p < 0.001). These data suggested that patients before HSCT and healthy individuals exhibited age-dependent thymic impairment, and that prior treatment for hematological diseases may exacerbate aging-related deterioration of natural thymic function. Furthermore, we analyzed these patients 9 months post-HSCT and compared patients who underwent autologous HSCT with those who underwent allogeneic HSCT. Both groups of patients achieved sjTREC copy numbers similar to those of healthy individuals. We did not find a close relationship between impaired thymic function prior to HSCT and worse thymic recovery after HSCT.
- Immunological Balance Is Associated with Clinical Outcome after Autologous Hematopoietic Stem Cell Transplantation in Type 1 Diabetes(2017) MALMEGRIM, Kelen C. R.; AZEVEDO, Julia T. C. de; ARRUDA, Lucas C. M.; ABREU, Joana R. F.; COURI, Carlos E. B.; OLIVEIRA, Gislane L. V. de; PALMA, Patricia V. B.; SCORTEGAGNA, Gabriela T.; STRACIERI, Ana B. P. L.; MORAES, Daniela A.; DIAS, Juliana B. E.; PIERONI, Fabiano; CUNHA, Renato; GUILHERME, Luiza; SANTOS, Nathalia M.; FOSS, Milton C.; COVAS, Dimas T.; BURT, Richard K.; SIMOES, Belinda P.; VOLTARELLI, Julio C.; ROEP, Bart O.; OLIVEIRA, Maria C.Autologous hematopoietic stem cell transplantation (AHSCT) increases C-peptide levels and induces insulin independence in patients with type 1 diabetes. This study aimed to investigate how clinical outcomes may associate with the immunological status, especially concerning the balance between immunoregulation and autoreactivity. Twenty-one type 1 diabetes patients were monitored after AHSCT and assessed every 6 months for duration of insulin independence, C-peptide levels, frequencies of islet-specific autoreactive CD8+ T cells (CTL), regulatory lymphocyte subsets, thymic function, and T-cell repertoire diversity. In median follow-up of 78 (range 15-106) months, all patients became insulin-independent, resuming insulin after median of 43 (range 6-100) months. Patients were retrospectively divided into short-or prolonged-remission groups, according to duration of insulin independence. For the entire follow-up, CD3+ CD4+ T-cell numbers remained lower than baseline in both groups, whereas CD3+ CD8+ T-cell levels did not change, resulting in a CD4/CD8 ratio inversion. Memory CTL comprehended most of T cells detected on long-term follow-up of patients after AHSCT. B cells reconstituted to baseline levels at 2-3 months post-AHSCT in both patient groups. In the prolonged-remission-group, baseline islet-specific T-cell autoreactivity persisted after transplantation, but regulatory T cell counts increased. Patients with lower frequencies of autoreactive islet-specific T cells remained insulin-free longer and presented greater C-peptide levels than those with lower frequencies of these cells. Therefore, immune monitoring identified a subgroup of patients with superior clinical outcome of AHSCT. Our study shows that improved immunoregulation may balance autoreactivity endorsing better metabolic outcomes in patients with lower frequencies of islet-specific T cells. Development of new strategies of AHSCT is necessary to increase frequency and function of T and B regulatory cells and decrease efficiently autoreactive islet-specific T and B memory cells in type 1 diabetes patients undergoing transplantation.