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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- Rheumatic Heart Disease and Myxomatous Degeneration: Differences and Similarities of Valve Damage Resulting from Autoimmune Reactions and Matrix Disorganization(2017) MARTINS, Carlo de Oliveira; DEMARCHI, Lea; FERREIRA, Frederico Moraes; POMERANTZEFF, Pablo Maria Alberto; BRANDAO, Carlos; SAMPAIO, Roney Orismar; SPINA, Guilherme Sobreira; KALIL, Jorge; CUNHA-NETO, Edecio; GUILHERME, LuizaAutoimmune inflammatory reactions leading to rheumatic fever (RF) and rheumatic heart disease (RHD) result from untreated Streptococcus pyogenes throat infections in individuals who exhibit genetic susceptibility. Immune effector mechanisms have been described that lead to heart tissue damage culminating in mitral and aortic valve dysfunctions. In myxomatous valve degeneration (MXD), the mitral valve is also damaged due to non-inflammatory mechanisms. Both diseases are characterized by structural valve disarray and a previous proteomic analysis of them has disclosed a distinct profile of matrix/structural proteins differentially expressed. Given their relevance in organizing valve tissue, we quantitatively evaluated the expression of vimentin, collagen VI, lumican, and vitronectin as well as performed immunohistochemical analysis of their distribution in valve tissue lesions of patients in both diseases. We identified abundant expression of two isoforms of vimentin (45 kDa, 42 kDa) with reduced expression of the full-size protein (54 kDa) in RHD valves. We also found increased vitronectin expression, reduced collagen VI expression and similar lumican expression between RHD and MXD valves. Immunohistochemical analysis indicated disrupted patterns of these proteins in myxomatous degeneration valves and disorganized distribution in rheumatic heart disease valves that correlated with clinical manifestations such as valve regurgitation or stenosis. Confocal microscopy analysis revealed a diverse pattern of distribution of collagen VI and lumican into RHD and MXD valves. Altogether, these results demonstrated distinct patterns of altered valve expression and tissue distribution/ organization of structural/matrix proteins that play important pathophysiological roles in both valve diseases.
- Rheumatic Fever and Rheumatic Heart Disease(2017) GUILHERME, L.; SAMPAIO, R. O.; BARROS, S. Freschi de; KöHLER, K. F.; SPINA, G. S.; TARASOUTCHI, F.; KALIL, J.Rheumatic fever (RF) is the prototype of postinfectious autoimmune diseases. Similarities of structure and/or spatial conformation between Streptococcus pyogenes and human tissue proteins lead to autoimmune reactions due to molecular mimicry. The activation of T and B lymphocytes involves several genetically controlled molecules that act in both the innate and adaptive immune response. In this chapter, we describe the strains of bacteria that are more commonly involved in the development of RF worldwide as well as the genetic predisposition of diverse ethnic groups. The disease manifests in susceptible children and teenagers, usually starting as polyarthritis or Sydenham's chorea. This condition generally occurs several months after streptococcal infection. Erythema marginatum and subcutaneous nodules are rare cutaneous manifestation, and carditis is the most serious sequelae and can lead to severe valve damage and rheumatic heart disease (RHD). The immune mechanisms that lead to the diverse manifestations mentioned above are discussed. The diagnosis and treatment, particularly the revision of Jones Criteria in the era of Doppler echocardiography, as well as the perspective of vaccine development, are also presented. © 2017 Elsevier Inc. All rights reserved.
- 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.