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INTRODUCTION: Rheumatic Fever represents a serious public health problem in developing countries, with thousands of new cases each year. It is an autoimmune disease, which occurs in response to infection by streptococcus A. OBJECTIVE: The aim of this study was to evaluate the immunolabeling and protein expression for endothelin-1 and 3 (ET-1, ET-3) and its receptors (ETA, ETB) in rheumatic mitral valves. METHODS: Immunohistochemistry was used to identify ET-1/ET-3 and ETA/ETB receptors in rheumatic and control mitral valves. Quantitative analysis of immunostaining for ET-1/ET-3 and ETA/ETB receptors was performed. In addition, western blot analysis was carried out to assess protein levels in tissue samples. RESULTS: ET-1 and ETA receptor immunostaining predominated in stenotic valves, mainly associated with fibrotic regions, inflammatory areas and neovascularization. Quantitative analysis showed that the average area with positive expression of ET-1 was 18.21 ± 14.96%. For ETA and ETB, the mean expressed areas were respectively 15.06 ± 13.13% and 9.20 ± 11.09%. ET-3 did not have a significant expression. The correlation between the expression of both endothelin receptors were strongly positive (R = 0.74, P = 0.02), but the correlation between ET-1 and its receptor were negative for both ETA (R = -0.37, P = 0.25), and ETB (R = -0.14, P = 0.39). This data was supported by western blot analysis. CONCLUSION: The strong correlation between ET-1 and its receptors suggests that both play a role in the pathophysiology of rheumatic mitral valve stenosis and may potentially act as biomarkers of this disease.

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Abstract Introduction: Rheumatic Fever represents a serious public health problem in developing countries, with thousands of new cases each year. It is an autoimmune disease, which occurs in response to infection by streptococcus A. Objective: The aim of this study was to evaluate the immunolabeling and protein expression for endothelin-1 and 3 (ET-1, ET-3) and its receptors (ETA, ETB) in rheumatic mitral valves. Methods: Immunohistochemistry was used to identify ET-1/ET-3 and ETA/ETB receptors in rheumatic and control mitral valves. Quantitative analysis of immunostaining for ET-1/ET-3 and ETA/ETB receptors was performed. In addition, western blot analysis was carried out to assess protein levels in tissue samples. Results: ET-1 and ETA receptor immunostaining predominated in stenotic valves, mainly associated with fibrotic regions, inflammatory areas and neovascularization. Quantitative analysis showed that the average area with positive expression of ET-1 was 18.21±14.96%. For ETA and ETB, the mean expressed areas were respectively 15.06±13.13% and 9.20±11.09%. ET-3 did not have a significant expression. The correlation between the expression of both endothelin receptors were strongly positive (R=0.74, P=0.02), but the correlation between ET-1 and its receptor were negative for both ETA (R=-0.37, P=0.25), and ETB (R=-0.14, P=0.39). This data was supported by western blot analysis. Conclusion: The strong correlation between ET-1 and its receptors suggests that both play a role in the pathophysiology of rheumatic mitral valve stenosis and may potentially act as biomarkers of this disease. .

Resumo Introdução: A febre reumática representa um sério problema de saúde pública em países em desenvolvimento, com milhares de novos casos a cada ano. Ela é uma doença autoimune que ocorre em resposta à infecção por estreptococos do grupo A. Objetivo: O objetivo deste estudo foi avaliar a expressão proteica e imunohistoquímica para a endotelina-1 e 3 (ET-1 e ET-3) e seus receptores (ETA e ETB) em valvas mitrais reumáticas. Métodos: Imunohistoquímica foi utilizada para identificar receptores de ET1/ET3 e ETA/ETB em valvas mitrais reumáticas e controles. A análise quantitativa da expressão imunohistoquímica para receptores de ET1/ET3 e ETA/ETB foi também efetuada. Adicionalmente, foi feita análise do western blot para mensurar níveis de proteínas em extratos tissulares. Resultados: A expressão imunohistoquímica de ET-1 e de seu receptor predominou em valvas estenóticas, estando associada com regiões fibróticas, áreas inflamatórias e neovascularização. A análise quantitativa mostrou que a área média com expressão positiva para ET-1 foi de 18,21±14,96%. Para o ETA e o ETB, as áreas médias expressas foram, respectivamente, 15,06±13,13% e 9,20±11,09%. ET-3 não teve uma expressão significante. A correlação entre a expressão dos dois receptores de endotelina foi fortemente positiva (R=0,74, P=0,02); mas a correlação entre ET-1 e o seu receptor foi negativa tanto para ETA (R=-0,37, P=0,25) como para ETB (R=-0,14, P=0,39). Estes dados foram confirmados pela análise do western blot. Conclusão: A forte correlação entre ET-1 e seus receptores sugere que ambos têm papel importante na fisiopatologia da estenose mitral reumática, podendo potencialmente atuar como biomarcadores desta doença. .

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Determination of anti-citrullinated peptide antibodies (ACPA) plays a relevant role in the diagnosis of rheumatoid arthritis (RA). To date, it is still unclear if the use of several tests for these autoantibodies in the same patient offers additional value as compared to performing only one test. Therefore, we evaluated the performance of using two assays for ACPA: second-generation anti-citrullinated cyclic peptides antibodies (anti-CCP2) and anti-mutated citrullinated vimentin (anti-MCV) antibodies for the diagnosis of RA. We compared three groups: RA (n = 142), chronic inflammatory disease (CIRD, n = 86), and clinically healthy subjects (CHS, n = 56) to evaluate sensitivity, specificity, predictive values, and likelihood ratios (LR) of these two assays for the presence of RA. A lower frequency of positivity for anti-CCP2 was found in RA (66.2%) as compared with anti-MCV (81.0%). When comparing RA versus other CIRD, sensitivity increased when both assays were performed. This strategy of testing both assays had high specificity and LR+. We conclude that adding the assay of anti-MCV antibodies to the determination of anti-CCP2 increases the sensitivity for detecting seropositive RA. Therefore, we propose the use of both assays in the initial screening of RA in longitudinal studies, including early onset of undifferentiated arthritis.

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La fiebre reumática es una enfermedad endémica en los países en desarrollo como Venezuela y es causa importante de valvulopatía crónica progresiva, siendo primeramente afectado el aparato valvular mitral. Evaluar el aspecto morfológico de la valvulitis crónica en su etapa inicial, en individuos quienes han sido sometidos a reemplazo valvular mitral o mitro-aórtico. Se seleccionaron 20 biopsias de válvulas mitrales y mitro/aórticas diagnosticadas como valvulopatía crónica reumática, representativas de la etapa inicial, en pacientes con edad igual o menos de 20 años. Los diagnósticos pre-operatorios fueron: disfunción valvular severa mitral (insuficiencia (60%), doble lesión (10%) y estenosis (5%) y mitro-aórtica (25%). Las biopsias (valvas y aparatos valvulares mitrales) fueron evaluadas macroscópicamente. El estudio histológico se hizo con secciones teñidas con Hematoxilina-eosina e inmunomarcadas con anticuerpos CD 34 y antimúsculo liso. Todos los casos mostraron lesiones morfológicas propias de la valvulitis crónica reumática inicial: inflamación grado 1 (81,6%), con nódulos de Aschoff (35%), fibrosis de grado 2 (40%) y 3 (60%) Con una alta densidad de neovascularización (14,78 ± 1,92). Se hizo el análisis de los hallazgos morfológicos y se consideró que este trabajo puede servir de base para investigaciones comparativas con casos de etapas más avanzadas de la enfermedad valvular en relación a la inflamación, remodelado colágeno y angiogénesis.

Rheumatic fever is an endemic disease in developing countries such as Venezuela and is an important cause of progressive chronic valve disease, the mitral valve apparatus being affected in the first place. To evaluate the morphologic aspect of chronic valvulitis in its initial stage among individuals that have gone through mitral and mitro-aortic valve replacement. Twenty (20) biopsies of mitral and mitro-aortic valves diagnosed with rheumatic chronic valvulopathy in its initial stage were selected from patients aged 20 years or younger. Preoperating diagnoses were as follows: severe mitral valve dysfunction (insufficiency: 60%, double injury: 10%, stenosis: 5%, and mitro-aortic: 25%). The biopsy material (valve apparatuses) was macroscopically evaluated. A histological study was made on haematoxylin-eosin stained and CD34 antibody immunomarked sections and smooth antimuscle. All cases showed morphologic lesions typical of initial chronic rheumatic valvulitis: grade 1 inflammation (81,6%), with Aschoff's bodies or nodules (35%), grade 2 fibrosis (40%), and grade 3 fibrosis (60%) with high density neovascularization (14,78 ± 1,92). Morphologic findings were analyzed, thus concluding that this work can serve as a basis for comparative investigations on case of valvular disease at more advanced stages in terms of inflammation, collagen remodeling and angiogenesis.

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Rheumatic fever (RF) is triggered by S. pyogenes and affects 3-4% of untreated susceptible children. The immune response against streptococcal antigens can lead cross-recognition of heart tissue proteins resulting in rheumatic heart disease (RHD). HLA class II alleles have been associated with the development of RF/RHD. Tumor necrosis factor (TNF)-alpha is also located in the same chromosomal region of HLA genes and has been investigated in RHD patients from Mexico, Turkey, and Brazil. Associations with the TNFA-308 allele were found and probably are related to the development of valvular lesions. A deficient mannose-binding lectin (MBL) allele was found in Brazilian patients. MBL is a protein important for the first line of host defense against the bacteria. The association with diverse genes probably indicates a role of certain molecules in both the innate and adaptive immune response. Antigen-presenting cells bearing the HLA-DR7 molecule from RHD patients preferentially recognized a heart-tissue protein cross-reactive M5 (81-96) peptide. The same peptide was also recognized by heart tissue T cell clones. Cardiac myosin peptides were recognized by high numbers of intralesional T cell clones. The cytokine pattern of infiltrating mononuclear cells in both myocardium and valvular tissue showed a predominance of proinflammatory cytokines (TNF-alpha and IFN-gamma) and scarce production of regulatory cytokines, such as IL-4, in the valve tissue. IL-10, a predominant regulatory cytokine, was also secreted by large numbers of cells in both valve and myocardium tissue. Data here indicate the complexity of immune reactions leading to autoimmune lesions in RF/RHD.

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Molecular mimicry between streptococcal and human proteins is considered as the triggering factor leading to autoimmunity in rheumatic fever (RF) and rheumatic heart disease (RHD). Here, we present a review of the genetic susceptibility markers involved in the development of RF/RHD and the major immunopathological events underlying the pathogenesis of RF and RHD. Several human leucocyte antigen (HLA) class II alleles are associated with the disease. Among these alleles, HLA-DR7 is predominantly observed in different ethnicities and is associated with the development of valvular lesions in RHD patients. Cardiac myosin is one of the major autoantigens involved in rheumatic heart lesions and several peptides from the LMM (light meromyosin) region were recognized by peripheral and intralesional T-cell clones from RF and RHD patients. The production of TNF-alpha and IFN-gamma from heart-infiltrating mononuclear cells suggests that Th-1 type cytokines are the mediators of RHD heart lesions while the presence of few interleukin-4 producing cells in the valve tissue contributes to the maintenance and progression of the valvular lesions.

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A febre reumática (FR) é seqüela da infecção de orofaringe pelo estreptococo beta-hemolítico do grupo A, em 3 a 4% das crianças (3 a 18 anos) acometidas por faringoamidalite, e não tratadas, que apresentam fatores genéticos predispondo ao desenvolvimento da doença. A doença reumática cardíaca (DRC) é considerada...

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A febre reumática é uma doença inflamatória, sistêmica e recorrente, que se manifesta cerca de uma a seis semanas após a infecção aguda da orofaringe por estreptococos beta-hemolíticos do grupo A. Presume-se que seja uma resposta imunológica a antígenos estreptocócicos ou uma reação auto-imune induzida pelos estreptococos, em indivíduos geneticamente suscetíveis. Acomete crianças de 5 a 15 anos, mas 20 por cento dos surtos iniciais ocorrem em indivíduos de meia idade ou idosos. No coração há comprometimento dos tecidos conjuntivos pericárdico, miocárdico e endocárdico. A pericardite é exuberante e predominantemente fibrinosa, com aspecto macroscópico de "pão com manteiga". A miocardite causa aumento cardíaco, principalmente por dilatação ventricular. No tecido conjuntivo cardíaco encontram-se nódulos de Aschoff, que retratam histologicamente as fases evolutivas da doença: exsudativa, proliferativa e cicatricial. O nódulo de Aschoff, na fase proliferativa, é patognomônico de atividade reumática, apresentando degeneração fibrinóide do colágeno e acúmulo de células inflamatórias, dentre elas as células de Anitsch-kow. Pequenas vegetações são encontradas nas linhas de fechamento valvar, mais comumente mitro-aórticas. Histologicamente são elevações da superfície valvar, decorrentes da deposição de fibrina e plaquetas ou da degeneração fibrinóide do colágeno local. O dano cardíaco é cumulativo, aumentando a cada episódio de atividade. As alterações reumáticas crônicas mais importantes resultam da cicatrização das lesões agudas valvares e podem ocorrer em todas as valvas. A estenose mitral é a seqüela reumática mais freqüente, seguida pela estenose mitro-aórtica e pela estenose aórtica isolada. Pode haver associação de estenose e insuficiência valvar, que é mais comum nas lesões aórticas.

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O trabalho atualiza os diferentes aspectos da febre reumática, enfatizando os modernos conceitos acerca de sua patogenia, o quadro clínico, compreendendo artrite, cardite, coréia de Syndenham e outras manifestaçöes, bem como os dados laboratoriais, o diagnóstico diferencial, patologia e terapêutica. Neste particular, analisa a erradicaçäo do estreptococo, o tratamento das síndromes e a profilaxia secundária.

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