CXCL9/Mig mediates T cells recruitment to valvular tissue lesions of chronic rheumatic heart disease patients.

Rheumatic fever (RF) is an autoimmune disease triggered by Streptococcus pyogenes infection frequently observed in infants from developing countries. Rheumatic heart disease (RHD), the major sequel of RF, leads to chronic inflammation of the myocardium and valvular tissue. T cells are the main population infiltrating cardiac lesions; however, the chemokines that orchestrate their recruitment are not clearly defined. Here, we investigated the expression of chemokines and chemokine receptors in cardiac tissue biopsies obtained from chronic RHD patients. Our results showed that CCL3/MIP1α gene expression was upregulated in myocardium while CCL1/I-309 and CXCL9/Mig were highly expressed in valvular tissue. Auto-reactive T cells that infiltrate valvular lesions presented a memory phenotype (CD4(+)CD45RO(+)) and migrate mainly toward CXCL9/Mig gradient. Collectively, our results show that a diverse milieu of chemokines is expressed in myocardium and valvular tissue lesions and emphasize the role of CXCL9/Mig in mediating T cell recruitment to the site of inflammation in the heart.

The possible role of selenium status in adverse pregnancy outcomes.

The present study reviews the possible role of Se status during pregnancy regarding adverse pregnancy outcomes, with emphasis on those related to diminished antioxidant activity and increased oxidative stress. Studies have reported that Se could play an important role in adverse outcomes such as miscarriages, neural tube defects, diaphragmatic hernia, premature birth, low birth weight, pre-eclampsia, glucose intolerance and gestational diabetes. Also, low Se status has been associated with adverse outcomes among HIV-infected pregnant women and their offspring. Nevertheless, the function of Se in the aetiology of pregnancy complications is yet to be elucidated. Available evidence presents the following limitations: most study designs do not allow conclusions about causal relationships; study populations, selection of subjects, research setting, procedures for defining sample size and analytical methods are often poorly described; many studies fail to adjust for important confounding variables. In addition, population studies assessing the relationship between Se intake during pregnancy and health outcomes are scarce. Further research is still needed to clarify the role of Se status in adverse pregnancy outcomes, especially those related to augmented oxidative stress.

Mothers' birth care experiences in a Brazilian birth centre.

OBJECTIVE: to explore the reasons why women with previous hospital experience seek care at a birth centre, and their perceptions related to the care received in both settings. DESIGN, SETTING AND PARTICIPANTS: in-depth interviews focusing on the care experiences of 18 women who received birth care in a birth centre of the Brazilian public health system. FINDINGS: three key themes emerged from the analysis: 'Confrontation with strong problems in the hospital setting', 'Reasons to seek the birth centre' and 'Satisfaction related to birth centre care'. The main aspects that the mothers mentioned in the first and third themes were related to the institutional structure and system of care. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: mothers' narratives suggested that their previous experience of problems in the hospital setting was the main motive for seeking care at the birth centre. The most important components of birth care were attention, meeting personal care demands and establishment of an adequate interpersonal relationship. More sensitive birthing care in the hospital setting is necessary, and this can be promoted through continuing professional education.

PDIA3, HSPA5 and vimentin, proteins identified by 2-DE in the valvular tissue, are the target antigens of peripheral and heart infiltrating T cells from chronic rheumatic heart disease patients.

Rheumatic fever (RF) is a post-infectious autoimmune disease due to sequel of group A streptococcus (GAS) pharyngitis. Rheumatic heart disease (RHD), the major manifestation of RF, is characterized by inflammation of heart valves and myocardium. Molecular mimicry between GAS antigens and host proteins has been shown at B and T cell level. However the identification of the autoantigens recognized by B and T cells within the inflammatory microenvironment of heart tissue in patients with RHD is still incompletely elucidated. In the present study, we used two-dimensional gel electrophoresis (2-DE) and mass spectrometry to identify valvular tissue proteins target of T cells from chronic RHD patients. We could identify three proteins recognized by heart infiltrating and peripheral T cells as protein disulfide isomerase ER-60 precursor (PDIA3), 78kD glucose-regulated protein precursor (HSPA5) and vimentin, with coverage of 45%, 43 and 34%, respectively. These proteins were recognized in a proliferation assay by peripheral and heart infiltrating T cells from RHD patients suggesting that they may be involved in the autoimmune reactions that leads to valve damage. We also observed that several other proteins isolated by 2-DE but not identified by mass spectrometry were also recognized by T cells. The identified cardiac proteins are likely relevant antigens involved in T cell-mediated autoimmune responses in RF/RHD that may contribute to the development of RHD.

Gestações sucessivas na adolescência / Successive pregnancies in adolescence

Buscou-se, por meio de uma revisão bibliográfica de publicações científicas no período de 1980 a 2005, levantar conhecimentos produzidos sobre a ocorrência de gestações sucessivas na adolescência. Inicialmente, investigou-se a dinâmica reprodutiva da população adolescente e, em seguida, é apresentada a revisão de vários estudos que tratam das gravidezes recorrentes dessas jovens, procurando, inclusive, elencar os vários conceitos usados para especificar o fenômeno. Foi localizada pequena produção científica acerca do tema, contudo, nos trabalhos encontrados foram detectados dados importantes que concorrem para o entendimento do fenômeno, especialmente aqueles referentes ao seu número, à grande possibilidade de sua repetição na ausência de recursos protetores ao pós-parto, à escolaridade das jovens grávidas, ao seu retorno à escolarização e ao uso adequado que elas fazem de métodos anticoncepcionais. Entretanto, esses dados devem ser relativizados uma vez que vários autores descrevem altos índices de gestações recorrentes de adolescentes quando em parceria sexual fixa, quer sejam casadas ou em uniões consensuais. Nesse caso se pode pensar que essa população, após a primeira gravidez, definitivamente assume uma vida conjugal estável, modificando consideravelmente o perfil clássico da "adolescente grávida"(AU)

This study aimed to survey the knowledge produced on the occurrence of successive pregnancies in adolescence, through a bibliographic review of scientific works published between 1980 and 2005. First, we investigate the reproductive dynamics of the youth population; then, we present the review of several studies that deal with successive pregnancies in adolescence, listing the several concepts used to specify the phenomenon. Very few scientific productions about the theme were found; however, they provided important data for the understanding of this phenomenon, specially concerning its number, the likelihood of its repetition in the absence of resources to protect the period after delivery, the education level of the pregnant youths, their return to school, and the adequate use they make of contraceptive methods. Nevertheless, these data can be questioned, since several authors describe high indexes of recurrent pregnancies of adolescents when they have a stable partner, whether they are married or in consensual unions. It is possible to think, in this case, that this population, after the first pregnancy, definitively assumes a stable conjugal life, considerably modifying the classic profile of the "pregnant adolescent".(AU)

T cell response in rheumatic fever: crossreactivity between streptococcal M protein peptides and heart tissue proteins.

Molecular mimicry between streptococcal and human proteins has been proposed as the triggering factor leading to autoimmunity in rheumatic fever (RF) and rheumatic heart disease (RHD). In this review we focus on the studies on genetic susceptibility markers involved in the development of RF/RHD and molecular mimicry mediated by T cell responses of RHD patients against streptococcal antigens and human tissue proteins. We identified several M protein epitopes recognized by peripheral T cells of RF/RHD patients and by heart tissue infiltrating T cell clones of severe RHD patients. The regions of the M protein preferentially recognized by human T cells were also recognized by murine T cells. By analyzing the T cell receptor (TCR) we observed that some Vbeta families detected on the periphery were oligoclonal expanded in the heart lesions. These results allowed us to confirm the major role of T cells in the development of RHD lesions.

Rheumatic heart disease: 15 years of clinical and immunological follow-up.

Rheumatic fever (RF) is a sequel of group A streptococcal throat infection and occurs in untreated susceptible children. Rheumatic heart disease (RHD), the major sequel of RF, occurs in 30%-45% of RF patients. RF is still considered endemic in some regions of Brazil and is responsible for approximately 90% of early childhood valvular surgery in the country. In this study, we present a 15-year clinical follow-up of 25 children who underwent surgical valvular repair. Histopathological and immunological features of heart tissue lesions of RHD patients were also evaluated. The patients presented severe forms of RHD with congestive symptoms at a very young age. Many of them had surgery at the acute phase of RF. Histological analysis showed the presence of dense valvular inflammatory infiltrates and Aschoff nodules in the myocardium of 21% of acute RHD patients. Infiltrating T-cells were mainly CD4+ in heart tissue biopsies of patients with rheumatic activity. In addition, CD4+ and CD8+ infiltrating T-cell clones recognized streptococcal M peptides and cardiac tissue proteins. These findings may open the possibilities of new ways of immunotherapy. In addition, we demonstrated that the surgical procedure during acute phase of the disease improved the quality of life of young RHD patients.

Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease.

Molecular mimicry between Streptococcus pyogenes Ags and human proteins has been considered as a mechanism leading to autoimmune reactions in rheumatic fever and rheumatic heart disease (RHD). Cardiac myosin has been shown as a putative autoantigen recognized by autoantibodies of rheumatic fever patients. We assessed the human heart-intralesional T cell response against human light meromyosin (LMM) and streptococcal M5 peptides and mitral-valve-derived proteins by proliferation assay. Cytokines induced by LMM peptides were also evaluated. The frequency of intralesional T cell clones that recognized LMM peptides was 63.2%. Thirty-four percent of T cell clones presented cross-reactivity with different patterns: 1) myosin and valve-derived proteins; 2) myosin and streptococcal M5 peptides; and 3) myosin, valve-derived proteins and M5 peptides. In addition, several LMM peptides were recognized simultaneously showing a multiple reactivity pattern of heart-infiltrating T cells. Inflammatory cytokines (IFN-gamma and TNF-alpha) were predominantly produced by heart-infiltrating T cells upon stimulation with LMM peptides. The alignment of LMM and streptococcal M5 peptides showed frequent homology among conserved amino acid substitutions. This is the first study showing the cellular response by human heart-infiltrating T cells against cardiac myosin epitopes in RHD patients. The high percentage of reactivity against cardiac myosin strengthens its role as one of the major autoantigens involved in rheumatic heart lesions. T cell reactivity toward myosin epitopes in RHD patients may also trigger the broad recognition of valvular proteins with structural or functional similarities.

Rheumatic heart disease: proinflammatory cytokines play a role in the progression and maintenance of valvular lesions.

Heart lesions of rheumatic heart disease (RHD) patients contain T-cell clones that recognize heart proteins and streptococcal M peptides. To functionally characterize heart-infiltrating T lymphocytes, we evaluated their cytokine profile, both directly in situ and in T-cell lines derived from the heart (HIL). Interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, and IL-10 expressions were characterized in 20 heart tissue infiltrates from 14 RHD patients by immunohistochemistry. IFN-gamma-, TNF-alpha-, and IL-10-positive cells were consistently predominant, whereas IL-4 was scarce in the valves. In agreement with these data, the in vitro experiments, in which 13 HILs derived from heart samples of eight patients were stimulated with M5 protein and the immunodominant M5 (81-96) peptide, IL-4 was detected in HIL derived from the atrium (three of six) but not from the valve (zero of seven). IFN-gamma and IL-10 production were detected in culture supernatants in 11 of 13 and 6 of 12 HILs, respectively. The predominant IFN-gamma and TNF-alpha expression in the heart suggests that Th1-type cytokines could mediate RHD. Unlike in reversible myocardium inflammation, the significantly lower IL-4 expression in the valvular tissue (P = 0.02) may contribute to the progression of the RHD leading to permanent valvular damage (relative risk, 4.3; odds ratio, 15.8). The lack of IL-4 in vitro production by valve-derived HIL also emphasizes the more severe tissue destruction in valves observed in RHD.