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Introduction The progressive forms of inflammatory external root resorption (IERR) and replacement external root resorption (RERR) are serious complications and the main causes of tooth loss after replantation. This study aimed to investigate the expression pattern of inflammatory molecules in extracted human teeth presenting with external root resorption (ERR) after replantation. Methods Root fragments from 22 teeth showing IERR and 20 teeth with RERR were triturated using a homogenizer to extract inflammatory molecules. Interleukin-1β (IL-1β), IL-1Ra, transforming growth factor beta, IL-8/CXCL8, CCL2, CCL3, and CCL5 were measured using double-ligand enzyme-linked immunosorbent assay, and IL-2, IL-4, IL-6, IL-10, tumor necrosis factor alpha, interferon gamma, and IL-17A detection was performed using the multiplex Th1/Th2/Th17 Cytometric Bead Array kit (BD Biosciences, San Jose, CA). Cytokine and chemokine concentrations were compared in the RERR and IERR groups corrected by patients' age at the moment of extraction, survival time after replantation, and index of ERR, adopting a generalized estimation equation model. Results The IERR group showed higher levels of tumor necrosis factor alpha than the RERR group, even after correction for the index of ERR ( P < .05). IL-1Ra levels were higher in the IERR group for moderate cases but higher in the RERR group for severe cases ( P < .05). IL-4 concentration became higher with the increase of patients' age in the RERR group but did not vary in the IERR group ( P < .05). CCL2 levels decreased with the increase of the patients' age at the moment of extraction irrespective of the type or index of ERR ( P < .05). Conclusions The present results showed differences in the immunologic profile of IERR and RERR that may be relevant to understanding the biological mechanisms underlying ERR. [ABSTRACT FROM AUTHOR]

Abstract: Until now, there are no conclusive data about the mechanisms involved in motor symptoms of Sydenham''s chorea (SC). Taking into account the autoreactive antibody-mediated hypothesis of SC pathogenesis, the SC may be associated with uncontrolled immune mechanisms. Besides the antibody hypothesis, the innate immune system has been underappreciated. Hence, we evaluated the activation state of monocytes, cells that are precursors of macrophages, to characterize the inflammation profile of patients. We assessed the surface molecules CD80, CD86, and human leukocyte antigen DR expression in patients with SC by flow cytometry analysis. Our results showed a decreased CD14+ (monocyte) frequency, with concomitant increased CD14− frequency inside monocyte population. Although monocyte population showed a decreased human leukocyte antigen DR and CD86 frequencies, the CD14− population showed an increased frequency of CD80+ monocyte from SC compared with controls. These data suggest that monocytes showed a reduced costimulatory potential in SC. [Copyright &y& Elsevier]

Abstract: Over the past 10 years, a plethora of information concerning the influence of gene polymorphisms on cytokine expression has been made available in the literature. Significant contribution to this field has come from studies of oral diseases, one of the widest spread health problems in the world, affecting hundreds of millions worldwide. Here we will discuss the importance of studies of gene polymorphism towards the identification of susceptible groups or prognostic indicators of oral disease. Additionally, we will highlight the differences in data obtained from genetically diverse populations and review the application of cytokine gene polymorphisms studies in oral diseases in autoimmune processes and parasitic infections. [Copyright &y& Elsevier]

Human infection with the protozoan parasite Trypanosoma cruzi leads to Chagas disease, which affects ∼17 million people in Latin America. A significant percentage of the infected population will develop clinical symptoms or present changes in laboratory and/or image evaluation. The existence of a large spectrum of clinical manifestations – with patients ranging from asymptomatic to severe cardiac involvement – emphasizes the need to use standardized and well-defined clinical criteria among different research groups. In this article, we carry out a systematic review of the immunology in human Chagas disease, discussing recent findings in the context of a clinical perspective. [Copyright &y& Elsevier]

Abstract: Leishmaniasis is an important parasitic disease affecting millions worldwide. In attempts to understand the clinical relevance of immunological measurements as determined using flow cytometry, several immunological phenotypes were determined for a group of well defined human leishmaniasis patients and correlated with clinical measurements of the disease (Montenegro skin test (MST) and lesion area). The analysis demonstrated a positive correlation between the MST size and the frequency of ex vivo recent activated CD4+ T cells. In contrast, higher frequencies of recent activated CD8+ T cells were correlated with a smaller MST size. Moreover, a positive correlation was observed between the lesion total area and the frequency of activated CD69+ (ex vivo) and CD40L+ (cultured with Leishmania soluble antigen (SLA)) T lymphocytes. Finally, larger lesions were also correlated with a higher frequency of SLA specific inflammatory cytokine (IFN-γ or TNF-α) producing lymphocytes. These studies demonstrate that immunological markers are correlated with clinical indicators of human leishmaniasis and serve to better understand the evolution of this important parasitic disease. [Copyright &y& Elsevier]

Abstract: CD4+ T cells can be divided into several distinct effector subpopulations, including Th1 and Th2. Human Th1 cells are essential for the establishment of cellular immune responses, whereas Th2 cells for immunoglobulin E synthesize by B cells and immunoregulation. This study determines the involvement of exogenously and endogenously produced T cell-derived cytokines during early differentiation of naive CD4+ T cells into Th1 and Th2 cells. Cytokine gene expression of purified experienced and naive CD4+T cells in the presence or absence of Th-directing cytokines and neutralizing anti–cytokine antibodies, was determined at early (20 and 40 h) time points, after in vitro activation. These studies demonstrated that: (1) endogenously produced, T cell-derived cytokines (interferon [IFN]-γ and interleukin [IL]-4), play an important role in the regulation of early gene expression of Th2, but not Th1 type cytokines; (2) Th1-related cytokines, IFN-γ, and IL-2, are preferentially expressed in cultures directed toward Th1, as compared with Th2; and (3) IL-4 and IFN-γ showed early message expression in both differentiating populations, indicating a mixed profile of Th1 and Th2 cytokine production in early human Th cell development. These findings point to the critical role for endogenously produced cytokines in the early differentiation of human Th1 or Th2 cells. [Copyright &y& Elsevier]

Recent publications by Zaph et al. have highlighted the distinct requirements for generating and maintaining different subpopulations of CD4+ memory T cells after infection with Leishmania major in mice. These studies have advanced the understanding of the nature of long-lasting immunity to Leishmania and, when considered within the context of previous work on both murine and human leishmaniasis, will aid the design of effective vaccines. [Copyright &y& Elsevier]

Hansen's disease (or leprosy) still persists as a serious public health issue. Its diagnosis is based primarily on the detection of clinical signs that are characteristic of the disease. Studies have pointed to the selection of a set of serological and cellular biomarkers of subclinical infection that result in an efficient diagnosis. The aim of this study was compare index cases and their household contacts to identify differentially expressed biomarkers of immune response in leprosy that could provide reliable evidence of subclinical infection in household contacts. The study population consisted of index cases with multibacillary form (IC, n = 13) and their household contacts (HC, n = 14). Serum cytokines and chemokines were quantified using the cytometric beads array (CBA) system. The humoral response was assessed by ELISA test. Flow cytometry was used to characterize the cellular immune response. Monocyte and CD4 + T lymphocytes frequency was significantly higher in IC. Both CD4+ and CD8 + T lymphocytes had a reduced CD25 expression in HC. The immunoglobulin (Ig)M profile anti- NDO-HSA, LID-1, and NDOLID antigens was significantly higher in IC. This study points to the monocyte and CD4+ lymphocyte frequency, as well as specific IgM profile, as predictors of subclinical infection in the household contacts. [ABSTRACT FROM AUTHOR]

Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), is the fourth most important tropical disease, which affects approximately 7 million people worldwide. The mechanisms involved in the development of this disease are not completely well understood. An important protective role of regulatory T cells (Treg) in Chagas disease has been observed; however, the specific mechanisms remain unclear. We evaluated apoptosis as a possible mechanism mediated by Treg cells (CD4+CD25HighFOXP3+) to orchestrate the immune response in chronic Chagas disease. Patients with Chagas disease were grouped as the indeterminate (IND; asymptomatic patients with Chagas disease; n = 10) and dilated cardiomyopathy (CARD; n = 10). Healthy T. cruzi- negative individuals (NI; n = 10) were included as a control group. In order to evaluate the apoptotic cell profile, the expression of PD1, PD1L, CD39, CD95, CD95L molecules were investigated. We also evaluated the proportion of CD14+ cells expressing caspase 3. The IND group presented a substantially higher expression of CD39 by Treg cells as compared to the CARD group. On the other hand, the CARD group showed higher expression of PD-1 by Treg cells than both NI and IND groups. Significant positive correlations were observed between Treg CD95L+ cells and CD14 cells expressing caspase 3 as well as between Treg CD39 cells and CD14+ Caspase3+ cells in the IND group. Our data indicate that the expressions of different molecules that induce apoptosis are associated with suppressive mechanisms mediated by Treg cells and suggest a possible role for PD1 and PDL1 molecules in the morbidity of chronic Chagas disease. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii infection is an important cause of infectious ocular disease. The physiopathology of retinochoroidal lesions associated with this infection is not completely understood. The present study was undertaken to investigate cytokine production by T cells from individuals with active toxoplasmic retinochoroiditis (TR) comparing with controls. Eighteen patients with active TR and 15 healthy controls (6 controls IgG + to Toxoplasma and 9 negative controls) were included in the study. Peripheral blood mononuclear cells were incubated in the presence or absence of T. gondii antigen (STAg), and stained against CD4, CD8, TNF, IL-10 and IFN-γ. Baseline expression of cytokines was higher in TR/IgG + patients in comparison with controls. Cytokine expression was not increased by STAg in vitro stimulation in controls. After stimulation, TR/IgG + patients’ lymphocytes increased cytokine as compared to cultures from both controls. While T cells were the main source of IL-10, but also IFN-γ and TNF, other lymphocyte populations were relevant source of inflammatory cytokines. Interestingly, it was observed a negative correlation between ocular lesion size and IL-10 expression by CD4 + lymphocytes. This study showed that T cells are the main lymphocyte populations expressing IL-10 in patients with TR. Moreover, expression of IL-10 plays a protective role in active TR. [ABSTRACT FROM AUTHOR]

Rheumatic heart disease (RHD) is associated with inflammation that damages cardiac valves, often requiring surgical interventions. The underlying mechanisms involved in the disease progression are not completely understood. This study aimed to evaluate cytokine plasma levels in patients with RHD as possible markers of disease severity. Eighty-nine patients with RHD, age of 41 years ±11.5 years, were prospectively enrolled. RHD severity was defined as valve dysfunction that required invasive intervention, either valve repair or replacement. Peripheral blood samples were collected from all patients for cytokine measurements. The patients were followed up to look at adverse clinical events defined as either the need for valve intervention or death. At baseline, 64 (71.9%) patients had previously undergone valve intervention, whereas 25 patients had stable clinical presentation. Patients with severe RHD displayed higher levels of inflammatory cytokines than patients with stable disease. Cluster analysis showed segregation of severe and stable RHD based on IL-6/TNF-α and IL-6/IL-17A, respectively. IL-6 and TNF-α expression were positively correlated in severe but not in stable RHD patients. During a median follow-up of 23 months, 16 patients (18%) had an adverse outcome. IL-10 at baseline (HR 1.24, 95% CI 1.08–1.43, p = 0.003), and IL-4 (HR 1.12, 95% CI 1.01–1.24, p = 0.041) were predictors of events during the follow-up. High levels of cytokines are associated with severity of RHD. The co-regulated expression of IL-6 and TNF-α is associated with severe valve dysfunction, whereas high IL-10 and IL-4 levels predicted subsequently adverse outcome. • Inflammatory cytokines are associated with severity of rheumatic heart disease • Cluster analysis showed segregation of severe rheumatic heart disease based on IL-6/TNF-α • IL-6 and TNF-α expression were positively correlated in patients with severe but not in stable rheumatic heart disease. • IL-10 and IL-4 measured at study enrollment were predictors of clinical events during the follow-up. • This study provides the first evidence for the applicability of measuring circulating cytokines as a non-invasive strategy to detect biomarkers of rheumatic heart disease severity. • Employing the analysis of circulating cytokines as markers of RHD severity provides a useful tool for risk stratification. [ABSTRACT FROM AUTHOR]

Abstract: The interconnection between immune and neuroendocrine systems influences regulation of inflammatory responses. The possible relevance that this integrative response may have during the course of Chagas disease remains poorly characterized. In this context, our study was designed to determine the expression of vasoactive intestinal peptide (VIP), a neuropeptide with anti-inflammatory properties, in blood from the indeterminate and cardiac polarized forms of Chagas disease. Moreover, we determined whether the differential expression of VIP is associated with the development of cardiomyopathy in individuals infected with Trypanosoma cruzi. Finally, we analyzed gene polymorphisms of VIP receptors, VPAC1 and VPAC2, and performed correlation analysis of these polymorphisms with the different clinical forms of Chagas disease. Our results demonstrated that low plasma levels of VIP were associated with the cardiac morbidity in Chagas disease. Accordingly, correlation analysis showed that low plasma levels of VIP were associated with worse cardiac function, as determined by left ventricular ejection fraction and left ventricular diastolic diameter values. Polymorphism analysis showed a significant association between VPAC1 and the indeterminate form of Chagas disease development. Our data indicate that VIP expression and its receptors’ polymorphism may be important in determining susceptibility to progression from mild to severe forms of Chagas disease. [Copyright &y& Elsevier]

Abstract: Cellular immune responses directed against protozoan parasites are key for controlling pathogen replication and disease resolution. However, an uncontrolled, or improperly controlled, response can be deleterious to the host in terms of both allowing for the establishment of pathology, as well as less effective establishment of memory responses. Human cutaneous leishmaniasis is a disease caused by the infection with Leishmania spp. following a bite from the sandfly, the natural vector of this disease. Tens of millions worldwide are currently infected with Leishmania and no effective vaccines have been developed to date. In the face of the complexity presented by the interaction between a host (humans) with the parasite, Leishmania, and the fact that this parasite is inoculated by another complex, biologically active, vector, the sandfly, it is clearly important to study the immunoregulatory mechanisms that are induced in humans naturally infected by this parasite if we hope to develop effective vaccines and immunotherapeutic treatments in the future. Our laboratory has focused over the years on the study of the local and systemic T cell response during the first episode of cutaneous leishmaniasis suffered by individuals before they undergo antimony treatment. The goal of this review is to briefly outline our findings with hopes of putting our most recent studies concerning the dichotomy between alpha/beta TCR and gamma/delta TCR expressing, CD4−CD8− (double negative—DN) T cells in the context of a balanced immune response against Leishmania and to discuss the implications of these findings toward our understanding of human leishmaniasis. [Copyright &y& Elsevier]

Abstract: The immune mechanisms that underlie resistance and susceptibility to leishmaniasis are not completely understood for all species of Leishmania. It is becoming clear that the immune response, the parasite elimination by the host and, as a result, the outcome of the disease depend both on the host and on the species of the infecting Leishmania. Here, we analyzed the outcome of the infection of BALB/c mice with L. guyanensis in vivo and in vitro. We showed that BALB/c mice, which are a prototype of susceptible host for most species of Leishmania, dying from these infections, develop insignificant or no cutaneous lesions and eliminate the parasite when infected with promastigotes of L. guyanensis. In vitro, we found that thioglycollate-elicited BALB/c peritoneal macrophages, which are unable to eliminate L. amazonensis without previous activation with cytokines or lipopolysaccharide, can kill L. guyanensis amastigotes. This is the first report showing that infection of peritoneal macrophages with stationary phase promastigotes efficiently triggers innate microbicidal mechanisms that are effective in eliminating the amastigotes, without exogenous activation. We demonstrated that L. guyanensis amastigotes die inside the macrophages through an apoptotic process that is independent of nitric oxide and is mediated by reactive oxygen intermediates generated in the host cell during infection. This innate killing mechanism of macrophages may account for the resistance of BALB/c mice to infection by L. guyanensis. [Copyright &y& Elsevier]

Adhesion molecules play a crucial role in cell migration and recruitment. Expression of adhesion molecules that preferentially address cells to inflammatory sites is a critical event in the formation and maintenance of leishmaniasis lesions. In this work, we analyzed the expression of CD11a, CD11b and CD62L, adhesion molecules involved in cell activation and circulation, in CD4+ and CD8+ T cells from peripheral blood and lymph nodes of patients with early cutaneous leishmaniasis. The percentage of expression of CD62L, CD11a and CD11b in total lymphocytes was lower in lymph nodes as compared to peripheral blood. Moreover, differences in adhesion molecule expression between blood and lymph nodes were more striking in CD4+ than CD8+ T cells. Stimulation of PBMC from leishmaniasis patients with soluble Leishmania antigens (SLA) lead to the expansion of CD4+CD62Lhigh cells, CD4+CD11b+ cells and to an increase in the intensity of expression of CD11a in CD4+, but not CD8+ T cells. Our data suggest that early activation events that occur in the lymph nodes of patients recently infected with Leishmania lead to changes in T cell adhesion molecule expression, favoring migration to the periphery and increasing the likelihood of further recruitment to lesion sites. [Copyright &y& Elsevier]