197 research outputs found
Mycobacterial ESAT-6 and katG are Recognized by Sarcoidosis CD4+ T Cells When Presented by the American Sarcoidosis Susceptibility Allele, DRB1*1101
Childhood sarcoidosis: A rare but fascinating disorder
Childhood sarcoidosis is a rare multisystemic granulomatous disorder of unknown etiology. In the pediatric series reported from the southeastern United States, sarcoidosis had a higher incidence among African Americans. Most reported childhood cases have occurred in patients aged 13–15 years. Macrophages bearing an increased expression of major histocompatibility class (MHC) II molecules most likely initiate the inflammatory response of sarcoidosis by presenting an unidentified antigen to CD4+ Th (helper-inducer) lymphocytes. A persistent, poorly degradable antigen driven cell-mediated immune response leads to a cytokine cascade, to granuloma formation, and eventually to fibrosis. Frequently observed immunologic features include depression of cutaneous delayed-type hypersensitivity and a heightened helper T cell type 1 (Th1) immune response at sites of disease. Circulating immune complexes, along with signs of B cell hyperactivity, may also be found. The clinical presentation can vary greatly depending upon the organs involved and age of the patient. Two distinct forms of sarcoidosis exist in children. Older children usually present with a multisystem disease similar to the adult manifestations, with frequent hilar lymphadenopathy and pulmonary infiltrations. Early-onset sarcoidosis is a unique form of the disease characterized by the triad of rash, uveitis, and arthritis in children presenting before four years of age. The diagnosis of sarcoidosis is confirmed by demonstrating a typical noncaseating granuloma on a biopsy specimen. Other granulmatous diseases should be reasonably excluded. The current therapy of choice for sarcoidosis in children with multisystem involvement is oral corticosteroids. Methotrexate given orally in low doses has been effective, safe and steroid sparing in some patients. Alternative immunosuppressive agents, such as azathioprine, cyclophosphamide, chlorambucil, and cyclosporine, have been tried in adult cases of sarcoidosis with questionable efficacy. The high toxicity profile of these agents, including an increased risk of lymphoproliferative disorders and carcinomas, has limited their use to patients with severe disease refractory to other agents. Successful steroid sparing treatment with mycophenolate mofetil was described in an adolescent with renal-limited sarcoidosis complicated by renal failure. Novel treatment strategies for sarcoidosis have been developed including the use of TNF-alpha inhibitors, such as infliximab. The long-term course and prognosis is not well established in childhood sarcoidosis, but it appears to be poorer in early-onset disease
Cystic fibrosis gene mutation in two sisters with mild disease and normal sweat electrolyte levels
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Markov model and markers of small cell lung cancer: assessing the influence of reversible serum NSE, CYFRA 21-1 and TPS levels on prognosis
High serum NSE and advanced tumour stage are well-known negative prognostic determinants of small cell lung cancer (SCLC) when observed at presentation. However, such variables are reversible disease indicators as they can change during the course of therapy. The relationship between risk of death and marker level and disease state during treatment of SCLC chemotherapy is not known. A total of 52 patients with SCLC were followed during cisplatin-based chemotherapy (the median number of tumour status and marker level assessments was 4). The time-homogeneous Markov model was used in order to analyse separately the prognostic significance of change in the state of the serum marker level (NSE, CYFRA 21-1, TPS) or the change in tumour status. In this model, transition rate intensities were analysed according to three different states: alive with low marker level (state 0), alive with high marker level (state 1) and dead (absorbing state). The model analysing NSE levels showed that the mean time to move out of state ‘high marker level’ was short (123 days). There was a 44% probability of the opposite reversible state ‘low marker level’ being reached, which demonstrated the reversible property of the state ‘high marker level’. The relative risk of death from this state ‘high marker level’ was about 2.24 times greater in comparison with that of state 0 ‘low marker level’ (Wald's test; P < 0.01). For patients in state ‘high marker level’ at time of sampling, the probability of death increased dramatically, a transition explaining the rapid decrease in the probability of remaining stationary at this state. However, a non-nil probability to change from state 1 ‘high marker level’ to the opposite transient level, state 0 ‘low marker level’, was observed suggesting that, however infrequently, patients in state 1 ‘high marker level’ might still return to state 0 ‘low marker level’. Almost similar conclusions can be drawn regarding the three-state model constructed using the tumour response status. For the two cytokeratin markers, the Markov model suggests the lack of a true reversible property of these variables as there was only a very weak probability of a patient returning to state ‘low marker level’ once having entered state ‘high marker level’. In conclusion, The Markov model suggests that the observation of an increase in serum NSE level or a lack of response of the disease at any time during follow-up (according to the homogeneous assumption) was strongly associated with a worse prognosis but that the reversion to a low mortality risk state remains possible. © 1999 Cancer Research Campaig
Overweight status is associated with extensive signs of microvascular dysfunction and cardiovascular risk
The aim of this present study was to investigate if overweight individuals exhibit signs of vascular dysfunction associated with a high risk for cardiovascular disease (CVD). One hundred lean and 100 overweight participants were recruited for the present study. Retinal microvascular function was assessed using the Dynamic Retinal Vessel Analyser (DVA), and systemic macrovascular function by means of flow-mediated dilation (FMD). Investigations also included body composition, carotid intimal-media thickness (c-IMT), ambulatory blood pressure monitoring (BP), fasting plasma glucose, triglycerides (TG), cholesterol levels (HDL-C and LDL-C), and plasma von Willebrand factor (vWF). Overweight individuals presented with higher right and left c-IMT (p = 0.005 and p = 0.002, respectively), average 24-h BP values (all p <0.001), plasma glucose (p = 0.008), TG (p = 0.003), TG: HDL-C ratio (p = 0.010), and vWF levels (p = 0.004). Moreover, overweight individuals showed lower retinal arterial microvascular dilation (p = 0.039) and baseline-corrected flicker (bFR) responses (p = 0.022), as well as, prolonged dilation reaction time (RT, p = 0.047). These observations emphasise the importance of vascular screening and consideration of preventive interventions to decrease vascular risk in all individuals with adiposity above normal range
An In Silico Modeling Approach to Understanding the Dynamics of Sarcoidosis
BACKGROUND: Sarcoidosis is a polygenic disease with diverse phenotypic presentations characterized by an abnormal antigen-mediated Th1 type immune response. At present, progress towards understanding sarcoidosis disease mechanisms and the development of novel treatments is limited by constraints attendant to conducting human research in a rare disease in the absence of relevant animal models. We sought to develop a computational model to enhance our understanding of the pathological mechanisms of and predict potential treatments of sarcoidosis. METHODOLOGY/RESULTS: Based upon the literature, we developed a computational model of known interactions between essential immune cells (antigen-presenting macrophages, effector and regulatory T cells) and cytokine mediators (IL-2, TNFα, IFNγ) of granulomatous inflammation during sarcoidosis. The dynamics of these interactions are described by a set of ordinary differential equations. The model predicts bistable switching behavior which is consistent with normal (self-limited) and "sarcoidosis-like" (sustained) activation of the inflammatory components of the system following a single antigen challenge. By perturbing the influence of model components using inhibitors of the cytokine mediators, distinct clinically relevant disease phenotypes were represented. Finally, the model was shown to be useful for pre-clinical testing of therapies based upon molecular targets and dose-effect relationships. CONCLUSIONS/SIGNIFICANCE: Our work illustrates a dynamic computer simulation of granulomatous inflammation scenarios that is useful for the investigation of disease mechanisms and for pre-clinical therapeutic testing. In lieu of relevant in vitro or animal surrogates, our model may provide for the screening of potential therapies for specific sarcoidosis disease phenotypes in advance of expensive clinical trials
Sarcoidosis activates diverse transcriptional programs in bronchoalveolar lavage cells
Abstract
Background
Sarcoidosis is a multisystem immuno-inflammatory disorder of unknown etiology that most commonly involves the lungs. We hypothesized that an unbiased approach to identify pathways activated in bronchoalveolar lavage (BAL) cells can shed light on the pathogenesis of this complex disease.
Methods
We recruited 15 patients with various stages of sarcoidosis and 12 healthy controls. All subjects underwent bronchoscopy with lavage. For each subject, total RNA was extracted from BAL cells and hybridized to an Affymetrix U133A microarray. Rigorous statistical methods were applied to identify differential gene expression between subjects with sarcoidosis vs. controls. To better elucidate pathways differentially activated between these groups, we integrated network and gene set enrichment analyses of BAL cell transcriptional profiles.
Results
Sarcoidosis patients were either non-smokers or former smokers, all had lung involvement and only two were on systemic prednisone. Healthy controls were all non-smokers. Comparison of BAL cell gene expression between sarcoidosis and healthy subjects revealed over 1500 differentially expressed genes. Several previously described immune mediators, such as interferon gamma, were upregulated in the sarcoidosis subjects. Using an integrative computational approach we constructed a modular network of over 80 gene sets that were highly enriched in patients with sarcoidosis. Many of these pathways mapped to inflammatory and immune-related processes including adaptive immunity, T-cell signaling, graft vs. host disease, interleukin 12, 23 and 17 signaling. Additionally, we uncovered a close association between the proteasome machinery and adaptive immunity, highlighting a potentially important and targetable relationship in the pathobiology of sarcoidosis.
Conclusions
BAL cells in sarcoidosis are characterized by enrichment of distinct transcriptional programs involved in immunity and proteasomal processes. Our findings add to the growing evidence implicating alveolar resident immune effector cells in the pathogenesis of sarcoidosis and identify specific pathways whose activation may modulate disease progression
Cardiac magnetic resonance imaging-indeterminate/negative cardiac sarcoidosis revealed by 18F-fluorodeoxyglucose-positron emission tomography: two case reports and a review of the literature
Abstract Background Sarcoidosis is an inflammatory disorder of immune dysregulation characterized by non-caseating granulomas that can affect any organ. Cardiac sarcoidosis is an under-recognized entity that has a heterogeneous presentation and may occur independently or with any severity of systemic disease. Diagnosing cardiac sarcoidosis remains problematic with endomyocardial biopsies associated with a high risk of complications. Several diagnostic algorithms are currently available that rely on histopathology or clinical and radiological measures. The dominant mode of diagnostic imaging to date for cardiac sarcoidosis has been cardiac magnetic resonance imaging with gadolinium enhancement. Case presentations We report the cases of two adult patients: case 1, a 50-year-old white man who presented with severe congestive cardiac failure; and case 2, a 37-year-old white woman who presented with complete heart block. Both patients had a background of untreated pulmonary sarcoidosis. Cardiac magnetic resonance imaging did not show evidence of sarcoidosis in either patient and both proceeded to 18F-fluorodeoxyglucose-positron emission tomography scans that were highly suggestive of cardiac sarcoidosis. Both patients were systemically immunosuppressed with orally administered prednisone and methotrexate and had subsequent improvement by clinical and nuclear medicine imaging measures. Conclusions Current consensus guidelines recommend all patients with sarcoidosis undergo screening for occult cardiac disease, with thorough history and examination, electrocardiogram, and transthoracic echocardiogram. If any abnormalities are detected, advanced cardiac imaging should follow. While cardiac magnetic resonance imaging identifies the majority of cardiac sarcoidosis, early disease may not be detected. These cases demonstrate 18F-fluorodeoxyglucose-positron emission tomography is warranted following an indeterminate or normal cardiac magnetic resonance imaging if clinical suspicion remains high. Unidentified and untreated cardiac sarcoidosis risks significant morbidity and mortality, but early detection can facilitate disease-modifying immunosuppression and cardiac-specific interventions
Linkage of Type I Interferon Activity and TNF-Alpha Levels in Serum with Sarcoidosis Manifestations and Ancestry
BACKGROUND: Both type I interferon (IFN), also known as IFN-α and tumor necrosis factor alpha (TNF-α) have been implicated in the pathogenesis of sarcoidosis. We investigated serum levels of these cytokines in a large multi-ancestral sarcoidosis population to determine correlations between cytokine levels and disease phenotypes. METHODS: We studied serum samples from 98 patients with sarcoidosis, including 71 patients of African-American ancestry and 27 patients of European-American ancestry. Serum type I IFN was measured using a sensitive reporter cell assay and serum TNF-α was measured using a commercial ELISA kit. Clinical data including presence or absence of neurologic, cardiac, and severe pulmonary manifestations of sarcoidosis were abstracted from medical records. Twenty age-matched non-autoimmune controls were also studied from each ancestral background. Differences in cytokine levels between groups were analyzed with Mann-Whitney U test, and correlations were assessed using Spearman's rho. Multivariate logistic regression models were used to detect associations between cytokines and clinical manifestations. RESULTS: Significant differences in cytokine levels were observed between African- and European-American patients with sarcoidosis. In African-Americans, serum TNF-α levels were significantly higher relative to matched controls (P = 0.039), and patients with neurologic disease had significantly higher TNF-α than patients lacking this manifestation (P = 0.022). In European-Americans, serum type I IFN activity was higher in sarcoidosis cases as compared to matched controls, and patients with extra-pulmonary disease represented a high serum IFN subgroup (P = 0.0032). None of the associations observed were shared between the two ancestral groups. CONCLUSIONS: Our data indicate that significant associations between serum levels of TNF-α and type I IFN and clinical manifestations exist in a sarcoidosis cohort that differ significantly by self-reported ancestry. In each ancestral background, the cytokine elevated in patients with sarcoidosis was also associated with a particular disease phenotype. These findings may relate to ancestral differences in the molecular pathogenesis of this heterogeneous disease
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