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Blockade of the programmed death-1 pathway restores sarcoidosis CD4(+) T-cell proliferative capacity.
Braun NA, Celada LJ, Herazo-Maya JD, Abraham S, Shaginurova G, Sevin CM, Grutters J, Culver DA, Dworski R, Sheller J, Massion PP, Polosukhin VV, Johnson JE, Kaminski N, Wilkes DS, Oswald-Richter KA, Drake WP
(2014) Am J Respir Crit Care Med 190: 560-71
MeSH Terms: Adult, Aged, Antibodies, B7-H1 Antigen, Biomarkers, CD4-Positive T-Lymphocytes, Case-Control Studies, Cell Proliferation, Female, Flow Cytometry, Humans, Immunohistochemistry, Lung Neoplasms, Male, Middle Aged, Programmed Cell Death 1 Receptor, Remission, Spontaneous, Sarcoidosis, Pulmonary, Up-Regulation
Show Abstract · Added February 20, 2015
RATIONALE - Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T-cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. Up-regulation of inhibitor receptors, such as programmed death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T-cell function.
OBJECTIVES - To determine the effects of PD-1 pathway blockade on sarcoidosis CD4(+) T-cell proliferative capacity.
METHODS - Gene expression profiles of sarcoidosis and healthy control peripheral blood mononuclear cells were analyzed at baseline and follow-up. Flow cytometry was used to measure ex vivo expression of PD-1 and PD-L1 on systemic and bronchoalveolar lavage-derived cells of subjects with sarcoidosis and control subjects, as well as the effects of PD-1 pathway blockade on cellular proliferation after T-cell receptor stimulation. Immunohistochemistry analysis for PD-1/PD-L1 expression was conducted on sarcoidosis, malignant, and healthy control lung specimens.
MEASUREMENTS AND MAIN RESULTS - Microarray analysis demonstrates longitudinal increase in PDCD1 gene expression in sarcoidosis peripheral blood mononuclear cells. Immunohistochemistry analysis revealed increased PD-L1 expression within sarcoidosis granulomas and lung malignancy, but this was absent in healthy lungs. Increased numbers of sarcoidosis PD-1(+) CD4(+) T cells are present systemically, compared with healthy control subjects (P < 0.0001). Lymphocytes with reduced proliferative capacity exhibited increased proliferation with PD-1 pathway blockade. Longitudinal analysis of subjects with sarcoidosis revealed reduced PD-1(+) CD4(+) T cells with spontaneous clinical resolution but not with disease progression.
CONCLUSIONS - Analogous to the effects in other chronic lung diseases, these findings demonstrate that the PD-1 pathway is an important contributor to sarcoidosis CD4(+) T-cell proliferative capacity and clinical outcome. Blockade of the PD-1 pathway may be a viable therapeutic target to optimize clinical outcomes.
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19 MeSH Terms
Reversal of global CD4+ subset dysfunction is associated with spontaneous clinical resolution of pulmonary sarcoidosis.
Oswald-Richter KA, Richmond BW, Braun NA, Isom J, Abraham S, Taylor TR, Drake JM, Culver DA, Wilkes DS, Drake WP
(2013) J Immunol 190: 5446-53
MeSH Terms: Adult, Aged, Bronchoalveolar Lavage Fluid, CD4-Positive T-Lymphocytes, Clonal Anergy, Female, Humans, Interleukin-2, Male, Middle Aged, Receptors, Antigen, T-Cell, Remission, Spontaneous, Sarcoidosis, Pulmonary, Signal Transduction, T-Lymphocyte Subsets, T-Lymphocytes, Helper-Inducer, T-Lymphocytes, Regulatory, Young Adult
Show Abstract · Added May 27, 2014
Sarcoidosis pathogenesis is characterized by peripheral anergy and an exaggerated, pulmonary CD4(+) Th1 response. In this study, we demonstrate that CD4(+) anergic responses to polyclonal TCR stimulation are present peripherally and within the lungs of sarcoid patients. Consistent with prior observations, spontaneous release of IL-2 was noted in sarcoidosis bronchoalveolar lavage CD4(+) T cells. However, in contrast to spontaneous hyperactive responses reported previously, the cells displayed anergic responses to polyclonal TCR stimulation. The anergic responses correlated with diminished expression of the Src kinase Lck, protein kinase C-θ, and NF-κB, key mediators of IL-2 transcription. Although T regulatory (Treg) cells were increased in sarcoid patients, Treg depletion from the CD4(+) T cell population of sarcoidosis patients did not rescue IL-2 and IFN-γ production, whereas restoration of the IL-2 signaling cascade, via protein kinase C-θ overexpression, did. Furthermore, sarcoidosis Treg cells displayed poor suppressive capacity indicating that T cell dysfunction was a global CD4(+) manifestation. Analyses of patients with spontaneous clinical resolution revealed that restoration of CD4(+) Th1 and Treg cell function was associated with resolution. Conversely, disease progression exhibited decreased Th1 cytokine secretion and proliferative capacity, and reduced Lck expression. These findings implicate normalized CD4(+) T cell function as a potential therapeutic target for sarcoidosis resolution.
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18 MeSH Terms
Natural history of Helicobacter pylori infection in Mexican schoolchildren: incidence and spontaneous clearance.
Duque X, Vilchis J, Mera R, Trejo-Valdivia B, Goodman KJ, Mendoza ME, Navarro F, Roque V, Moran S, Torres J, Correa P
(2012) J Pediatr Gastroenterol Nutr 55: 209-16
MeSH Terms: Adolescent, Anemia, Anemia, Iron-Deficiency, Child, Child, Preschool, Confidence Intervals, Dietary Supplements, Female, Helicobacter Infections, Helicobacter pylori, Humans, Incidence, Iron, Male, Mexico, Nutritional Status, Prevalence, Proportional Hazards Models, Remission, Spontaneous, Schools, Siblings, Students
Show Abstract · Added September 3, 2013
OBJECTIVES - The aim of the present study was to estimate the incidence and spontaneous clearance rate of Helicobacter pylori infection and the effect of some variables on these outcomes in schoolchildren.
METHODS - From May 2005 to December 2010, 718 schoolchildren enrolled in 3 public boarding schools in Mexico City participated in the follow-up. At the beginning of the study and every 6 months thereafter, breath samples were taken to detect H pylori infection; blood samples and anthropometric measurements were taken to evaluate nutritional status. Data on sociodemographic characteristics were collected.
RESULTS - The prevalence of H pylori infection was 38%. The incidence rate was 6.36%/year. Schoolchildren with anemia or iron deficiency at the beginning of the study (who received iron supplements) showed a higher infection acquisition rate than those with normal iron nutritional status, hazard ratio (HR) 12.52 (95% confidence interval [CI] 4.01%-39.12%), P < 0.001 and HR 2.05 (95% CI 1.09%-3.87%), P = 0.027, respectively. The spontaneous clearance rate of the infection was 4.74%/year. The spontaneous clearance rate was higher in children who had iron deficiency (who received iron supplements), HR 5.02 (95% CI 1.33%-18.99%), P = 0.017, compared with those with normal nutritional iron status. It was lower in schoolchildren with ≥ 2 siblings compared with schoolchildren with 1 or no siblings, HR 0.23 (95% CI 0.08%-0.63%), P = 0.004.
CONCLUSIONS - H pylori infection status is dynamic in schoolchildren. Variables related to health status and infection transmission, such as iron status and number of siblings, are important for the incidence and spontaneous clearance of H pylori infection.
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22 MeSH Terms
Infant communicating hydroceles--do they need immediate repair or might some clinically resolve?
Koski ME, Makari JH, Adams MC, Thomas JC, Clark PE, Pope JC, Brock JW
(2010) J Pediatr Surg 45: 590-3
MeSH Terms: Cohort Studies, Follow-Up Studies, Humans, Infant, Infant, Newborn, Linear Models, Male, Observation, Probability, Remission, Spontaneous, Retrospective Studies, Risk Assessment, Statistics, Nonparametric, Testicular Hydrocele, Time Factors, Treatment Outcome, Urogenital Surgical Procedures
Show Abstract · Added May 27, 2014
PURPOSE - Infant hydroceles that are communicating by history (fluctuation in size) or examination (reducible fluid) are often repaired soon after presentation. We have followed a series of infant boys with such hydroceles and reviewed their early natural history.
MATERIALS AND METHODS - Since 1998, we have followed 174 infant boys presenting with an apparent communicating hydrocele without immediate surgical repair. All boys were initially seen before 18 months of age and most (168) by 12 months. Most had been full term at delivery, although 32 had been premature (<37 weeks' gestational age) and 11 extremely so (<32 weeks). Most boys (120) had bilateral hydroceles at presentation.
RESULTS - Of the 110 boys followed to disposition, 69 (62.7%) had complete resolution without surgery by a mean age of 11.7 months. Forty-one patients (37.3%) underwent surgery for correction at a mean age of 14 months because of persistence in size or development of a hernia. Six developed a hernia during observation, none of whom had any episode of incarceration. Only 2 patients with apparent resolution subsequently had recurrence with a hernia. Age at presentation and gestational age at birth showed no effect on resolution. The hydroceles of 64 boys had improved in size after a mean follow-up of 13.9 months when last seen.
CONCLUSIONS - Many infant hydroceles that are communicating by history or examination do resolve clinically without surgery and deserve observation. Progression to hernia was rare in our experience and did not result in incarceration. Consequently, little risk is taken by initial observation.
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17 MeSH Terms
Current concepts in glomerulosclerosis.
Fogo AB
(1999) Am J Kidney Dis 34: liv-lvi
MeSH Terms: Biopsy, Cell Division, Disease Progression, Glomerulosclerosis, Focal Segmental, Humans, Kidney Glomerulus, Prognosis, Remission, Spontaneous
Added January 20, 2012
1 Communities
1 Members
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8 MeSH Terms