RESUMEN
Pulmonary immunity requires tight regulation, as interstitial inflammation can compromise gas exchange and lead to respiratory failure. Here we found a greater number of aged CD11bhiL-selectinloCXCR4+ polymorphonuclear leukocytes (PMNs) in lung vasculature than in the peripheral circulation. Using pulmonary intravital microscopy, we observed lung PMNs physically interacting with B cells via ß2 integrins; this initiated neutrophil apoptosis, which led to macrophage-mediated clearance. Genetic deletion of B cells led to the accumulation of aged PMNs in the lungs without systemic inflammation, which caused pathological fibrotic interstitial lung disease that was attenuated by the adoptive transfer of B cells or depletion of PMNs. Thus, the lungs are an intermediary niche in the PMN lifecycle wherein aged PMNs are regulated by B cells, which restrains their potential to cause pulmonary pathology.
Asunto(s)
Linfocitos B/inmunología , Enfermedades Pulmonares Intersticiales/patología , Neutrófilos/patología , Fibrosis Pulmonar/patología , Animales , Enfermedades Pulmonares Intersticiales/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fibrosis Pulmonar/inmunologíaRESUMEN
Lung capillaries, best known for vital gas exchange, also contribute to neutrophil margination, a phenomenon resulting in large numbers of pulmonary vascular neutrophils. Importantly, the functional relevance of neutrophil margination is unknown. Recent advances in microscopy have altered our understanding of why neutrophils marginate. Specifically, data show that lung capillaries provide a unique anatomical site for neutrophils to capture bloodstream pathogens, which contrasts the conventional monophagocytic-dominated vascular host defense of the spleen and liver. Moreover, lung capillaries provide an efficient site for direct cell-cell communication required for the induction of apoptosis in aged neutrophils. These new ideas transform our views of the pulmonary circulation as a site for immediate neutrophil-mediated host defense and regulation of their life cycle.
Asunto(s)
Pulmón/irrigación sanguínea , Microvasos/inmunología , Neutrófilos/inmunología , Animales , Comunicación Celular , Movimiento Celular , Humanos , Inmunidad Innata , Fagocitosis , Circulación Pulmonar/inmunologíaRESUMEN
INTRODUCTION: Despite expert-based recommendations, real-world adherence to immune thrombocytopenia (ITP) guidelines is unclear. The impact of geographic and socioeconomic disparities on the quality of care and outcomes is unknown. We sought to determine the association between geographic remoteness and material deprivation on ITP care and outcomes. METHODS: We conducted a multi-centre retrospective cohort study of adults with chronic ITP requiring a second-line therapy between 2012 and 2019 in the province of Alberta, Canada. Socioeconomic status was measured using the Pampalon material deprivation index quintiles. Geographic disparities were assessed by the driving distance to a major centre, with geographic remoteness defined as >200 km from major centre. We examined the impact of geographic and material deprivation on quality of care, resource utilization (hospitalizations, transfusions), and outcomes (major bleeding, all-cause mortality and ITP-related mortality). Cox proportional hazards models were used to examine the impact of geographic remoteness, rural residence and material deprivation on overall survival and ITP-related survival. RESULTS: We included 326 ITP patients, median age of ITP diagnosis was 57 years, 182 (56 %) were female. Most patients (58 %) lived within 20 km of a major centre, whereas 49 (15 %) lived in a geographically remote area (>200 km). Geographic remoteness was significantly associated with material deprivation and lower likelihood of management by hematologists (84 % vs 99 %, P = 0.0001). It was also associated with lower rates of hepatitis C (71 % vs 89 %, P = 0.005) and hepatitis B testing (69 % vs 86 %, P = 0.03), and a non-significant trend towards lower rates of HIV testing (73 % vs 83 %, P = 0.051) compared with those <20 km from a major centre. Incomplete hyposplenic vaccinations among splenectomized patients (52 %), early splenectomy within 12 months of ITP diagnosis (35 %), inappropriate platelet transfusions (41 %), and inappropriate hospitalizations for asymptomatic thrombocytopenia (16 %) were common regardless of geographic distribution. There were 28 (9 %) ITP-related deaths (major bleeding or infections), most occurred within the first year of ITP diagnosis. Material deprivation, but not geographic remoteness, was an independent predictor of all-cause mortality (aHR 1.9, 95 % CI 1.1-3.3 in the most deprived quintile vs least deprived quintile). Rural residence trended towards increased hazard of ITP-related deaths (aHR 1.7, 95 % CI 0.9-3.2). CONCLUSION: We demonstrated substantial deviations of ITP care from consensus guidelines, and geographic disparities in access to care and diagnostic workup. Future quality improvement initiatives are critical to improve the quality of care and reduce inequities.
Asunto(s)
Púrpura Trombocitopénica Idiopática , Trombocitopenia , Humanos , Adulto , Femenino , Persona de Mediana Edad , Masculino , Púrpura Trombocitopénica Idiopática/epidemiología , Púrpura Trombocitopénica Idiopática/terapia , Púrpura Trombocitopénica Idiopática/diagnóstico , Estudios Retrospectivos , Trombocitopenia/complicaciones , Hospitalización , Hemorragia/etiologíaRESUMEN
BACKGROUND: The optimal choice of second-line treatment for immune thrombocytopenia (ITP) is unclear. Guidelines recommend either rituximab, splenectomy, or thrombopoietin receptor agonists (TPO-RA). There is, however, scarce data comparing treatment patterns, outcomes and resource utilization across second-line treatments. Despite Canada's universal healthcare system, publicly funded access to second-line ITP therapies is highly variable across provinces/territories. OBJECTIVES: To describe treatment patterns and compare health service utilization and outcomes among recipients of second-line rituximab and TPO-RA for ITP. METHODS: In this multicentre retrospective cohort study, we included adults who received second-line ITP therapies rituximab, eltrombopag and romiplostim (2012-2020) in Alberta, Canada. Patients were identified through a provincially-funded special drug access (STEDT) program. We examined treatment patterns, predictors of second-line treatment, hospitalizations, blood product utilization, and outcomes. Kaplan-Meier survival curves were used to estimate the cumulative incidence of ITP-related hospitalizations (bleeding or infections), overall survival (OS) and relapse-free survival (RFS). Cox proportional hazards regression was used to examine the impact of second-line therapy on OS. RESULTS: 223 patients received rituximab (67 %), eltrombopag (29 %), and romiplostim (4 %). TPO-RA recipients experienced significantly longer time from ITP diagnosis to second-line therapy compared with rituximab recipients (15.9 vs 6.7 months, P < 0.0001), accompanied by significantly higher platelet and IVIG utilization prior to second-line therapy. Age (adjusted odds ratio [aOR] 1.04, 95 % CI 1.02-1.07, P < 0.0001) and prior intracranial hemorrhage (aOR 12.7, 95 % CI 1.6-272.8, P = 0.03) were significant predictors of second-line TPO-RA. TPO-RA is associated with a trend towards longer median RFS (6.3 vs 3.8 years, P = 0.06) compared with rituximab, and similar rates of ITP-related hospitalizations, major bleeding, and thromboembolism. Age, time period, and Charlson comorbidity index, but not second-line ITP therapy, were significant predictors of OS. CONCLUSIONS: Our study identified older age and intracranial hemorrhage as predictors of second-line TPO-RA prescription in a real-world practice. There were no significant differences in hospitalizations and outcomes between second-line rituximab and TPO-RA, although delayed initiation of TPO-RA was associated with higher blood product utilization.
Asunto(s)
Púrpura Trombocitopénica Idiopática , Trombocitopenia , Humanos , Adulto , Púrpura Trombocitopénica Idiopática/diagnóstico , Receptores de Trombopoyetina , Rituximab/uso terapéutico , Estudios Retrospectivos , Canadá , Trombopoyetina/uso terapéutico , Hidrazinas/uso terapéutico , Receptores Fc/uso terapéutico , Trombocitopenia/inducido químicamente , Hemorragia/inducido químicamente , Enfermedad Crónica , Proteínas Recombinantes de Fusión/uso terapéutico , Hemorragias Intracraneales/inducido químicamenteRESUMEN
Pulmonary innate immunity is required for host defense; however, excessive neutrophil inflammation can cause life-threatening acute lung injury. B lymphocytes can be regulatory, yet little is known about peripheral transitional IgM+ B cells in terms of regulatory properties. Using single-cell RNA sequencing, we discovered eight IgM+ B cell subsets with unique gene regulatory networks in the lung circulation dominated by transitional type 1 B and type 2 B (T2B) cells. Lung intravital confocal microscopy revealed that T2B cells marginate in the pulmonary capillaries via CD49e and require CXCL13 and CXCR5. During lung inflammation, marginated T2B cells dampened excessive neutrophil vascular inflammation via the specialized proresolving molecule lipoxin A4 (LXA4). Exogenous CXCL13 dampened excessive neutrophilic inflammation by increasing marginated B cells, and LXA4 recapitulated neutrophil regulation in B cell-deficient mice during inflammation and fungal pneumonia. Thus, the lung microvasculature is enriched in multiple IgM+ B cell subsets with marginating capillary T2B cells that dampen neutrophil responses.
Asunto(s)
Linfocitos B/patología , Pulmón/patología , Neutrófilos/patología , Neumonía/patología , Animales , Aspergilosis/microbiología , Aspergilosis/patología , Linfocitos B/fisiología , Capilares/patología , Adhesión Celular , Quimiocina CXCL13/metabolismo , Integrina alfa5/metabolismo , Microscopía Intravital , Lipoxinas/metabolismo , Pulmón/irrigación sanguínea , Pulmón/diagnóstico por imagen , Ratones Mutantes , Neumonía/diagnóstico por imagen , Receptores CXCR5/metabolismo , Análisis de la Célula IndividualRESUMEN
STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disorder characterized by blood vessel occlusions, acral necrosis, myositis, rashes, and pulmonary inflammation that are the result of activating mutations in the STimulator of Interferon Genes (STING). We generated a transgenic line that recapitulates many of the phenotypic aspects of SAVI by targeting the expression of the human STING-N154S-mutant protein to the murine hematopoietic compartment. hSTING-N154S mice demonstrated failure to gain weight, lymphopenia, progressive paw swelling accompanied by inflammatory infiltrates, severe myositis, and ear and tail necrosis. However, no significant lung inflammation was observed. X-ray microscopy imaging revealed vasculopathy characterized by arteriole occlusions and venous thromboses. Type I interferons and proinflammatory mediators were elevated in hSTING-N154S sera. Importantly, the phenotype was prevented in hSTING-N154S mice lacking the type I interferon receptor gene (Ifnar1). This model, based on a mutant human STING protein, may shed light on the pathophysiological mechanisms operative in SAVI.