RESUMO
CTLA-4 is a critical gatekeeper of T-cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA-4 in SLE. Our results reveal increased CTLA-4 expression in FOXP3(-) responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA-4 was unable to regulate T-cell proliferation, lipid microdomain formation and phosphorylation of TCR-zeta following CD3/CD28 co-stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co-stimulation, there was no parallel increase in CTLA-4 expression, which would normally provide a break on T-cell proliferation. These defects were associated with exclusion of CTLA-4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA-4 dysfunction as a potential cause for abnormal T-cell activation in patients with SLE, which could be targeted for therapy.
Assuntos
Antígenos CD/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Antígenos CD/metabolismo , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Complexo CD3/imunologia , Complexo CD3/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Antígeno CTLA-4 , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/metabolismo , Microdomínios da Membrana/imunologia , Microdomínios da Membrana/metabolismo , Microscopia Confocal , Linfócitos T/metabolismoRESUMO
Interventional pulmonology is a dynamic and evolving field in respiratory medicine. Advances have improved the ability to diagnose and manage diseases of the airways. A shift toward early detection of malignant disease has generated a focus on innovative diagnostic techniques. With patient populations living longer with malignant and benign diseases, the role for interventional bronchoscopy has grown. In cancer groups, novel immunotherapies have improved the prospects of clinical outcomes and reignited a focus on optimizing patient performance status to enable access to anticancer therapy. This review discusses current and emerging diagnostic modalities and therapeutic approaches available to manage airway diseases.