Regulation of type 2 immunity by type 2 innate lymphoid cells and T helper 2 cells2형 선천 림프구와 보조 T 세포에 의한 제 2형 면역반응의 조절

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Part 1. Enhanced Th2 cell differentiation and function in the absence of Nox2 in allergic disease Chronic granulomatous disease (CGD) inherits abnormal function of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2). Nox2 originally identified in phagocytes is responsible for the production of reactive oxygen species (ROS) that kill engulfed pathogens. Thus, CGD patients are susceptible to infections by bacteria and fungi and also suffer from persistent inflammatory responses in liver, kidney, colon and lung. There have been studies to reveal the function of Nox2 in hyper-inflammatory diseases, especially in asthma, but the exact role of Nox2 in asthma is still unclear and controversial. To determine whether Nox2 deficiency affects allergic lung inflammation, we utilized various experimental asthma models to clarify the recent debates. Furthermore, we attempted to reveal the precise mechanism of Nox2 deficiency in a T cell intrinsic manner by using in vitro activation. Asthma phenotypes were analyzed in response to various allergen-induced experimental asthma. To understand the underlying mechanisms of exaggerated Th2 effector functions, we investigated the degree of T cell activation, levels of activation induced cell death (AICD), and regulatory T (Treg) cell differentiation in Nox2-deficient T cells. All experimental asthma phenotypes including airway hyper-responsiveness, lung inflammation with eosino- philia, and mucus production were increased through enhanced Th2 differentiation in Nox2- null mice. Nox2-deficient T cells also showed hyper-activation, reduced AICD, and diminished Treg cell differentiation through increased AKT phosphorylation and enhanced mito- chondrial ROS production. Our findings indicate that Nox2 deficiency results in exaggerated experimental asthma, which is caused by enhanced Th2 effector function in a T cell intrinsic manner. Part 2. Innate type 2 immunity is associated with eosinophilic pleural effusion in pri- mary spontaneous pneumothorax Eosinophilic pleural effusion (EPE) is characterized by greater than 10% eosinophilia and is frequently associated with air and/or blood in the pleural cavity. Primary spontaneous pneumothorax (PSP), defined as the spontaneous presence of air in the pleural space, is one of the most common causes of EPE. Recent studies have shown that type 2 immune responses play important roles in eosinophilic airway inflammation resulting in pleural pathology. However, the exact predominant mediator that induce type 2 immunity, resulting in EPE with PSP in humans, remains unclear. Thus, we examined whether T helper 2 (Th2) cells, IL-33, thymic stromal lymphopoietin (TSLP) or type 2 innate lymphoid cells (ILC2) are associated factors. First, eosinophil-associated cytokines were measured in the pleural fluid of patients with PSP and control subjects. Second, Th2 cell and ILC2 responses in the pleural cavity and peripheral blood were also evaluated by in vitro re-stimulation and intracellular cytokine staining of T cells and ILC2s in patients with PSP and control subjects. Third, innate type 2 cytokines such as IL-33 and TSLP levels were measured. Lastly, IL-33-mediated IL-5 pro- duction by ILC2 was also evaluated. As a result, significantly higher concentrations of IL-5 and eotaxin-3 were detected in the pleural fluid of patients with PSP, in addition to signifi- cantly higher concentrations of IL-33 and TSLP. Although IL-5 production was induced by IL-33 treatment of ILC2s, other Th2 cell-mediated immune responses were not detected. Based on these results, we concluded that innate immune responses characterized by the pro- duction of IL-33, TSLP, and IL-5 are associated with the development of EPE in PSP by an ILC2-dependent and Th2-independent mechanism.
Advisors
Lee, Seung-Hyoresearcher이승효researcher
Description
한국과학기술원 :의과학대학원,
Publisher
한국과학기술원
Issue Date
2015
Identifier
325007
Language
eng
Description

학위논문(박사) - 한국과학기술원 : 의과학대학원, 2015.2,[viii, 81 p. :]

Keywords

Nox2; Th2 cells; Allergic asthma; AKT; Mitochondrial ROS; Pneumothorax; Eosinophil; IL-33; IL-5; Type 2 innate lymphoid cells; NADPH 산화효소 2; 2형 도움 T 세포; 알러지성 천식; 단백질인산화효소 B; 미토콘드리아 활성산소; 기흉; 호산구; 인터류킨-33; 인터류킨-5; 2형 선천 림프구

URI
http://hdl.handle.net/10203/241969
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=669254&flag=dissertation
Appears in Collection
MSE-Theses_Ph.D.(박사논문)
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