Regulation of Autoantibody Responses in Hyperlipidemia

Abstract

자가면역 질환 환자에서 동맥경화 발병률이 증가되어 있음이 알려져있다. 하지만 고지혈 환경이 어떠한 기전으로 자가면역질환을 조절하는지에 대해 보고되지 않았다. 자가면역질환이 helper T세포, 특히 TFH 세포 (T follicular helper cell),와 자가항체 (autoantibody)에 의해 매개되는 것이 알려져 있기때문에, 고지혈 환경 유발 인자, 예를 들면 지방대사체와 지방 활성 전사인자 (transcription factor) 등이 항체 생성과 항체 생성을 담당하는 배중심반응 (germinal center reaction)에 어떠한 영향을 주는지 확인하였다. 루푸스 질환 마우스 모델인 BXD2마우스의 골수세포를 동맥경화 마우스 모델인 Apoe–/– 마우스에 이식하였을 때, 자가항체 생성 및 사구체신염 증상이 야생형 마우스 대비 증가하여있음을 확인하였다. 또한 증가된 항체생성은 CXCR3+TFH세포와 정적 상관관계를 보였으며, Apoe–/– 마우스에서 분리한 TFH세포는 항체 생성 유발 능력이 뛰어난 것으로 확인되었다. 고지혈 환경에서 증가 되어있는 지질체들이Toll-like receptor 4 (TLR4)와 Liver X receptor (LXR)의 조절을 통하여 수지상세포 (dendritic cell, DC)에 의해서 생성되는 염증성 사이토카인 IL-27의 생성을 조절한다. 특히 고지혈 환경에서 Interleukine-27 (IL-27)의 양을 증가되어 있음을 마우스모델을 통해 확인하였다. 증가한 IL-27은 STAT1과 STAT3 신호전달을 통하여, TFH세포, 특히 CXCR3를 발현하는 TFH 아형을 증가시켜, B세포로 하여금 루푸스에 병원성 항체인IgG2c의 생성을 촉진시킨다. 본 연구를 통하여 고지혈 환경 유발 인자, 특히 LXR 전사인자의 작용을 통해, 자가면역질환에 중요한 항체생성반응이 조절됨을 확인하였다. 현재까지 면역질환에서 시도되고 있지 않은 고지혈 환경 유발 인자를 활용한 혁신적인 치료 방법 및 신약 표적을 제시하였다.

Systemic lupus erythematosus (SLE) is an antibody-mediated autoimmune disease that exhibits abnormal activation of immune systems, which leads failure of multiple organs. Meanwhile, atherosclerosis is a chronic inflammatory disease that caused by accumulation of fatty materials in inner artery and alteration in lipid metabolism. Patients with SLE exhibited higher incidence of atherosclerosis. However, despite of the tight associated between proatherogenic factors and immune systems, the contribution of hyperlipidemic conditions to immune responses, particularly antibody-mediated humoral responses, remains unclear. In this study, I propose a novel mechanism by which alteration in lipid metabolism regulates germinal center reactions and consequent antibody production. Atherosclerosis-prone Apoe–/– and Ldlr–/– mice reconstituted with lupus-prone BXD2 bone marrow showed exacerbated glomerulonephritis phenotypes and autoantibody production, particular increase in pathogenic IgG2c isotype. Alteration in lipid metabolism by feeding high-fat diet also enhanced theses phenomena. The severity of disease and antibody production were strongly associated with increased follicular helper T cells (TFH cells). TFH cells isolated from Apoe–/– mice had higher expression of genes associated with inflammatory responses and SLE, and were more potent in inducing IgG2c production. Among TFH cell subsets, CXCR3-expressing TFH cells are susceptible to promote IgG2c in IFN--dependent manner. Mechanistically, the atherogenic environment and proatherogenic factor, oxidized low-density lipoprotein (oxLDL), induced IL-27 from dendritic cells (DCs), particularly in CD11b+ DCs. Alteration in lipid metabolism and Liver X receptor (LXR) expression regulated IL-27 production by atherogenic DCs. Deletion of Toll-like receptor 4 (TLR4) diminished IL-27 production as well as antibody-generating germinal center reactions. IL-27 stimulated STAT1 and STAT3 signaling pathway in TFH cells to increase the numbers of CXCR3+ TFH cells while suppressing follicular regulatory T cells (TFR cells). Blockade of IL-27 signals diminished the increased TFH responses in atherogenic mice. Patients with hypercholesterolemia exhibited elevated levels of IL-27 as well as IgG1 and IgG3 antibodies in circulation, which is in a good agreement with the findings in animal models. Thus hyperlipidemia–TLR4/LXR–IL-27–CXCR3+ TFH cell axis might explain the tight association between atherosclerosis and SLE in humans, can be a potential therapeutic target for atherosclerosis-related autoimmune diseases.