Cholera toxin B accelerates disease progression in lupus-prone mice by promoting lipid raft aggregation

被引:82
作者
Deng, Guo-Min [1 ]
Tsokos, George C. [1 ]
机构
[1] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Rheumatol, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
D O I
10.4049/jimmunol.181.6.4019
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Infectious agents, including bacteria and viruses, are thought to provide triggers for the development or exacerbation of autoimmune diseases such as systemic Inputs erythematosus in the genetically predisposed individual. Molecular mimicry and engagement of TLRs have been assigned limited roles that link infection to autoimmunity, but additional mechanisms are suspected to be involved. In this study we show that T cells from lupus-prone mice display aggregated lipid rafts that harbor signaling, costimulatory, inflammatory, adhesion, and TLR molecules. The percentage of T cells with clustered lipid rafts increases with age and peaks before the development of lupus pathology. We show that cholera toxin B, a component of Vibrio cholerae, promotes autoantibody production and glomerulonephritis in lupus-prone mice by enhancing lipid raft aggregation in T cells. In contrast, disruption of lipid raft aggregation results in delay of disease pathology. Our results demonstrate that lipid rafts contribute significantly to the pathogenesis of lupus and provide a novel mechanism whereby aggregated lipid rafts represent a potential link between infection and autoimmunity.
引用
收藏
页码:4019 / 4026
页数:8
相关论文
共 48 条
[1]   Phosphoinositide 3-kinase γ participates in T cell receptor-induced T cell activation [J].
Alcázar, Isabela ;
Marqués, Miriam ;
Kumar, Amit ;
Hirsch, Emilio ;
Wymann, Matthias ;
Carrera, Ana C. ;
Barber, Domingo F. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2007, 204 (12) :2977-2987
[2]   TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity [J].
Baccala, Roberto ;
Hoebe, Kasper ;
Kono, Dwight H. ;
Beutler, Bruce ;
Theofilopoulos, Argyrios N. .
NATURE MEDICINE, 2007, 13 (05) :543-551
[3]   Trafficking of cholera toxin-ganglioside GM1 complex into Golgi and induction of toxicity depend on actin cytoskeleton [J].
Badizadegan, K ;
Wheeler, HE ;
Fujinaga, Y ;
Lencer, WI .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2004, 287 (05) :C1453-C1462
[4]   PI3Kγ inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus [J].
Barber, DF ;
Bartolomé, A ;
Hernandez, C ;
Flores, JM ;
Redondo, C ;
Fernandez-Arias, C ;
Camps, M ;
Ruckle, T ;
Schwarz, MK ;
Rodríguez, S ;
Martinez-A, C ;
Balomenos, D ;
Rommel, C ;
Carrera, AC .
NATURE MEDICINE, 2005, 11 (09) :933-935
[5]   Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry? [J].
Benoist, C ;
Mathis, D .
NATURE IMMUNOLOGY, 2001, 2 (09) :797-801
[6]   Manipulation of host-cell pathways by bacterial pathogens [J].
Bhavsar, Amit P. ;
Guttman, Julian A. ;
Finlay, B. Brett .
NATURE, 2007, 449 (7164) :827-834
[7]   Antigen-induced translocation of PKC-θ to membrane rafts is required for T cell activation [J].
Bi, K ;
Tanaka, Y ;
Coudronniere, N ;
Sugie, K ;
Hong, SJ ;
van Stipdonk, MJB ;
Altman, A .
NATURE IMMUNOLOGY, 2001, 2 (06) :556-563
[8]   Regulation of T-cell activation by the cytoskeleton [J].
Billadeau, Daniel D. ;
Nolz, Jeffrey C. ;
Gomez, Timothy S. .
NATURE REVIEWS IMMUNOLOGY, 2007, 7 (02) :131-143
[9]   Acute ethanol treatment modulates Toll-like receptor-4 association with lipid rafts [J].
Dolganiuc, A ;
Bakis, G ;
Kodys, K ;
Mandrekar, P ;
Szabo, G .
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH, 2006, 30 (01) :76-85
[10]   Location is everything: Lipid rafts and immune cell signaling [J].
Dykstra, M ;
Cherukuri, A ;
Sohn, HW ;
Tzeng, SJ ;
Pierce, SK .
ANNUAL REVIEW OF IMMUNOLOGY, 2003, 21 :457-481