2005 Fiscal Year Final Research Report Summary
Defective immuno-surveillance owing to the disorganization of lipid rafts and its roles in the pathogenesis of autoimmune diseases
| Project/Area Number |
16590976
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
膠原病・アレルギー・感染症内科学
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| Research Institution | The University of Tokyo |
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Principal Investigator |
HONDA Zen-ichiro The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (70238814)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Takeshi The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (50272555)
TSUCHIYA Naoyuki The University of Tokyo, Graduate School of Medicine, 大学院・医学系研究科, 助教授 (60231437)
HONDA Hiroaki Hiroshima University, Department of Developmental Biology, Research Institute for Radiation Biology and Medicine, 原爆放射線医科学研究所, 教授 (40245064)
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| Project Period (FY) |
2004 – 2005
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| Keywords | FcgRIIB / systemic lupus erythematodes / polymorphism / lipid rafts / Src family kinase |
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| Research Abstract |
FcgRIIB is a prototypical low-affinity IgG receptor exerting inhibitory effects on a variety of immune-cell activating receptors including B cell antigen receptor, FcgRI and FcgRIII. FcgRIIB knockout mice turn into susceptible to systemic autoimmune diseases resembling systemic lupus erythematodes (SLE) under the conditions of excessive antigen challenge, of simultaneous loss of other immunosuppressive genes such as PD-1, and of coexisting autoimmune-prone genetic traits. Therefore, FCGRIIB has long been ascribed to a candidate of disease-associated genes, and we and colleagues have identified a variant form with a transmembrane 1 amino acid exchange that alters 232Ile with an alkyl side chain at the middle of the transmembrane helix to Thr containing -OH residue. We introduced the 232Ile and 232Thr FcgRIIB into ST486 human B cell line defective of intrinsic FcgRIIB using retrovirus expression system, and created polyclonal cell populations with a comparable level of the receptor expression. Precise analysis of the biochemical behaviors of the cells underscored the reduction-of-function characteristics of the SLE-associated 232Thr variant in inhibiting BCR-mediated PIP3 accumulation, Akt activation, phospholipase Cg2 activation and calcium mobilization. Simultaneously, the 232Thr variant shows a reduced affinity to the functional membrane microdomain, referred to as lipid rafts, therefore providing a possible mechanistic bases explaining the reduced inhibitory activity. The altered activity of the SLE-associated FcgRIIB may in part explain the uncontrolled B cell activation observed in a subset of SLE possessing the genotype.
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Research Products
(4 results)
