Mechanisms for Human TLR8 induced pregnancy loss in a mouse model of SLE
人 TLR8 诱导 SLE 小鼠模型妊娠失败的机制
基本信息
- 批准号:10301657
- 负责人:
- 金额:$ 22.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-18 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAmino AcidsAntibodiesAntigen-Antibody ComplexAntiphospholipid AntibodiesAttenuatedAutoantibodiesAutoimmune DiseasesAutoimmunityB-Lymphocyte SubsetsB-LymphocytesBacterial Artificial ChromosomesBindingBinding SitesBlood VesselsCell LineCell LineageCellsCharacteristicsCleaved cellDevelopmentDoseExposure toFemaleFetal DeathFetal ResorptionGene ExpressionGenetic PolymorphismGenetic studyGoalsHumanIL8 geneImmuneImmunologic ReceptorsIn VitroInflammationInflammatoryInjuryInnate Immune SystemInterferon Type ILeadLigand BindingLigandsLupusLymphocyteMediatingMemory B-LymphocyteMessenger RNAMicroRNAsModelingMorphologyMusMyelogenousMyeloid CellsNucleic AcidsPathogenicityPathway interactionsPatientsPatternPhenotypePhospholipidsPhysiologicalPlacentaPlasma CellsPregnancyPregnancy OutcomePregnancy lossProductionPurinesQuality of lifeRNARNA BindingRibonucleasesRoleSLEB1 geneSusceptibility GeneSyndromeSystemic Lupus ErythematosusTLR7 geneTLR8 geneTestingTissuesToll-like receptorsTransgenesTransgenic MiceUridineWomancell injurycytokineeffective therapyexperimental studyexposed human populationfetalfetal lossfetus cellimproved outcomein vivoinflammatory milieulupus prone micemacrophagemonocytemortalitymouse modelneutrophilnovelnovel strategiespathogenic autoantibodiesplacental morphologypreventpromoterreceptorrecruitresponsesensortherapeutic targettransgene expressiontrophoblast
项目摘要
Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease that causes
a significant decrease in quality of life and early mortality. Genetic studies have identified
activation of the innate immune system, with excess production of Type I interferons as a major
causative pathway. RNA-sensing Toll-like receptors are crucial protective receptors of the innate
immune system but are also implicated in autoimmunity because they can recognize nucleic acids
released from damaged cells and within nucleic acid containing immune complexes. Functional
polymorphisms of the endosomal RNA-recognizing innate receptors TLR7 and TLR8 predispose
to SLE and excess mouse TLR7 and human TLR8 accelerate lupus in mouse models. Human
TLR8 differs in its function from TLR7 because it recognizes different ligands and is expressed
on different immune cell subsets.
TLR8 is not an RNA sensor in mice because of a 5 amino acid deletion that attenuates its
RNA-binding site. We therefore bred a human TLR8 BAC transgene (huTLR8) into mice in which
a mild lupus phenotype is conferred by the susceptibility locus Sle1. Expression of the transgene
is physiologically regulated such that huTLR8 is expressed at high levels in myeloid DCs and
monocytes but at 50-100-fold lower levels in lymphocytes. We found that huTLR8 induces an anti-
phospholipid like syndrome in Sle1 mice that leads to spontaneous placental inflammation, fetal
resorptions and late-term pregnancy loss in up to 60% of female dams. In this proposal we will
test the mechanism for huTLR8 mediated pregnancy loss by addressing the role of huTLR8 as a
sensor of RNA in placental trophoblasts and immune cells.
In Aim 1 we will examine the role of autoantibodies in placental injury in mice with or
without huTLR8 expression and determine whether huTLR8 expression in B cells results in the
production of autoantibodies with enhanced pathogenicity. In Aim 2 we will determine the timing
and characteristics of placental injury, the contribution of huTLR8 in maternal vs. fetal cells to
injury and whether placental trophoblasts activated by anti-phospholipid antibodies release
huTLR8 ligands that enhance local inflammation. In Aim 3 we will determine whether myeloid
cells from huTLR8tg mice are intrinsically more pro-inflammatory than those of their wild-type
counterparts and therefore amplify the effector response to antibody mediated placental injury.
These experiments should allow us to distinguish the role of huTLR8 in maternal cells,
trophoblasts and immune cell subsets in the induction of placental damage that leads to
pregnancy loss. Our studies will inform us whether specific huTLR8 antagonists or antagonists of
huTLR8 ligands should be tested for their ability to prevent or treat placental injury.
系统性红斑狼疮(SLE)是一种多系统的自身免疫性疾病,
生活质量和早期死亡率显著下降。遗传学研究表明
先天免疫系统的激活,I型干扰素的过量产生作为主要的免疫抑制剂。
致病途径RNA敏感Toll样受体是先天性免疫缺陷的重要保护性受体。
但也涉及自身免疫,因为它们可以识别核酸
从受损细胞和含有免疫复合物的核酸中释放。功能
识别内体RNA的先天受体TLR 7和TLR 8的多态性
而过量的小鼠TLR 7和人TLR 8在小鼠模型中加速狼疮。人类
TLR 8在其功能上不同于TLR 7,因为它识别不同的配体并表达
不同免疫细胞亚群的免疫系统。
TLR 8在小鼠中不是RNA传感器,因为5个氨基酸的缺失减弱了它的
RNA结合位点。因此,我们将人TLR 8 BAC转基因(huTLR 8)培育到小鼠中,
易感性基因座Sle 1赋予轻度狼疮表型。转基因的表达
在生理上受到调节,使得huTLR 8在髓样DC中以高水平表达,
在单核细胞中,但在淋巴细胞中的水平低50-100倍。我们发现huTLR 8诱导抗-
Sle 1小鼠中的磷脂样综合征导致自发性胎盘炎症,胎儿
高达60%的雌性母体发生吸收和晚期妊娠丢失。在本提案中,我们将
通过阐述huTLR 8作为一种免疫调节剂的作用,测试huTLR 8介导的妊娠丢失的机制。
胎盘滋养层细胞和免疫细胞中的RNA传感器。
在目的1中,我们将研究自身抗体在胎盘损伤中的作用,
并确定B细胞中的huTLR 8表达是否会导致
产生具有增强的致病性的自身抗体。在目标2中,我们将确定
和胎盘损伤的特征,母体与胎儿细胞中huTLR 8对胎盘损伤的贡献,
损伤以及抗磷脂抗体激活的胎盘滋养层细胞是否释放
增强局部炎症的huTLR 8配体。在目标3中,我们将确定髓样细胞是否
来自huTLR 8 tg小鼠的细胞本质上比它们的野生型细胞更促炎
因此增强了对抗体介导的胎盘损伤的效应子应答。
这些实验应该使我们能够区分huTLR 8在母体细胞中的作用,
滋养层细胞和免疫细胞亚群诱导胎盘损伤,导致
流产我们的研究将告知我们是否特异性huTLR 8拮抗剂或
应测试huTLR 8配体预防或治疗胎盘损伤的能力。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Anne Davidson其他文献
Anne Davidson的其他文献
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{{ truncateString('Anne Davidson', 18)}}的其他基金
Dissecting the heterogeneity and function of myeloid cells in lupus nephritis
剖析狼疮性肾炎骨髓细胞的异质性和功能
- 批准号:
10588862 - 财政年份:2023
- 资助金额:
$ 22.94万 - 项目类别:
T32 Training Grant in Translational Immunology
T32 转化免疫学培训补助金
- 批准号:
10470893 - 财政年份:2021
- 资助金额:
$ 22.94万 - 项目类别:
T32 Training Grant in Translational Immunology
T32 转化免疫学培训补助金
- 批准号:
10653079 - 财政年份:2021
- 资助金额:
$ 22.94万 - 项目类别:
Mechanisms for Human TLR8 induced pregnancy loss in a mouse model of SLE
人 TLR8 诱导 SLE 小鼠模型妊娠失败的机制
- 批准号:
10434117 - 财政年份:2021
- 资助金额:
$ 22.94万 - 项目类别:
Induction of lupus-related autoantibodies by TNF inhibitors
TNF 抑制剂诱导狼疮相关自身抗体
- 批准号:
10405223 - 财政年份:2021
- 资助金额:
$ 22.94万 - 项目类别:
T32 Training Grant in Translational Immunology
T32 转化免疫学培训补助金
- 批准号:
10269999 - 财政年份:2021
- 资助金额:
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Heterogeneous pathways to autoantibody production: implications for prognosis and therapeutic targeting
自身抗体产生的异质途径:对预后和治疗靶向的影响
- 批准号:
10159859 - 财政年份:2019
- 资助金额:
$ 22.94万 - 项目类别:
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