Borrelia burgdorferi-Induced Autoimmunity in Lyme Disease
伯氏疏螺旋体诱导的莱姆病自身免疫
基本信息
- 批准号:9757687
- 负责人:
- 金额:$ 50.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-06-01 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AftercareAllelesAnnexinsAnti-inflammatoryAntibiotic TherapyAntibioticsAntibodiesAntigen PresentationAntigen Presentation PathwayAntigen-Presenting CellsAntigensAutoantibodiesAutoantigensAutoimmune ProcessAutoimmunityB-LymphocytesBindingBlood VesselsBorrelia burgdorferiCD4 Positive T LymphocytesCell Culture TechniquesCell ProliferationCell-Mediated CytolysisCellsCharacteristicsClinicalCytotoxic T-LymphocytesDataData ReportingDiagnosticDiseaseEarly identificationEarly treatmentEndothelial CellsEnvironmentEragrostisFibroblast Growth FactorFibroblastsFibrosisGene Expression ProfileGene Expression RegulationGoalsGrantGranzymeHLA-DR AntigensHistocompatibility Antigens Class IIIgG4ImmuneImmune responseImmunoglobulin GInfectionInflammationInflammatoryInterferonsInterleukin-10LesionLinkLyme ArthritisLyme DiseaseMicroRNAsOutcomePathogenesisPathologyPatientsPeptidesPeripheral Blood Mononuclear CellPhenotypePolysaccharidesPopulationProcessProliferatingProteinsRefractoryRegulatory T-LymphocyteReportingShapesSigns and SymptomsSourceSpecificitySyndromeSynovitisT cell responseT-Cell ActivationT-Cell ReceptorT-LymphocyteT-Lymphocyte SubsetsTestingTh1 CellsTissue SampleTissuesTo autoantigenTranslational ResearchUp-Regulationapolipoprotein B-100basecytokinecytotoxiceffective therapyerythema migransgenetic risk factorimmunogenicimmunogenicityinnovationmaltreatmentnovelovertreatmentpatient subsetspreventresponsesingle-cell RNA sequencingstromelysin 2transcriptome sequencingtumor
项目摘要
This grant seeks to characterize autoimmune features of a post-infectious Lyme disease (LD)
syndrome called antibiotic-refractory Lyme arthritis (LA), the only post-treatment LD syndrome
for which a specific pathology has been defined. We have previously reported that excessive
inflammation, immune dysregulation of the Teff/Treg cell ratio, up-regulation of certain
microRNAs, and infection-induced autoimmunity are features of this untoward outcome.
Moreover, the greatest genetic risk factor for refractory LA is certain HLA-DR alleles, and we
have identified immunogenic HLA-DR-presented peptides directly from synovial tissue in these
patients. In this way, we have shown that 4 autoantigens, endothelial cell growth factor (ECGF),
MMP-10, apoB-100, and annexin A2, are targets of T and B cell responses in subsets of
patients with each of the manifestations of LD; and nearly half of patients with antibiotic-
refractory LA have autoantibody responses to 1 or more of these autoantigens. Based on RA-
seq data, we report in this grant that the synovial lesion in refractory LA has a highly
inflammatory expression signature, which includes up-regulation of genes associated with IFN-
-responses, MHC class II antigen processing and presentation, cell-mediated cytotoxicity, and
cell proliferation. We now propose that synovial fibroblast-like synoviocytes (FLS), the most
common cell in the lesion, become unconventional antigen presenting cells (uAPC), and CD4+
T cells with cytotoxic potential may be directed against FLS. As detailed in Aim 1, we have
identified two types of CD4+ SLAMF7+ T cells with cytotoxic potential in LA patients, and we will
further determine their phenotype using single-cell RNA-seq. In Aim 2, we will identify a greater
range of HLA-DR-peptides presented to CD4+ T cells by professional APCs or uAPC (FLS),
and we will delineate molecular interactions between CD4+SLAMF7+T cells and FLS in cell
cultures. In Aim 3, we present preliminary data that autoantibodies in refractory LA may
participate in this disease process. In these patients, high levels of IgG4 autoantibodies to
ECGF, MMP-10 and apoB-100 each correlate with marked fibrosis and obliterative microvasular
lesions in synovial tissue. We will assess whether the binding characteristics and glycan
composition of these autoantibodies shift from an anti-inflammatory to a pro-inflammatory
phenotype in refractory patients. Finally, we will determine the utility of autoantibody
determinations as part of a diagnostic platform for early identification of patients with
maladaptive immune responses, which may allow earlier therapy to ameliorate or prevent this
post-infectious syndrome.
该赠款旨在表征感染后莱姆病(LD)的自身免疫特征
综合征称为抗生素 - 饮食莱姆关节炎(LA),治疗后LD综合征
为此定义了特定的病理。我们以前已经报道了超级
炎症,TEFF/Treg细胞比率的免疫失调,某些上调
microRNA和感染引起的自身免疫性是这种不良结果的特征。
此外,难治性LA的最大遗传危险因素是某些HLA-DR等位基因,我们
在这些中直接从滑膜组织中鉴定出免疫原性HLA-DR呈现肽
患者。通过这种方式,我们已经证明了4种自身抗原,内皮细胞生长因子(ECGF),
MMP-10,APOB-100和ANNEXIN A2是T和B细胞反应的靶标
LD的每种表现的患者;几乎一半的抗生素患者
难治性LA对1个或更多这些自身抗原具有自身抗体反应。基于ra-
SEQ数据,我们在这笔赠款中报告说,难治性LA中的滑膜病变具有很高的
炎症表达特征,其中包括与IFN-相关的基因上调
反应,MHC II类抗原加工和表现,细胞介导的细胞毒性和
细胞增殖。现在,我们建议滑膜成纤维细胞状的滑膜细胞(FLS),最多
病变中的常见细胞,成为非常规抗原呈递细胞(UAPC)和CD4+
具有细胞毒性电位的T细胞可以针对FLS。如AIM 1所述,我们有
在LA患者中鉴定了两种类型的CD4+ SLAMF7+ T细胞,具有细胞毒性潜力,我们将
进一步使用单细胞RNA-seq确定其表型。在AIM 2中,我们将确定更大的
专业APC或UAPC(FLS)呈现给CD4+ T细胞的HLA-DR肽范围
我们将在CD4+SLAMF7+T细胞和细胞中的FLS之间描述分子相互作用
文化。在AIM 3中,我们提供了初步数据,该数据是在难治性la中自动抗体
参加此疾病过程。在这些患者中,高水平的IgG4自身抗体
ECGF,MMP-10和APOB-100每个都与明显的纤维化和闭塞性微量相关
滑膜组织中的病变。我们将评估结合特征和聚糖是否
这些自身抗体的组成从抗炎药转变为促炎性
难治性患者的表型。最后,我们将确定自身抗体的实用性
确定作为诊断平台的一部分,用于早期鉴定患者
适应不良的免疫反应,这可能使早期的治疗可以改善或预防这种治疗
感染后综合症。
项目成果
期刊论文数量(0)
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ALLEN C STEERE其他文献
ALLEN C STEERE的其他文献
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{{ truncateString('ALLEN C STEERE', 18)}}的其他基金
Cellular and humoral immunity in Lyme arthritis
莱姆关节炎的细胞和体液免疫
- 批准号:
10317057 - 财政年份:2019
- 资助金额:
$ 50.39万 - 项目类别:
Cellular and humoral immunity in Lyme arthritis
莱姆关节炎的细胞和体液免疫
- 批准号:
10541106 - 财政年份:2019
- 资助金额:
$ 50.39万 - 项目类别:
Autoimmunity to ECGF in Lyme disease and its post-infectious syndromes
莱姆病及其感染后综合征中 ECGF 的自身免疫
- 批准号:
8501754 - 财政年份:2013
- 资助金额:
$ 50.39万 - 项目类别:
Borrelia burgdorferi-Induced Autoimmunity in Lyme Disease
伯氏疏螺旋体诱导的莱姆病自身免疫
- 批准号:
10215511 - 财政年份:2013
- 资助金额:
$ 50.39万 - 项目类别:
Autoimmunity to ECGF in Lyme disease and its post-infectious syndromes
莱姆病及其感染后综合征中 ECGF 的自身免疫
- 批准号:
9067207 - 财政年份:2013
- 资助金额:
$ 50.39万 - 项目类别:
Borrelia burgdorferi-Induced Autoimmunity in Lyme Disease
伯氏疏螺旋体诱导的莱姆病自身免疫
- 批准号:
9980768 - 财政年份:2013
- 资助金额:
$ 50.39万 - 项目类别:
Autoimmunity to ECGF in Lyme disease and its post-infectious syndromes
莱姆病及其感染后综合征中 ECGF 的自身免疫
- 批准号:
8667985 - 财政年份:2013
- 资助金额:
$ 50.39万 - 项目类别:
Autoimmunity to ECGF in Lyme disease and its post-infectious syndromes
莱姆病及其感染后综合征中 ECGF 的自身免疫
- 批准号:
8543853 - 财政年份:2012
- 资助金额:
$ 50.39万 - 项目类别:
IMMUNE RESPONSE TO B BURGDORFERI PROTEINS IN LYME ARTHRITIS
莱姆关节炎中对布氏 B 蛋白的免疫反应
- 批准号:
8365544 - 财政年份:2011
- 资助金额:
$ 50.39万 - 项目类别:
IMMUNE RESPONSE TO B BURGDORFERI PROTEINS IN LYME ARTHRITIS
莱姆关节炎中对布氏 B 蛋白的免疫反应
- 批准号:
8170913 - 财政年份:2010
- 资助金额:
$ 50.39万 - 项目类别:
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