Immune Modulation During Acute Lyme Disease Infection as the Result of Aberrant Immunoglobulin Glycosylation
异常免疫球蛋白糖基化导致急性莱姆病感染期间的免疫调节
基本信息
- 批准号:10726417
- 负责人:
- 金额:$ 22.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-16 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAcute DiseaseAmericanAnti-Inflammatory AgentsAntibiotic TherapyAntibodiesAntibody TherapyAntigenic VariationAntigensB-LymphocytesBacterial InfectionsBindingBiological AssayBiological MarkersBorreliaBorrelia burgdorferiBorrelia burgdorferi GroupBrainCOVID-19CellsClinicalComplementComplement 1qComplement ActivationComplexContractsCytolysisDataDepositionDevelopmentDiagnostic testsDiseaseEarly DiagnosisEarly treatmentEnzymesExoglycosidasesFab ImmunoglobulinsFab domainFc ReceptorFc domainFunctional disorderFutureGalactoseGlycoengineeringGoalsHIVHealthHeartHumanImmuneImmune EvasionImmune TargetingImmune responseImmune signalingImmunoglobulin AlterationsImmunoglobulin GImmunoglobulin MImmunoglobulinsImmunology procedureImpairmentIncidenceIncubatedInfectionInflammationInflammatoryInflammatory ResponseIntravenousIntravenous ImmunoglobulinsJointsLabelLinkLyme DiseaseLyme disease diagnosisLyme disease diagnosticMasksMeasuresMediatingMucocutaneous Lymph Node SyndromeMultiple SclerosisNatureOrder SpirochaetalesOrganPatientsPatternPeptidesPolysaccharidesPopulationPost-Translational Protein ProcessingReportingResearchRheumatoid ArthritisRoleSamplingSerumSerum ProteinsSialic AcidsSignal TransductionSolidStructure of germinal center of lymph nodeTestingTuberculosisWorkantibody-dependent cell cytotoxicityantibody-dependent cellular phagocytosisclinical diagnosticsdiagnostic assayglycosylated IgGglycosylated IgMglycosylationimmunoregulationimprovedin vitro Assaylyme pathogenesisneutravidinnovelpathogenpotential biomarkerpreventreceptorresponseseroconversionsugar
项目摘要
Abstract: Lyme disease (LD) leads to lifelong health problems if standard antibiotic therapy is not initiated
during the first 2-3 weeks after infection. Diagnosis for LD currently relies on seroconversion and is unreliable
during acute disease. Cases of suspected acute LD should be confirmed using clinical diagnostic assays. N-
linked glycosylation is one of the most abundant post-translational modifications of serum proteins. While it is
dynamic in nature, it is also highly consistent in a healthy state. N-linked glycosylation of serum immunoglobulins
(Igs) are known to change in a disease specific manner and can direct the host immune response toward a pro-
or an anti-inflammatory response. We previously observed that Ig N-glycans produced during acute LD contain
specific alterations in the abidance of galactose and sialic acid. We hypothesize that these Ig alterations are
antigen-specific, and that the glycosylation patterns present will negatively impact downstream immune
responses. This hypothesis is based on our preliminary data, known LD B-cell perturbations, and reports of IgG
N-glycans altering the immune response to COVID-19, tuberculosis, multiple sclerosis, and HIV.
This proposal is novel and unique because it is the only study that examines the role of glycosylation
during the human immune response to LD. This proposal is built on our preliminary work where we identified
aberrant glycosylation on the total serum IgG and IgM in acute LD patients prior to seroconversion. In this
proposal, we examine the glycosylation of Igs specific to LD antigens and determine if acute LD infection will
alter B-cell responses to produce antigen specific Igs with the same unique glycosylation changes seen in our
preliminary data. Additionally, we examine how the glycosylation pattern on antigen specific Igs effect the
immune response to LD.
In Aim 1, we isolate Igs specific to the LD antigen VlsE and establish the IgG and IgM N-glycan profiles.
The result will determine if antigen specific Igs contain the same aberrant glycosylation found in the total Ig
population of acute LD patients. In Aim 2, we quantify the impact of LD antigen-specific IgG glycosylation on the
promotion of ADCC and complement deposition. The result will determine if there is a link between IgG
glycosylation and the inability of the patients to clear the Borrelia burgdorferi spirochete that causes LD. In Aim
3, we quantify the impact of antigen-specific IgM glycosylation on the complement deposition rate. Complement
deposition leads to rapid clearance of Lyme disease pathogens. Altered glycosylation of IgM could impair
complement deposition and impede the ability of the human host to clear the infection.
This work will establish a new mechanism of Borrelial immune evasion, characterize the host-response
to LD pathogenesis in humans. Additionally, the results will potentiate the use of Ig N-glycans to serve as
multiplexed biomarkers in a novel Lyme disease diagnostic assay and guide the glycoengineering of
antibodies for use in intravenous therapy in hard-to-treat disseminated Lyme disease cases.
翻译后摘要:莱姆病(LD)导致终身健康问题,如果不开始标准的抗生素治疗
在感染后的前2-3周内。LD的诊断目前依赖于血清转化,并且是不可靠的
在急性疾病期间。疑似急性LD的病例应使用临床诊断检测进行确认。不,不
连接的糖基化是血清蛋白最丰富的翻译后修饰之一。虽然
在本质上是动态的,在健康状态下也是高度一致的。血清免疫球蛋白的N-连接糖基化
(Igs)已知以疾病特异性方式变化,并可将宿主免疫应答导向亲-
或者抗炎反应我们先前观察到急性LD期间产生的IG N-聚糖含有
半乳糖和唾液酸的存在的特定改变。我们假设这些IG改变是
抗原特异性,并且存在的糖基化模式将对下游免疫产生负面影响。
应答这一假设是基于我们的初步数据,已知的LD B细胞扰动,和IgG的报告,
N-聚糖改变对COVID-19、结核病、多发性硬化症和HIV的免疫反应。
这项建议是新颖和独特的,因为它是唯一的研究,检查糖基化的作用,
在人体对LD的免疫反应中。这项建议是建立在我们的初步工作,我们确定
血清转换前急性LD患者血清总IgG和IgM的异常糖基化。在这
建议,我们检查了特异性免疫球蛋白的糖基化LD抗原,并确定是否急性LD感染将
改变B细胞反应以产生抗原特异性Ig,其具有与我们在研究中所见相同的独特糖基化变化。
初步数据。此外,我们还研究了抗原特异性Ig上的糖基化模式如何影响免疫球蛋白的表达。
免疫反应LD。
在目的1中,我们分离出对LD抗原VlsE特异性的Ig,并建立IgG和IgM N-聚糖谱。
结果将确定抗原特异性Ig是否含有与总IG中发现的相同的异常糖基化
急性LD患者人群。在目标2中,我们量化LD抗原特异性IgG糖基化对免疫应答的影响。
促进ADCC和补体沉积。结果将确定IgG之间是否存在联系
糖基化和患者不能清除导致LD的伯氏疏螺旋体螺旋体。在Aim中
3、定量分析了抗原特异性IgM糖基化对补体沉积率的影响。补充
沉积导致莱姆病病原体的快速清除。IgM的糖基化改变可能会损害
补体沉积并阻碍人类宿主清除感染的能力。
这项工作将建立疏螺旋体免疫逃避的新机制,表征宿主反应
LD的发病机制。此外,这些结果将加强IG N-聚糖作为免疫调节剂的用途。
在新型莱姆病诊断测定中的多重生物标志物,并指导
抗体用于静脉内治疗难以治疗的播散性莱姆病病例。
项目成果
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