Complement and CR2/CD21 in the Immune Pathogenesis of HIT

HIT 免疫发病机制中的补体和 CR2/CD21

• 批准号: 10077790
• 负责人: Gowthami M Arepally
• 金额: $ 46.42万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077790
• 关键词: Allergic Disease; Allergic Reaction; Antibodies; Antibody Formation; Anticoagulants; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Biological Assay; Blood; Blood Circulation; Blood Platelets; Carbohydrates; Charge; Communicable Diseases; Complement; Complement 3d Receptors; Complement Activation; Complex; Data; Deposition; Development; Disease; Dose; Event; Follicular Dendritic Cells; Funding; Grant; Heparin; Heparin Binding; Humoral Immunities; Hypersensitivity; Immune; Immune response; Immunoassay; In Vitro; Incubated; Individual; Knowledge; Lectin; Leukocytes; Life; Link; Mannose Binding Lectin; Mediating; Mus; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma; Play; Polysaccharides; Predisposition; Proteins; Proteome; Regulation; Role; Sampling; Signal Transduction; Structure; Testing; Thrombosis; Time; Transgenic Organisms; Variant; adaptive immunity; antigen binding; base; ficolin; ficolin-beta; heparin-induced thrombocytopenia; immune activation; immunogenic; immunogenicity; in vivo; novel; recruit; response; sample fixation; seroconversion

ABSTRACT Heparin-induced thrombocytopenia (HIT) is a life-threatening immune-mediated thrombotic disorder caused by antibodies to PF4/heparin complexes. The immune response is common and yet little is understood about its occurrence. In the last funding period, we made fundamental observations related to early events surrounding the host’s encounter with the PF4/heparin antigenic complex. Specifically, we showed: 1) preferential binding of PF4/heparin to circulating B-cells, compared with other leukocytes or platelets, 2) heparin-dependent binding of PF4/heparin to B-cells in patients receiving heparin, 3) complement fixation by PF4/heparin antigen, 4) complement-mediated PF4/heparin binding to circulating B-cells in patients receiving heparin, and 5) binding of complement-coated antigen to B-cells via complement receptor 2 (CR2/ CD21). In the following aims, we will test the hypothesis that complement activation by PF4/heparin complexes and deposition of antigen on B-cells via CD21 is essential for development of HIT autoantibodies. Specific Aim 1: Mechanism of complement activation by PF4/heparin complexes. In preliminary data, we show that mannose-binding lectin and ficolin-2 bind PF4/heparin complexes. Based on these findings, we will test the hypothesis that PF4/heparin complexes activate complement via the lectin pathway. We will define the structural basis of PF4/heparin-lectin interactions, study functional interactions of lectins with PF4/heparin complexes, and examine the role of complement inhibition in HIT. Specific Aim 2: Cellular consequences of CD21 engagement by PF4/heparin and complement. Binding of complement-coated antigen to CD21 augments humoral immunity by 103 to 104 fold. We hypothesize that binding of complement-coated multivalent PF4/heparin to the CD21 complex facilitates recruitment and signaling of antigen-specific B-cells. We will examine downstream signaling, activation and proliferation of cognate and non-cognate B-cells, perform in vivo studies in mice with a fixed B-cell receptor and characterize the contribution of CD21-expressing follicular dendritic cells to Ab formation. Specific Aim 3: Examine host predictors of PF4/heparin seroconversion. Complement-coated antigen can be detected on B-cells in some, but not all, patients receiving heparin therapy. Using a novel C3 capture immunoassay, we also show significant donor to donor variation in healthy donor plasma incubated with a fixed dose of PF4/heparin. Based on these observations, we will examine host susceptibility to anti- PF4/heparin seroconversions by characterizing the complement proteome and using antigen-positive B-cells as a marker for seroconversions in heparinized patients. By defining the cellular pathways that initiate formation of PF4/heparin Abs, we hope to uncover mechanisms relevant to the immunogenicity of other auto- or exogenous antigens.

摘要

项目成果

Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass.

• DOI: 10.1038/nbt.4153
• 发表时间: 2018-08
• 期刊: Nature biotechnology
• 影响因子: 46.9
• 作者: Gunaratne R;Kumar S;Frederiksen JW;Stayrook S;Lohrmann JL;Perry K;Bompiani KM;Chabata CV;Thalji NK;Ho MD;Arepally G;Camire RM;Krishnaswamy S;Sullenger BA
• 通讯作者: Sullenger BA

Molecular and cellular pathogenesis of heparin-induced thrombocytopenia (HIT).

肝素诱导的血小板减少症（HIT）的分子和细胞发病机制。

• DOI: 10.1016/j.autrev.2018.05.003
• 发表时间: 2018
• 期刊: Autoimmunity reviews
• 影响因子: 13.6
• 作者: Rauova,Lubica;Arepally,Gowthami;Poncz,Mortimer;Cines,DouglasB
• 通讯作者: Cines,DouglasB

Vaccine-induced immune thrombotic thrombocytopenia: what we know and do not know.

• DOI: 10.1182/blood.2021012152
• 发表时间: 2021-07-29
• 期刊: Blood
• 影响因子: 20.3
• 作者: Arepally GM;Ortel TL
• 通讯作者: Ortel TL

Heparin-Induced Thrombocytopenia: A Focus on Thrombosis.

• DOI: 10.1161/atvbaha.120.315445
• 发表时间: 2021-01
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Arepally GM;Padmanabhan A
• 通讯作者: Padmanabhan A

Neutrophil functional heterogeneity is a fixed phenotype and is associated with distinct gene expression profiles.

• DOI: 10.1002/jlb.4a0322-164r
• 发表时间: 2022-12
• 期刊: JOURNAL OF LEUKOCYTE BIOLOGY
• 影响因子: 5.5
• 作者: Maskarinec, Stacey A.;McKelvy, Margaret;Boyle, Kimberly;Hotchkiss, Halie;Duarte, Madelaine E.;Addison, Bechtler;Amato, Nicholas;Khandelwal, Sanjay;Arepally, Gowthami M.;Lee, Grace M.
• 通讯作者: Lee, Grace M.