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Distinct Functional Outcomes of BCR/TLR7 and BCR/TLR9 Co-engagement

BCR/TLR7 和 BCR/TLR9 共同参与的不同功能结果

基本信息

批准号：
9033830
负责人：
Ann Marshak-Rothstein
金额：
$ 51.36万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-12 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9033830
关键词：
Accounting Adverse effects American Animal Disease Models Antibodies Antigen-Antibody Complex Autoantibodies Autoantigens Autoimmune Process Autophagosome B cell repertoire B-Cell Activation B-Lymphocytes Biochemical Biological Assay Bone Marrow CRISPR/Cas technology Cells Cessation of life ChIP-seq Chimera organism Clinical Computer Analysis Confocal Microscopy DNA Data Defect Dendritic Cells Dependence Development Diagnosis Disease Disease Progression Etiology Feedback Future Gene Expression Profile Gene Targeting Genetic Genomics Goals Health IRF4 gene Immunosuppressive Agents In Vitro Inbred BALB C Mice Inbred MRL lpr Mice Indium Lead Life Ligands Longevity Lupus Mediating MicroRNAs Modeling Molecular Monitor Mus Mutation Nature Nucleic Acid Binding Onset of illness PTPRC gene Pathway interactions Patients Pattern Pattern recognition receptor Phenotype Phosphorylation Phosphorylation Site Plasma Cells Plasmablast Play Population Post-Translational Protein Processing Pristane Process Production RNA Regimen Regulation Regulator Genes Risk Factors Role Scheme Source Staging Stem cells Surface Symptoms System Systemic Lupus Erythematosus TLR7 gene Techniques Technology Testing Therapeutic Toll-like receptors Transgenic Organisms Variant anti-IgM autoreactive B cell base cell type cohort design ds-DNA functional outcomes in vivo in vivo Model insight interest macrophage mouse model neutrophil novel protective effect purge receptor reconstitution response small molecule systemic autoimmune disease trafficking transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): SLE is a devastating systemic autoimmune disease of unknown etiology that presents with a diverse array of clinical symptoms and afflicts over 1.5 million Americans. Numerous risk factors have been identified, and it is generally accepted that SLE can result from a spectrum of immunoregulatory defects. Current treatments can involve immunosuppressive regimens associated with debilitating adverse side effects. Given the heterogeneous nature of the disease, it is remarkable that nucleic acid binding Toll-like receptors TLR7 and TLR9 has been found to play a critical role in the production of autoantibodies and disease development in all animal models of disease, and may prove to be critical targets for future therapies. Intriguingly, TLR9 appears to play both a protective and disease promoting role in the disease onset and progression - TLR9 is required for the production of autoantibodies against DNA-associated autoantigens but, quite inexplicably, TLR9-deficient autoimmune-prone mice develop much more severe clinical disease than their TLR9- sufficient counterparts. Our recent studies have now demonstrated a unique role for TLR9 in purging the autoreactive B cell repertoire - B cells activated by BCR/TLR9 engagement first undergo several rounds of division and then undergo a quite profound post-proliferative death. By contrast, BCR/TLR7 activated B cells survive and readily convert to plasmablasts. The goals of this project are to gain a better understanding of: (1) where in the course of disease TLR9 can mediate this protective effect; (2) when in the course of disease TLRs play a key role in B cell activation; (3) whether TLR9 mediates a suppressive role in any other cell types; (4) what unique features of the transcriptional networks downstream of BCR/TLR9 vs BCR/TLR7 co- engagement account for the distinct functional outcomes of these activation schemes, (5) how TLR9 and TLR7 contribute to autophagosome formation, and (6) how specific Unc93b post translational modifications preferentially promote TLR9 vs TLR7 activation in primary B cells, dendritic cells and macrophages. Our studies are based on a unique experimental system in which B cells are activated by physiologically relevant autoantigen immune complexes (IC), by using either IgG2a-specific transgenic B cells or by using a novel anti-IgM/IC dual variable domain polyclonal targeting antibody. ICs that incorporate both DNA and RNA will be used to parse the unique features of BCR/TLR9 and BCR/TLR7 activation pathways by varying the genetic background (TLR7- or TLR9-deficient) of the responder B cell populations. Advanced genomic and computational analyses will be used to elucidate gene regulatory networks. A highly efficient lentiviral retrogenesis strategy will be used to rapidly screen Unc93b variants for their capacity to support TLR9 vs TLR7 driven responses in specific cell types. These studies should provide important insights regarding the best strategies for designing effect TLR-based therapeutics for the treatment of patients diagnosed with SLE and other related systemic autoimmune diseases.