Project 1 - Dioxin-like Compounds Suppress IgM Responses by Targeting CD5+ (Innate-like) B cells, which can Serve as a Biomarker of Susceptibility to Environmental AHR Ligands

项目 1 - 二恶英类化合物通过靶向 CD5（先天类）B 细胞抑制 IgM 反应，CD5 细胞可作为对环境 AHR 配体敏感性的生物标志物

• 批准号: 10353531
• 负责人: Norbert E Kaminski
• 金额: $ 25.35万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10353531
• 关键词: AHR gene; Adaptive Immune System; Affinity; Agonist; Amendment; Antibody Formation; Antibody Response; Antibody Suppression; Aromatic Hydrocarbons; Aryl Hydrocarbon Receptor; B-Lymphocytes; Biochemical Pathway; Biological; Biological Availability; Biological Markers; Blood; Carbon; Cells; Collaborations; Computer Models; Dioxins; Elderly; Environmental Pollution; Epidemiology; Exhibits; Genes; Goals; Human; Humoral Immunities; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunoglobulin M; Immunology; Immunosuppression; Impairment; Infection prevention; Interferon Type II; Laboratory Animals; Leukocytes; Life; Ligands; Link; Lymphocyte-Specific p56LCK Tyrosine Protein Kinase; Mediating; Modeling; Molecular; Molecular Probes; Mus; Nature; Phosphotransferases; Population; Predisposition; Production; Protein Analysis; Protein Tyrosine Kinase; Proteins; Rattus; Receptor Activation; Refractory; Research; Risk Assessment; Role; Signal Transduction; Source; Steatohepatitis; T-Lymphocyte; Testing; Tetrachlorodibenzodioxin; Time; Toxic effect; Up-Regulation; adaptive immunity; aryl hydrocarbon receptor ligand; base; cell type; differential expression; experimental study; immunoregulation; immunotoxicity; insight; microbial; novel; pathogen; physiologically based pharmacokinetics; programmed cell death protein 1; receptor; receptor expression; remediation; response; single-cell RNA sequencing; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT: Suppression of humoral immunity by environmental contaminants that are prototypical aryl hydrocarbon receptor (AHR) ligands (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)) have been demonstrated to suppress humoral immunity in laboratory animals and suggested by epidemiological evidence. The overall goal of this research is to define the molecular mechanism(s) responsible for AHR agonist-mediated suppression of antibody production by human primary B cells. Prior studies comparing activated mouse, rat and human primary B cells, RNAseq showed a small number of differentially expressed genes by TCDD. One gene that was only differentially regulated in human B cells compared to mouse and rat was the lymphocyte specific protein tyrosine kinase (LCK). While LCK is expressed by T cells, subpopulations of B cells also express LCK, specifically CD5+ B cells. We have shown that decreased IgM secretion by TCDD is due, in part, to selective effects on CD5+ B cells, termed innate-like B (ILB) cells. Although CD5+ ILBs constitute approximately 10-25% of circulating B cells and are the source for the majority of circulating IgM in the absence of an immune response. Further, CD5+ ILBs are the primary B cell type mediating humoral immunity early and late in life when the adaptive immune system is still developing or during late life stages when adaptive immunity is in decline. Protein analysis also showed induction by TCDD of LCK, the inhibitory receptor PD-1 and its ligand, PD-L2 on CD5+ ILBs. Induction of PD-1 and PD-L2 are especially important as they provide a mechanism for the suppression of the IgM response by AHR activation in CD5+ ILBs. LCK can phosphorylate the inhibitory region of the PD-1 receptor, facilitating immune suppression by PD-1. Inhibition of LCK activity protected CD5+ B cells from IgM suppression by TCDD, demonstrating LCK is critically involved. Therefore, we will test the hypothesis: AHR-mediated suppression of IgM occurs through induction of the inhibitory receptor PD-1 and LCK, a kinase known to initiate PD-1- mediated immune regulation, preferentially on human primary CD5+ (innate-like) B cells. Specific Aim (SA) 1 will characterize human CD5+ (innate-like) B cells as a highly sensitive population susceptible to suppression by AHR ligands. SA2 is to identify the role of induced checkpoint inhibitor, PD-1, and tyrosine kinase, LCK, in TCDD-mediated suppression of IgM production by CD5+ B cells. Completion of the above aims has a strong potential to: (a) define B cell population(s) highly sensitive to impairment by AHR ligands critical for immunity against common pathogens; (b) identify a novel mechanism of immunotoxicity involving upregulation of the inhibitory receptor, PD-1; (c) characterize the role of LCK in IgM suppression by AHR activation using IFNγ as a molecular probe; (d) utilize percent circulating CD5+ B cells as biomarker of sensitive populations to suppression of IgM by AHR ligands and (e) results for this experimental plan will be used to develop a calibrated TCDD PBPK model for risk assessment in collaboration with the Computational Modeling Core.

项目摘要/摘要：环境污染物对体液免疫的抑制作用