title: Di-(2-ethylhexyl) phthalate adjuvantly induces imbalanced humoral immunity in ovalbumin-sensitized BALB/c mice ascribing to T follicular helper cells hyperfunction.
abstract: Di-(2-ethylhexyl) phthalate (DEHP) has been considered as a widespread environmental persistent organic pollutant and its potential concern on human health is raised by previous studies. In particular, children are more likely to be exposed to DEHP through gastrointestinal route and consequently are more susceptible to DEHP hazards. Some reports have uncovered a positive association between DEHP exposure and an increased prevalence of allergic diseases in infants and juveniles. Allergy is a hypersensitive reaction rooted in imbalanced humoral immunity. T follicular helper cell (Tfh), an important CD4(+) Th cell subset, until recently has been identified as a key player in humoral immune response by modifying B cells functions. Tfh cells are therefore perceived as the therapeutic target of immune disorders. In the present study, focusing on the newly confirmed Tfh cells, we examined the effects of DEHP on humoral immunity and investigated the underlying mechanisms. Using ovalbumin (OVA) sensitization weanling mice model under the condition of gastrointestinal exposure to DEHP, we found that DEHP acted as an immunoadjuvant to augment OVA-specific IgE and IgG1 production, amplified germinal center formation in lymphoid nodule, as well as stimulated the expansion of CD4(+)CXCR5(+)ICOS(+)/CD4(+)CXCR5(+)PD-1(+) Tfh cells and CD19(+)CD138(+)GL7(+) plasma cells. Based on the results of immune adoptive transfusion, DEHP-related anaphylactic response was ascribed to Tfh cells hyperfunction directly. We further proved that DEHP gavage together with OVA sensitization adjuvantly promoted the synthesis of cytokines IL-21 and IL-4 and the expression of transcription factors Bcl-6 and c-Maf in Tfh cells. In conclusion, our study demonstrates that DEHP has adjuvant toxic effects on Tfh cells by synthesizing an excess of cytokines IL-21 and IL-4 via over-expression of transcription factors Bcl-6 and c-Maf, leading to an increasing secretion of allergy-related IgE and IgG1.
authors.affiliation: Department of Cell and Molecular Biology, College of Medicine, Soochow University, Suzhou 215123, Jiangsu, PR China; Department of Occupational Medicine and Environmental Hygiene, College of Public Health, Nantong University, Nantong 226019, Jiangsu, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Immunology, College of Medicine, Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Occupational Medicine and Environmental Hygiene, College of Public Health, Nantong University, Nantong 226019, Jiangsu, PR China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Nutrition and Food Hygiene, College of Public Health, Nantong University, Nantong 226019, Jiangsu, PR China.
authors.forename: Guangfei
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Pathogen Biology, College of Medicine, Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Immunology, College of Medicine, Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Immunology, College of Medicine, Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Hu
authors.affiliation: Department of Immunology, College of Medicine, Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Occupational Medicine and Environmental Hygiene, College of Public Health, Nantong University, Nantong 226019, Jiangsu, PR China.
authors.forename: Chaoyong
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Cell and Molecular Biology, College of Medicine, Soochow University, Suzhou 215123, Jiangsu, PR China. Electronic address: jcmiaosuda@163.com.
authors.forename: Jingcheng
authors.initials: J
authors.lastname: Miao
mesh_terms: D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004051:Diethylhexyl Phthalate / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D018858:Germinal Center / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006967:Hypersensitivity / Q000097:blood / Q000209:etiology* / Q000276:immunology; D056724:Immunity, Humoral / Q000187:drug effects*; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D015847:Interleukin-4 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D051560:Proto-Oncogene Proteins c-bcl-6; D051257:Proto-Oncogene Proteins c-maf / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D000098546:Interleukin-21
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D007074:Immunoglobulin G; D007378:Interleukins; C495608:Maf protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D051257:Proto-Oncogene Proteins c-maf; D015847:Interleukin-4; D007073:Immunoglobulin E; D010047:Ovalbumin; D004051:Diethylhexyl Phthalate; D000098546:Interleukin-21
keywords: Adjuvant effect; Cellular differentiation; Cytokine regulation; Di-(2-ethylhexyl) phthalate (DEHP); T follicular helper cell (Tfh)