title: Developmental Activation of the AHR Increases Effector CD4+ T Cells and Exacerbates Symptoms in Autoimmune Disease-Prone Gnaq+/- Mice.
abstract: Perinatal environmental exposures are potentially important contributors to the increase in autoimmune diseases. Yet, the mechanisms by which these exposures increase self-reactive immune responses later in life are poorly understood. Autoimmune diseases require CD4(+) T cells for initiation, progression, and/or clinical symptoms; thus, developmental exposures that cause durable changes in CD4(+) T cells may play a role. Early life activation of the aryl hydrocarbon receptor (AHR) causes persistent changes in the response of CD4(+) T cells to infection later in life but whether CD4(+) T cells are affected by developmental exposure in the context of an autoimmune disease is unknown. Gnaq(+/-) mice develop symptoms of autoimmune disease similar to those measured clinically, and therefore can be used to evaluate gene-environment interactions during development on disease progression. Herein, we examined the effect of AHR activation in utero and via lactation, or solely via lactation, on disease onset and severity in adult Gnaq(+/-) offspring. Developmental activation of the AHR-accelerated disease in Gnaq(+/-) mice, and this correlates with increases in effector CD4(+) T-cell populations. Increased symptom onset and cellular changes due to early life AHR activation were more evident in female Gnaq(+/-) mice compared with males. These observations suggest that developmental AHR activation by pollutants, and other exogenous ligands, may increase the likelihood that genetically predisposed individuals will develop clinical symptoms of autoimmune disease later in life.
authors.affiliation: *Department of Microbiology and Immunology.
authors.forename: Lisbeth A
authors.initials: LA
authors.lastname: Boule
authors.affiliation: *Department of Microbiology and Immunology.
authors.forename: Catherine G
authors.initials: CG
authors.lastname: Burke
authors.affiliation: Department of Radiation Oncology.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Fenton
authors.affiliation: Department of Public Health Sciences, and.
authors.forename: Kelly
authors.initials: K
authors.lastname: Thevenet-Morrison
authors.affiliation: Department of Public Health Sciences, and Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Jusko
authors.affiliation: *Department of Microbiology and Immunology, Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York paige_lawrence@urmc.rochester.edu.
authors.forename: B Paige
authors.initials: BP
authors.lastname: Lawrence
mesh_terms: D000367:Age Factors; D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000172:deficiency* / Q000235:genetics; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005865:Gestational Age; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000378:metabolism; D012307:Risk Factors; D012720:Severity of Illness Index; D012737:Sex Factors
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004785:Environmental Pollutants; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse
keywords: 2,3,7,8-tetrachlorodibenzo-p-dioxin; CD4 T cell; TCDD; aryl hydrocarbon receptor; autoimmune disease; developmental exposure; gene-environment interactions