title: Lymphocyte Activation Gene-3 (LAG-3) negatively regulates environmentally-induced autoimmunity.
abstract: Environmental factors including drugs, mineral oils and heavy metals such as lead, gold and mercury are triggers of autoimmune diseases in animal models or even in occupationally exposed humans. After exposure to subtoxic levels of mercury (Hg), genetically susceptible strains of mice develop an autoimmune disease characterized by the production of highly specific anti-nucleolar autoantibodies, hyperglobulinemia and nephritis. However, mice can be tolerized to the disease by a single low dose administration of Hg. Lymphocyte Activation Gene-3 (LAG-3) is a CD4-related, MHC-class II binding molecule expressed on activated T cells and NK cells which maintains lymphocyte homeostatic balance via various inhibitory mechanisms. In our model, administration of anti-LAG-3 monoclonal antibody broke tolerance to Hg resulting in autoantibody production and an increase in serum IgE level. In addition, LAG-3-deficient B6.SJL mice not only had increased susceptibility to Hg-induced autoimmunity but were also unresponsive to tolerance induction. Conversely, adoptive transfer of wild-type CD4(+) T cells was able to partially rescue LAG-3-deficient mice from the autoimmune disease. Further, in LAG-3-deficient mice, mercury elicited higher amounts of IL-6, IL-4 and IFN-γ, cytokines known to play a critical role in mercury-induced autoimmunity. Therefore, we conclude that LAG-3 exerts an important regulatory effect on autoimmunity elicited by a common environmental pollutant.
authors.affiliation: Temple Autoimmunity Center and Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Vibha
authors.initials: V
authors.lastname: Jha
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Creg J
authors.initials: CJ
authors.lastname: Workman
authors.affiliation: Department of Medicine, Section of Rheumatology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: McGaha
authors.affiliation: Temple Autoimmunity Center and Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Liping
authors.initials: L
authors.lastname: Li
authors.affiliation: Temple Autoimmunity Center and Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jaya
authors.initials: J
authors.lastname: Vas
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
authors.affiliation: Temple Autoimmunity Center and Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Marc
authors.initials: M
authors.lastname: Monestier
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004785:Environmental Pollutants / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008628:Mercury / Q000009:adverse effects / Q000276:immunology; D051379:Mice; D016273:Occupational Exposure; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000974:Antibodies, Antinuclear; D015703:Antigens, CD; D001323:Autoantibodies; D004785:Environmental Pollutants; D015850:Interleukin-6; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D008628:Mercury; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse