Lymphocyte Activation Gene-3 (LAG-3) negatively regulates environmentally-induced autoimmunity.
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 aut...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2014-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC4133201?pdf=render |
id |
doaj-5c1115ec90f34be88e60808ad7e01a85 |
---|---|
record_format |
Article |
spelling |
doaj-5c1115ec90f34be88e60808ad7e01a852020-11-24T22:04:04ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0198e10448410.1371/journal.pone.0104484Lymphocyte Activation Gene-3 (LAG-3) negatively regulates environmentally-induced autoimmunity.Vibha JhaCreg J WorkmanTracy L McGahaLiping LiJaya VasDario A A VignaliMarc MonestierEnvironmental 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.http://europepmc.org/articles/PMC4133201?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Vibha Jha Creg J Workman Tracy L McGaha Liping Li Jaya Vas Dario A A Vignali Marc Monestier |
spellingShingle |
Vibha Jha Creg J Workman Tracy L McGaha Liping Li Jaya Vas Dario A A Vignali Marc Monestier Lymphocyte Activation Gene-3 (LAG-3) negatively regulates environmentally-induced autoimmunity. PLoS ONE |
author_facet |
Vibha Jha Creg J Workman Tracy L McGaha Liping Li Jaya Vas Dario A A Vignali Marc Monestier |
author_sort |
Vibha Jha |
title |
Lymphocyte Activation Gene-3 (LAG-3) negatively regulates environmentally-induced autoimmunity. |
title_short |
Lymphocyte Activation Gene-3 (LAG-3) negatively regulates environmentally-induced autoimmunity. |
title_full |
Lymphocyte Activation Gene-3 (LAG-3) negatively regulates environmentally-induced autoimmunity. |
title_fullStr |
Lymphocyte Activation Gene-3 (LAG-3) negatively regulates environmentally-induced autoimmunity. |
title_full_unstemmed |
Lymphocyte Activation Gene-3 (LAG-3) negatively regulates environmentally-induced autoimmunity. |
title_sort |
lymphocyte activation gene-3 (lag-3) negatively regulates environmentally-induced autoimmunity. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2014-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4133201?pdf=render |
work_keys_str_mv |
AT vibhajha lymphocyteactivationgene3lag3negativelyregulatesenvironmentallyinducedautoimmunity AT cregjworkman lymphocyteactivationgene3lag3negativelyregulatesenvironmentallyinducedautoimmunity AT tracylmcgaha lymphocyteactivationgene3lag3negativelyregulatesenvironmentallyinducedautoimmunity AT lipingli lymphocyteactivationgene3lag3negativelyregulatesenvironmentallyinducedautoimmunity AT jayavas lymphocyteactivationgene3lag3negativelyregulatesenvironmentallyinducedautoimmunity AT darioaavignali lymphocyteactivationgene3lag3negativelyregulatesenvironmentallyinducedautoimmunity AT marcmonestier lymphocyteactivationgene3lag3negativelyregulatesenvironmentallyinducedautoimmunity |
_version_ |
1725830679984340992 |