Lymphocyte Activation Gene-3 (LAG-3) negatively regulates environmentally-induced autoimmunity

Area of Science:

• Immunology
• Environmental Medicine
• Toxicology

Background:

• Environmental factors like heavy metals can trigger autoimmune diseases.
• Mercury (Hg) exposure in susceptible mice induces autoimmunity, characterized by autoantibodies and nephritis.
• Immune tolerance to Hg-induced autoimmunity can be established via low-dose Hg administration.

Purpose of the Study:

• To investigate the role of Lymphocyte Activation Gene-3 (LAG-3) in regulating mercury-induced autoimmunity.
• To determine if LAG-3 blockade affects tolerance to mercury.
• To explore the impact of LAG-3 deficiency on susceptibility to mercury-induced autoimmune responses.

Main Methods:

• Administration of anti-LAG-3 monoclonal antibody to mercury-exposed mice.
• Assessment of autoantibody production, serum IgE levels, and cytokine profiles in wild-type and LAG-3-deficient mice.
• Adoptive transfer of CD4(+) T cells into LAG-3-deficient mice.

Main Results:

• Blocking LAG-3 with an antibody broke tolerance to mercury, leading to autoantibody production and increased IgE.
• LAG-3-deficient mice exhibited heightened susceptibility to mercury-induced autoimmunity and failed to develop tolerance.
• Adoptive transfer of wild-type CD4(+) T cells partially protected LAG-3-deficient mice from autoimmunity.
• LAG-3-deficient mice showed elevated levels of IL-6, IL-4, and IFN-γ following mercury exposure.

Conclusions:

• LAG-3 is a key regulator of mercury-induced autoimmunity.
• LAG-3 functions to maintain immune tolerance to environmental pollutants like mercury.
• Targeting LAG-3 may influence the development or exacerbation of autoimmune diseases triggered by environmental factors.