Proapoptotic Bak and Bax guard against fatal systemic and organ-specific autoimmune disease

Area of Science:

• Immunology
• Molecular Biology
• Cell Death Pathways

Background:

• Dysregulation of the intrinsic apoptotic pathway is implicated in cancer and autoimmune diseases.
• Bak and Bax are crucial proapoptotic proteins in the Bcl-2 family, essential for lymphocyte homeostasis.
• The roles of Bak and Bax in immunological tolerance are unclear due to perinatal lethality of double knockout mice.

Purpose of the Study:

• To investigate the roles of Bak and Bax in maintaining immunological tolerance and preventing autoimmune disease.
• To determine the specific contributions of Bak and Bax to the development of autoimmune pathologies.

Main Methods:

• Hematopoietic stem cell transplantation using Bak/Bax doubly deficient or Bak-deficient cells into recipient mice.
• Analysis of reconstituted mice for autoimmune disease development, including serological, histological, and clinical assessments.
• Comparison of disease phenotypes between Bak/Bax deficient and Bak-deficient models.

Main Results:

• Mice with a Bak/Bax doubly deficient hematopoietic compartment developed fatal systemic lupus erythematosus-like autoimmune disease.
• This included hypergammaglobulinemia, autoantibodies, lymphadenopathy, glomerulonephritis, vasculitis, and glandular atrophy.
• Mice with only Bak deficiency exhibited a similar but less severe autoimmune phenotype, suggesting a critical role for Bak.

Conclusions:

• Bak plays a critical role, and Bax an ancillary role, in safeguarding immunological tolerance.
• Deficiency in Bak and Bax proteins leads to severe autoimmune disease, underscoring their importance in preventing self-reactivity.
• Targeting the intrinsic apoptotic pathway with BH3 mimetics could be a therapeutic strategy for autoimmune diseases.