Systemic autoimmunity in BAFF-R-mutant A/WySnJ strain mice

Area of Science:

• Immunology
• Autoimmunity
• B cell biology

Background:

• Systemic lupus erythematosus (SLE) is an autoimmune disease linked to B lymphocyte tolerance failure.
• Excessive B cell-activating factor (BAFF) signaling through BAFF-R is implicated in lupus pathogenesis.
• Current understanding suggests BAFF-R over-activation subverts B cell tolerance.

Purpose of the Study:

• To investigate the role of B cell-activating factor receptor (BAFF-R) signaling in lupus development.
• To explore the unexpected phenotype of mice with a B cell maturation defect (Bcmd-1) in the Baffr gene.

Main Methods:

• Studied A/WySnJ mice with the Bcmd-1 mutant allele of the Baffr gene.
• Assessed B cell populations, autoantibody production (IgM, IgG to dsDNA), and renal pathology.
• Utilized congenic mice (AW.Baffr(+/+)) to genetically link phenotypes to the Bcmd-1 mutation.

Main Results:

• Baffr-mutant A/WySnJ mice exhibited profound B cell deficiency but developed a lupus-like syndrome.
• Increased frequency of dsDNA-specific antibody-secreting splenocytes and elevated circulating dsDNA autoantibodies were observed.
• Renal pathology, including proteinuria and glomerular damage, was evident in affected mice by 11 months.

Conclusions:

• Altered BAFF-R signaling, specifically a defect (Bcmd-1), can paradoxically lead to B cell-mediated autoimmunity.
• This study provides the first evidence linking impaired BAFF-R signaling to the development of lupus-like disease.
• Findings challenge the prevailing hypothesis that only excessive BAFF-R signaling drives lupus pathogenesis.