Modeling primary immune regulatory disorders: Ferrari or Yugo?

Despite about 75 million years of evolutionary separation, mice have proven to be remarkably informative for understanding the human immune system. Many immune signaling and developmental pathways are nearly identical between mouse and man, and some pathways, such as NK cell sensing of self, display clear evolutionary convergence. In this issue, Burnett et al. and Gamez-Diaz et al. independently describe the phenotype of Lipopolysaccharide Responsive Beige-like Anchor (LRBA) deficient mice. LRBA-deficient humans have a striking and severe syndrome of varied autoimmunity, lymphoproliferation, gut inflammation and immune deficiency.1 In contrast, these two groups report that LRBA-deficient mice are generally quite well. Despite aging and/or challenge with infectious organisms, these animals display none of the pathologies seen in humans. Of note, LRBA knockout mice have decreased CTLA4 protein levels, as is seen in LRBA-deficient patients, and is thought to underlie disease development. Both groups also noted other subtle immune abnormalities not correlated in patients to date: a decrease of the innate-like B1 B cells, and evidence of increased IgA production. These abnormalities are not predicted by any known function of LRBA, but may provide additional clues to disease pathogenesis.