Publications

Abstract

Inherited mutations in Lipopolysaccharide Responsive Beige-like Anchor (LRBA) cause a recessive human immune dysregulation syndrome with memory B cell and antibody deficiency (common variable immunodeficiency, CVID), inflammatory bowel disease, enlarged spleen and lymph nodes, accumulation of activated T cells, and multiple autoimmune diseases. To understand the pathogenesis of the syndrome, C57BL/6 mice carrying a homozygous truncating mutation in Lrba were produced using CRISPR/Cas9-mediated gene targeting. These mice revealed that LRBA plays a critical, cell autonomous role in promoting CTLA-4 accumulation within CD4 effector T cells and FOXP3+ T regulatory cells (Tregs). In young mice, or in chimeric mice where only half of the T cells are LRBA-deficient, low CTLA-4 was the only detectable abnormality in Tregs, whereas in old mice FOXP3 was also decreased. Low CTLA-4 did not translate into increased CD86 on B cells unless the LRBA-deficient mice were immunized, and neither immunization nor chronic LCMV virus infection precipitated immune dysregulation. LRBA-deficiency did not alter antigen-specific B cell activation, germinal centre (GC) formation, isotype switching or affinity maturation. Paradoxically, CD86 was decreased on GC B cells in LRBA-deficient mice, pointing to compensatory mechanisms for controlling CD86 in the face of low CTLA-4. These results add to the experimental rationale for treating LRBA-deficiency with the CTLA4-Ig fusion protein, Abatacept, and pose questions about the limitations of laboratory experiments in mice to reproduce human disease in natura