Mechanism of Disease Development in Patient with LRBA Deficiency

Abstract

Lipopolysaccharide-responsive and beige-like anchor (LRBA) deficiency is a primary immunodeficiency disorder characterized by autoimmunity, recurrent infections, and hypogammaglobulinemia. It is caused by mutations in the LRBA gene, which encodes the LRBA protein crucial for the regulation of immune cell activation. LRBA mediates the cycling of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) from the endosomes to the surface of T cells, where it acts as a competitive inhibitor of the co-activator CD28, resulting in diminished T cells activation. CTLA-4 is constitutively expressed in Tregs, while its expression in T effector (Teff) cells is dependent on their activation. Therefore, in the absence of LRBA, CTLA-4 surface expression is impaired, resulting in the inability of Teff cells to self-regulate, and that of Tregs to inhibit Teff cell activation, predisposing the patients to immunodysregulation. Using next generation sequencing, we identified a homozygous mutation in LRBA that abolishes protein expression in a female patient. Surprisingly, she presents with an unusually mild clinical course of her disease, which differentiates her from most patients with LRBA deficiency. A detailed immunophenotyping demonstrated normal T cell development but decreased memory B cells percentage and IgG secretion. Consistent with other patients, the expression of CTLA-4 on Tregs was severely diminished in the patient. However, activation of Teff cells was abnormal in the patient and the expression of CTLA-4 on their surface was slightly increased. Since the role of LRBA in CTLA-4 expression was only studied in Tregs, it was believed that regulation of CLTA-4 was also defective in Teff cells from patients with LRBA deficiency. However, our results suggest that the expression of CTLA-4 in Teff cells might not depend entirely on LRBA, and patients with a mild course of the disease might have a compensatory mechanism. This represents the first study that focuses on CTLA4 expression on Teff cells in patients with LRBA deficiency, and might have uncovered a different mechanism of CTLA-4 regulation in Teff cells that is different than that in Tregs.