The biology of the beige-like protein LRBA in health and disease
Human Genetics
Immunology
Final Report Abstract
LRBA deficiency is a primary immunodeficiency (PID) caused by biallelic mutations in LRBA that abolish its protein expression. Within this grant we reported on the clinical, laboratory, and genetic characterization of the largest LRBA deficiency worldwide cohort, compound of 22 LRBA-deficient patients harboring 17 different novel mutations in LRBA. The analysis of this cohort indicated that LRBA deficiency has a very broad and variable phenotype and should be considered especially in children with severe autoimmune manifestations, enteropathy, recurrent respiratory infections, and hypogammaglobulinemia. Generally, LRBA-deficient patients diagnosed at early stages of the disease have a better prognosis and an improved quality of life due to an earlier and more accurate management. However, the high diversity of clinical manifestations and the fact that current diagnosis of LRBA deficiency is based on genome sequencing approaches, called for a prompt diagnosis of patients. Therefore, we developed a fast and cost-effective assay to screen for LRBA deficiency with 94% sensitivity and 80% specificity, based in the detection of LRBA protein in terms of mean fluorescence intensity (MFI) by flow cytometry in stimulated PBMCs. With these two studies we intended to offer guidelines to physicians for suspecting LRBA deficiency and to Diagnostic Units worldwide to screen for LRBA deficiency. Our study on mouse models revealed that murine LRBA deficiency does not mirror the human LRBA deficiency. Lrba-/- mice did not show any severe clinical or immunological signs of disease, either at steady state or after vaccination. Instead they produced normal antibody responses to thymus-dependent and thymus-independent model antigens, normal cellular response to acute infections, normal B-and T-lymphocyte development, and normal proliferation and cell survival. However, we found that LRBA plays a role in the production of IgA and in the regulation mechanisms of regulatory T- (low CTLA-4 expression in Tregs) and B-cell populations (reduced frequency of peritoneal B-1a cells and increased T follicular helper cells). This suggests that LRBA may be important for the maintenance of tolerance to self-antigens and in intestinal immunity. The use of induced models of autoimmunity and chronic colitis will enable us to further investigate the pathogenicity of LRBA-deficiency. Finally, by combining quantitative proteomics and in silico predictions, we identified 90 potential LRBA-interacting partners in B cells. From those we confirmed that LRBA interacts with phosphoinositide 3-kinase regulatory subunit 4 (PI3KR4). This interaction facilitates the formation of autophagolysosomes upon autophagy induction dependent of the production of PI(3)P. In the absence of LRBA, autophagy is impaired due to a blockage of autophagosome-lysosome fusion that led to defects in size, frequency and movement of autophagosomes, as well as to abnormal lysosome distribution, but without affecting autophagosome or lysosome biogenesis. Defective autophagy in B cells might lead to defects of plasma cell formation resulting in low antibody titers and high frequency of infections as observed in LRBA-deficient patients.
Publications
- The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. J Allergy Clin Immunol. 2016 Jan;137(1):223-230
Gámez-Díaz L, August D, Stepensky P, Revel-Vilk S, Seidel MG, Noriko M, Morio T, Worth AJJ, Blessing J, Van de Veerdonk F, Feuchtinger T, Kanariou M, Schmitt- Graeff A, Jung S, Seneviratne S, Burns S, Belohradsky BH, Rezaei N, Bakhtiar S, Speckmann C, Jordan M, Grimbacher B
(See online at https://doi.org/10.1016/j.jaci.2015.09.025) - Immunological phenotype of the murine Lrba knockout. Immunol Cell Biol. 2017 Oct;95(9):789-802
Gámez-Díaz L, Neumann J, Jäger F, Proietti M, Felber F, Soulas-Sprauel P, Perruzza L, Grassi F, Kögl T, Aichele P, Kilimann M, Grimbacher B, Jung S
(See online at https://doi.org/10.1038/icb.2017.52) - Rapid Flow Cytometry-Based Test for the Diagnosis of Lipopolysaccharide Responsive Beige-Like Anchor (LRBA) Deficiency. Front Immunol. 2018 Apr 23;9:720
Gámez-Díaz L, Sigmund EC, Reiser V, Vach W, Jung S, Grimbacher B
(See online at https://doi.org/10.3389/fimmu.2018.00720)
