Abstract
The diagnosis of lipopolysaccharide-responsive beige-like-anchor-protein (LRBA) deficiency currently relies on gene sequencing approaches that do not support a timely diagnosis and clinical management. We developed a rapid and sensitive test for clinical implementation based on the detection of LRBA protein by flow cytometry in peripheral blood cells after stimulation. LRBA protein was assessed in a prospective cohort of 54 healthy donors and 57 patients suspected of LRBA deficiency. Receiver operating characteristics analysis suggested an LRBA:MFI ratio cutoff point of 2.6 to identify LRBA-deficient patients by FACS with 94% sensitivity and 80% specificity and to discriminate them from patients with a similar clinical picture but other disease-causing mutations. This easy flow cytometry-based assay allows a fast screening of patients with suspicion of LRBA deficiency reducing therefore the number of patients requiring LRBA sequencing and accelerating the treatment implementation. Detection of biallelic mutations in LRBA is however required for a definitive diagnosis.
Highlights
Primary immunodeficiencies (PIDs) are genetic disorders of the immune system with heterogeneous and variable clinical phenotypes
We describe a flow cytometry-based assay as a reliable tool for the screening of lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency based on the detection of LRBA expression in stimulated peripheral blood mononuclear cells (PBMCs)
Our results showed that patient P2 had normal LRBA expression (MFI ratio: 2.6), patient P3 had a severely reduced expression (MFI ratio: 1.4), Figure 1 | A broad panel of stimuli promotes the expression of LRBA protein in total peripheral blood mononuclear cells (PBMCs)
Summary
Primary immunodeficiencies (PIDs) are genetic disorders of the immune system with heterogeneous and variable clinical phenotypes. The worldwide prevalence of LRBA deficiency is still unknown, we and others have diagnosed a total of more than 80 patients [2, 6,7,8,9,10,11,12,13,14,15,16,17] These patients show a wide spectrum of clinical manifestations including autoimmune manifestations, enteropathy, and organomegaly, as well as with hypogammaglobulinemia leading to recurrent pulmonary infections [2, 6,7,8,9,10,11,12,13,14]. 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. This calls for a prompt diagnosis of patients. We describe a flow cytometry-based assay as a reliable tool for the screening of LRBA deficiency based on the detection of LRBA expression in stimulated peripheral blood mononuclear cells (PBMCs)
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