Lipopolysaccharide-Responsive Beige-like Anchor Is Required for Both Activation and Deactivation of NFkB

RationaleThe molecular mechanisms why mutations of the lipopolysaccharide-responsive beige-like anchor (LRBA) paradoxically cause both autoimmunity and common variable immunodeficiency (CVID) are unknown. LRBA regulates vesicle trafficking and signal transduction required for the regulation and function of many immune molecules. It is hypothesized that LRBA deficiency attenuates both activation and deactivation of nuclear factor kappa beta (NFkB) resulting in immunodeficiency and autoimmunity.MethodsLRBA was knocked down or repressed in Raji lymphoma cells by the short hairpin RNA (shRNA) or dominant negative mutant (DNM) techniques. The transcription activity and phosphorylated levels of NFkB was analyzed using the luciferase reporter assay, Western blot and flow cytometry.ResultsLRBA repression attenuates both NFkB activation and deactivation, inhibits NFkB nuclear translocation and increases tumor necrosis factor alpha (TNFa) and cell survival. The attenuated NFkB activation may result from inhibited NFkB nuclear translocation, while the attenuated NFkB deactivation may result in the increased TNFa and cell survival.ConclusionsThese results suggest that the attenuation of NFkB activation may explain LRBA deficient immunodeficiency, while the prolonged NFkB activity and the increased proinflammatory cytokine TNFa and cell survival may explain LRBA deficient autoimmunity. This activation and deactivation (AnDA) model reveals a novel regulation mode for NFkB. It also provides a molecular mechanism for the paradoxical association of immunodeficiency and autoimmunity, which is a fundamental question in the immune system. RationaleThe molecular mechanisms why mutations of the lipopolysaccharide-responsive beige-like anchor (LRBA) paradoxically cause both autoimmunity and common variable immunodeficiency (CVID) are unknown. LRBA regulates vesicle trafficking and signal transduction required for the regulation and function of many immune molecules. It is hypothesized that LRBA deficiency attenuates both activation and deactivation of nuclear factor kappa beta (NFkB) resulting in immunodeficiency and autoimmunity. The molecular mechanisms why mutations of the lipopolysaccharide-responsive beige-like anchor (LRBA) paradoxically cause both autoimmunity and common variable immunodeficiency (CVID) are unknown. LRBA regulates vesicle trafficking and signal transduction required for the regulation and function of many immune molecules. It is hypothesized that LRBA deficiency attenuates both activation and deactivation of nuclear factor kappa beta (NFkB) resulting in immunodeficiency and autoimmunity. MethodsLRBA was knocked down or repressed in Raji lymphoma cells by the short hairpin RNA (shRNA) or dominant negative mutant (DNM) techniques. The transcription activity and phosphorylated levels of NFkB was analyzed using the luciferase reporter assay, Western blot and flow cytometry. LRBA was knocked down or repressed in Raji lymphoma cells by the short hairpin RNA (shRNA) or dominant negative mutant (DNM) techniques. The transcription activity and phosphorylated levels of NFkB was analyzed using the luciferase reporter assay, Western blot and flow cytometry. ResultsLRBA repression attenuates both NFkB activation and deactivation, inhibits NFkB nuclear translocation and increases tumor necrosis factor alpha (TNFa) and cell survival. The attenuated NFkB activation may result from inhibited NFkB nuclear translocation, while the attenuated NFkB deactivation may result in the increased TNFa and cell survival. LRBA repression attenuates both NFkB activation and deactivation, inhibits NFkB nuclear translocation and increases tumor necrosis factor alpha (TNFa) and cell survival. The attenuated NFkB activation may result from inhibited NFkB nuclear translocation, while the attenuated NFkB deactivation may result in the increased TNFa and cell survival. ConclusionsThese results suggest that the attenuation of NFkB activation may explain LRBA deficient immunodeficiency, while the prolonged NFkB activity and the increased proinflammatory cytokine TNFa and cell survival may explain LRBA deficient autoimmunity. This activation and deactivation (AnDA) model reveals a novel regulation mode for NFkB. It also provides a molecular mechanism for the paradoxical association of immunodeficiency and autoimmunity, which is a fundamental question in the immune system. These results suggest that the attenuation of NFkB activation may explain LRBA deficient immunodeficiency, while the prolonged NFkB activity and the increased proinflammatory cytokine TNFa and cell survival may explain LRBA deficient autoimmunity. This activation and deactivation (AnDA) model reveals a novel regulation mode for NFkB. It also provides a molecular mechanism for the paradoxical association of immunodeficiency and autoimmunity, which is a fundamental question in the immune system.