Original articleImmune dysregulation in Alagille syndrome: A new feature of the evolving phenotype

SummaryAlagille syndrome (ALGS) is a rare autosomal dominant, multi-system disease caused by mutations in one of two NOTCH signaling pathway genes. Mutations in JAG1 are found in more than 94% of patients, with associated Jagged1 defects. We previously showed that CD46, which is a complement and immune regulator, regulates NOTCH expression during T cell activation after binding to C3b/C4b. We have identified 25% of our ALGS cohort with frequent infections and studied a subgroup of 4 in detail who were not showing current features of infections in order to show if Jagged1 abnormalities could affect immune function. We used cytometric bead arrays and FACS to measure cytokines and cell membrane expression. Resting and activated T cells were studied in both low and high IL-2 concentration to assess the TH1 ability to shift from INFγ to IL-10 production. In vitro initial PBMC cell population and subpopulation assessment were normal but further assessment of the lymphocytes revealed that while NOTCH1 expression and regulation was normal on resting TH1, Jagged1 expression was exaggerated. Resting TH1 cells from some patients exhibited high CD132 levels. Upon activating T cells, TH1 cells managed to produce TNF but failed to produce sufficient IFNγ levels (in two patients TH1 produced no IFNγ). TH2 exhibited exaggerated response with high IL-4 and IL-5 levels. TH1 were unable to down-regulate CD127, resulting in prolonged immune activation, and failed to shift from IFNγ to IL-10 production maintaining high IL-2 levels suggesting an impaired T cell response. Disturbed CD46-Jagged1 interaction may explain recurrent infections among ALGS patients, and could predispose to Th2-driven conditions such as asthma, eczema, food allergies and airway atopy and otitis media. The ALGS description could now be extended to include immune dysregulation.