Panel A: A molecular diagram illustrates how P K C may inhibit spleen tyrosine kinase, influencing downstream P I 3 K-dependent signals in B lymphocytes. Panel B: A clinical comparison highlights various clinical features such as lymphadenopathy, hepatosplenomegaly, anemia, leukopenia, thrombocytopenia, and immune cell subsets. Panel C: Representative flow cytometry assays from a healthy donor, Patient 1, and Patient 2 are shown. The assays include cells pretreated with C A L 101 to inhibit P I 3 K signaling or rapamycin to inhibit m T O R signaling. Panel D: Summarized data showing patients with A P D S display increased p S 6 upon in vitro stimulation compared with healthy donors.
Rationale for leniolisib treatment. (A) Potential interactions of PKCδ and PI3K pathways. (B) Clinical comparison of APDS and PRKCD deficiency. (C) Representative pS6 flow cytometry assay of stimulated and nonstimulated CD4+ and CD8+ T cells from an HD (top), patient 1 (index case described in the report), and patient 2 (his affected sibling). Stimulated cells were also pretreated with CAL101 (idelalisib, black dashed line) to inhibit PI3Kδ signaling or rapamycin (grey dashed line) to inhibit mTOR signaling. (D) Summarized data showing CD4+ and CD8+ T cells from the index patient and patients with APDS display increased pS6 upon in vitro stimulation compared with HDs. BCR, B cell receptor; Comp-FITC-A, compensation control fluorescein isothiocyanate; DAG, diacylglycerol; ERK, extracellular signal-regulated kinase; HD, healthy donor; MFI, mean fluorescence intensity; PLCγ, phospholipase C γ; PRKCD; protein kinase C δ gene; Pt, patient; SLE, systemic lupus erythematosus; stim; stimulated; Syk; spleen tyrosine kinase.