Fig. 3.
(A) Multiple cytokine secretion by whole-blood cells from three healthy donors and three MyD88-deficient patients (P2, P3, and P4), activated by incubation with various TLR agonists for 24 hours. Cytokine levels are presented as ratios of secretion by cells from MyD88-deficient patients to secretion by cells from the healthy control. (B) Transcriptional profiles of fibroblasts from healthy controls and patients stimulated with IL-1β, TNF-α, and poly(I:C) for 2 hours. Transcriptional signature of 275 genes differentially regulated upon stimulation with IL-1β,TNF-α, or poly(I:C) in at least two of three control fibroblast lines. Genes were arranged by hierarchical clustering and, for each donor, changes in expression with respect to the corresponding untreated conditions are represented on a heat map. Red indicates a relative increase in expression levels, blue indicates a relative decrease, and yellow indicates no change in expression level. Samples are grouped by stimulus and ordered by donor: controls (1 to 3), IRAK-4–deficient patient (3), MyD88-deficient patient, UNC-93B–deficient patients (1 and 2) (11), STAT1-deficient patient (12), and NEMO-deficient patient (10). (C) Transcriptional profiles of fibroblasts stimulated with IL-1β, TNF-α, and poly(IC) for 8 hours. Transcriptional signature of 1451 genes differentially regulated upon stimulation with IL-1β,TNF-α, or poly(IC)in at least two of three control fibroblast lines. (D) Functional pathways regulated in fibroblasts treated with IL-1β, TNF-α, or poly(IC) for 2 hours. Genes or gene products regulated by these factors are represented as nodes, and the biological relation between two nodes is represented as an edge (line). Solid and dashed lines indicate direct and indirect relations, respectively. All edges are supported by at least one reference from the literature. Nodes are arranged according to the cellular distribution of the corresponding gene products. Expression levels of individual genes are represented on a color scale on the main network: white denotes <1.5-fold difference from nonstimulated conditions; solid red denotes >5-fold difference from nonstimulated conditions. The main network indicates the average expression level for the three control cell lines. The scaled-down networks indicate the levels of expression obtained for cells derived from patients.