Children with autosomal recessive deficiency suffer from life-threatening, often recurrent viral or bacterial infections. We have profiled transcriptional responses of fibroblast cell lines derived from patients deficient for key regulators of immune responses such as MYD88, IRAK4, UNC93B, STAT1 or NEMO. This systems immunology approach revealed distinct patterns or responsiveness to stimuli activating the Toll-like/IL1 Receptor pathway in either an MYD88-dependent (IL1B) or independent (poly(I:C)) fashion, or activating the TNF pathway. The prototypic signatures in cell lines derived from patients were as follows: NEMO-deficient cells were unresponsive to all three stimuli, UNC-93B-deficient cells did not respond to poly(I:C), and STAT1-deficient cells responded only weakly to poly(I:C) after eight hours (not shown). MyD88- and IRAK-4-deficient cells had indistinguishable phenotypes, both being unresponsive to IL-1B at both time points. The signatures obtained in response to TNF and poly(I:C) (via TLR3) in these cells were similar to that of control fibroblasts.

Skin fibroblast cell lines were derived from controls (n=3), patients with deficiencies for MYD88 (n=1), IRAK4 (n=1), UNC93B (n=2), STAT1 (n=1) and NEMO (n=1). Cells were cultured for 2 or 8 hours in the presence of TNF, IL1B or poly(IC) or left unstimulated for the same length of time. Transcriptional profiles were acquired using Illumina Hu6 V2 BeadChips in two separate batches (2 hours, 8 hours).