Dataset Information

In vitro response of fibroblasts isolated from patients with immunodeficiencies

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE12124 | GEO | 2009/07/15

SECONDARY ACCESSION(S): PRJNA113783

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Pathologic activation of the Toll-like receptor (TLR) pathway underlies various human disorders such as autoimmune diseases, chronic inflammatory diseases and lymphoid malignancies. Current therapy of these diseases relies on immunosuppressive or chemotherapeutic agents, but more effective therapeutics tailored to disease-causing mechanisms are needed. Pivotal to TLR signaling is the IL-1 receptor-associated kinase 4 (IRAK4), which is recruited to TLRs by the adaptor protein MyD88. Recruitment of IRAK kinases to MyD88, triggers the formation of a signaling competent myddosome complex, which underlies the pathogenesis of many immuno-inflammatory disorders, suggesting that IRAK4 inhibitors might be useful in the treatment of these diseases. Gain-of-function MYD88 mutations activate IRAK4 in several mature B cell malignancies, including activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). Development of selective IRAK4 inhibitors has been confounded by the challenging structure of the IRAK4 catalytic domain. Using structure-based drug design methodologies, we identified potent and selective IRAK4 inhibitors. These small molecules suppress LPS-induced TNFalpha production in vitro and in vivo, and are efficacious in mouse models of collagen-induced arthritis and MyD88-dependent inflammatory gout. Human ABC DLBCL cell lines that harbor the activating, oncogenic MyD88 L265P mutation are killed by IRAK4 inhibitors, both in vitro and in mouse xenograft models. IRAK4 inhibitors synergize with the BTK inhibitor ibrutinib, with the Syk inhibitor PRT062607, and with the Bcl-2 inhibitor ABT-199 in killing ABC DLBCL cells, suggesting new therapeutic strategies for this refractory cancer. Four ABC DLBCL cell lines (OCI-Ly10, TMD8, HBL1 and OCI-Ly3), were treated with either ND-2158 or the structurally related negative control compound ND-1659 for 6, 12, 24 or 36 h in culture. Gene expression profiling was performed using two-color human Agilent 4x44K gene expression arrays comparing signal from control compound-treated (ND-1659) control cells (Cy3), toÂ cells treated with ND-2158 for the indicated times (Cy5).

Dataset Information

In vitro response of fibroblasts isolated from patients with immunodeficiencies

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets