Congratulations to our Platform 1 Co-Lead Dr. Philippe Gros on this recent publication!
Abstract
The transcription factor IRF8 (ICSBP) is required for the development and maturation of myeloid cells (dendritic cells, monocytes, macrophages), and for expression of intrinsic anti-microbial function such as antigen capture, processing and presentation to lymphoid cells, and for activation of these cells in response to cytokines and pro-infammatory stimuli (IFN-γ, IFN-β, LPS). IRF8 deficiency in humans causes a severe primary immunodeficiency presenting as susceptibility to infections, complete or severe depletion of blood dendritic cells (DC) subsets, depletion of CD14+ and CD16+ monocytes and reduced numbers and impaired activity of NK cells. In genome-wide association studies (GWAS), sequence variants near IRF8 are signifcant risk factors for multiple chronic infammatory diseases in humans including infammatory bowel disease, lupus, rheumatoid arthritis, multiple sclerosis, and several others. Recent studies have cataloged all the genes bound by and transcriptionally activated by IRF8 in myeloid cells, either alone or in combination with other transcription factors (PU.1, IRF1, STAT1) at steady state and in response to pro-infammatory stimuli. This IRF1/IRF8 regulome comprises immune pathways such as antigen processing and presentation pathways, expression of costimulatory molecules, cytokines and chemokines, response to stimuli such as cytokine receptors, pathogen associated molecular pattern receptors, TLRs and nucleotide-binding oligomerization domain-like receptor signaling pathways, and small antiviral GTPases. Members of the IRF8/IRF1 regulome are over-represented amongst genes in which mutations cause primary immunodefciencies, and are specifcally enriched at GWAS loci associated with chronic infammatory diseases in humans. These recent studies highlight a critical role of IRF8 in the activity of several immune cell types for protection against infections, but also in pathological inflammation associated with common human infammatory conditions.
Publication: Role of IRF8 in immune cells functions, protection against infections, and susceptibility to inflammatory diseases. Salem S, Salem D, Gros P. Human Genetics. 30 Mar 2020.
