Transcriptional profiling unveils type I and II interferon networks in blood and tissues across diseases

Abstract

Understanding how immune challenges elicit different responses is critical for diagnosing and deciphering immune regulation. Using a modular strategy to interpret the complex transcriptional host response in mouse models of infection and inflammation, we show a breadth of immune responses in the lung. Lung immune signatures are dominated by either IFN-γ and IFN-inducible, IL-17-induced neutrophil- or allergy-associated gene expression. Type I IFN and IFN-γ-inducible, but not IL-17- or allergy-associated signatures, are preserved in the blood. While IL-17-associated genes identified in lung are detected in blood, the allergy signature is only detectable in blood CD4 + effector cells. Type I IFN-inducible genes are abrogated in the absence of IFN-γ signaling and decrease in the absence of IFNAR signaling, both independently contributing to the regulation of granulocyte responses and pathology during Toxoplasma gondii infection. Our framework provides an ideal tool for comparative analyses of transcriptional signatures contributing to protection or pathogenesis in disease.

Development of a Fixed Repertoire of Blood Transcriptome Modules Based on Co-expression Patterns Across Immunological States

“…Analyses of other tissues or in the context of other species would require the development and use of separate frameworks. Indeed, we also developed fixed modular frameworks for various mouse tissues (29) and in vitro culture systems, including human whole blood (30) and human dendritic cells (31). Second, we generated our transcriptome datasets for module construction using Illumina BeadArrays, a technology that pre-dates RNA sequencing.…”

Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

“…Hierarchical clustering of gene expression in livers with PBC in conjunction with data on single‐cell RNA sequences in the human liver identified several cell type–specific genes in the downstream of IFNG (Table 5), thus providing a rationale for the development of anti‐IFNG pathway therapies in a cell type–specific manner. ( 41 )…”

The physical form of microbial ligands bypasses the need for dendritic cell migration to stimulate adaptive immunity

“…Hence, it is conceivable that mannan-elicited IFN signatures affect LN-resident myeloid and stromal compartments eventually leading to lymphocyte recruitment. Of note, a combined type I and II IFN signature has recently been described in a range of infectious and inflammatory disease models (37), suggesting that its mechanistic dissection can provide insights into the pathophysiology of several immune-related disorders.…”