Summary The analysis of patient blood transcriptional profiles offers a means to investigate immunological mechanisms relevant to human diseases on a genome-wide scale. In addition, such studies provide a basis for the discovery of clinically-relevant biomarker signatures. We designed a strategy for microarray analysis that is based on the identification of transcriptional modules formed by genes coordinately expressed in multiple disease datasets. Mapping changes in gene expression at the module-level generated disease-specific transcriptional fingerprints which provide a stable framework for the visualization and functional interpretation of microarray data. These transcriptional modules were used as a basis for the selection of biomarkers and the development of a multivariate transcriptional indicator of disease progression in patients with systemic lupus erythematosus. Thus, this work describes the implementation and application of a methodology designed to support systems-scale analysis of the human immune system in translational research settings.

Our studies in children with rheumatic diseases have led to the identification of two of the oldest cytokines, type I Interferon (IFN) and Interleukin 1 (IL-1), as important pathogenic players in Systemic Lupus Erythematosus (SLE) and Systemic onset Juvenile Arthritis (SoJIA) respectively. These findings were obtained by studying the transcriptional profiles of patient blood cells and by assessing the biological and transcriptional effect(s) of active patient sera on healthy blood cells. We also identified a signature which can be used to promptly diagnose SoJIA from other febrile conditions. Finally, our pilot clinical trials using IL-1 blockers have shown remarkable clinical benefits in SoJIA patients refractory to other medications.

Blood monocytes from children with systemic lupus erythematosus (SLE) behave like dendritic cells (DCs), and SLE serum induces healthy monocytes to differentiate into DCs in a type I Interferon (IFN)-dependent manner. Here, we found that these monocytes display significant transcriptional changes, including a prominent IFN signature, compared to healthy controls. Few of those changes, however, explain DC function. Exposure to allogeneic T cells in vitro reprograms SLE monocytes to acquire DC phenotype and function, and this correlates with both IFN-inducible (IP10) and pro-inflammatory cytokine (IL1b and IL6) expression. Furthermore, we found that both IFN and SLE serum induce the upregulation of CCR7 transcription in these cells. CCR7 protein expression requires however a second signal provided by TLR agonists such as LPS. Thus, SLE serum “primes” a subset of monocytes to readily (<24h) respond to TLR agonists and acquire migratory DC properties. Our findings might explain how microbial infections exacerbate lupus.