Understanding variability in induced immune responses
Immune responses are highly variable between individuals and populations with variance driven by genetic and environmental factors. To better define this inherent variability and to dissect its causes the Milieu Interieur cohort was established consisting of 1,000 healthy donors stratified by age and sex. To study functional immune responses, we have worked with a whole blood syringe-based system, TruCulture®, which permits point-of-care standardized immune stimulation. Utilizing a Nanostring® transcriptional assay we tested the hypothesis that responses to Toll-like receptor ligands or whole microbes can be defined by the transcriptional signatures of key cytokines. We found 44 genes, identified using Support Vector Machine learning, that captured the diversity of complex innate immune responses with improved segregation between distinct stimuli. Furthermore, we used donor variability to identify shared inter-cellular pathways and trace cytokine loops involved in gene expression. This provides strategies for dimension reduction of large datasets and deconvolution of innate immune responses applicable for characterizing immuno- modulatory molecules. Taking advantage of this improved standardization, we have more recently applied our approach to the 1,000 healthy donors of the Milieu Interieur consortium to dissect the impact of age, sex, genetics, and environmental factors to these diverse immune stimuli at the population level. In doing so we identified numerous genetic variants that manifested their regulatory effects exclusively on immune stimulation. The results to be presented will lay the foundation for the integration of immune response variability in smart clinical study design and eventually precision medicine strategies.