“In sickness and in health”: how individual immune response variability in health may influence how we respond to illness and therapy.

Laura Tabellini on July 29, 2019

Thomas Fuller once said:  “Health is not valued till sickness comes.” Well, that may not be true anymore.

It turns out that the key to successful disease management strategies may lie with a better understanding of individual immune response variabilities in healthy individuals.

Immunological research has neglected for a long time the concept of interindividual heterogeneity, but there is now a growing interest in studies that seek to understand variation of the immune response and its determinants in healthy populations —a strategy known as “systems immunology”.

This approach has been embraced by the scientists of the Milieu Interieur Multi-disciplinary Consortium at the Institut Pasteur in Paris led by Dr. Darragh Duffy, where the team is dissecting the immune response in healthy individuals to quantify the effects of age, sex, genetics, and cellular heterogeneity with the intention of providing a valuable resource for further exploration in the context of different infection risks or disease outcomes.

The need for standardization

The immune response has been a pressure point throughout evolutionary history with infections and diseases driving selection of different immune genes, thus leading to variability within populations and between individuals.

By dissecting this variability in a healthy state, researchers and clinicians across several disciplines, through the integration of cutting-edge technology in the fields of immunology, genomics, molecular biology and bioinformatics, are dissecting this variability within the boundaries of a functional healthy immune response identifying outliers, associating natural immune variance with physiological, environmental and genetic factors, and comparing studies in disease populations.

This level of integration of several disciplines on large population studies requires a high degree of standardization to reduce technical variation and noise to focus on real biological variation.

The team started with controlling the sample source and preparation by adopting Myriad RBM Inc’s TruCulture, a whole blood collection and culture system for quantifying physiological interactions of the human immune system.

The transcriptomic analysis of whole blood is also hard to standardize, but NanoString was the only method that met all requirements: it is robust even with low quality RNA, doesn’t require cDNA preparation or PCR nor amplification steps, and returns absolute counts of the target genes hybridized to the probes so the results are not overwhelmed by globin RNA.

Let the fun begin

In their initial data set, whole blood from 25 subjects was stimulated with specific cytokines and the supernatant screened with the NanoString Human Immunology Gene Expression Panel . The team demonstrated that the response induced by cytokines  is similar to an intracellular innate immune signature produced upon stimulation by adjuvant or microbes, showing that these cytokines can impact communication within cells and revealing how different immune responses may impact response to vaccinations or infections.

Encouraged by these preliminary results, the team enrolled 1,000 healthy, unrelated people of Western European ancestry, balanced in sex and age, to identify the relative effects of environmental and genetic factors on variation in the parameters of innate and adaptive immune cells in homeostatic conditions. They combined clinical data, serology, whole blood, nasal swab/tool , lifestyle questionnaire information, 10 panel flow cytometry, genome-wide DNA genotyping, protein supernatant analysis, cell pellet transcriptomic analysis, enterotypes and fibroblasts analysis.

Curious to hear about the results? Don’t let us spoil the fun for you! In the on-demand webinar presented here, Dr. Darragh Duffy from the Milieu Interieur Consortium will show you their initial findings and the next steps towards deciphering immune responses in a healthy state to better understand disease pathogenesis.

Post by Laura Tabellini