Epigenomics and Early Life Human Humoral Immunity: Novel Paradigms and Research Opportunities

Abstract

The molecular machinery controlling immune development has been extensively investigated. Studies in animal models and adult individuals have revealed fundamental mechanisms of disease and have been essential to understanding how humans sense and respond to cellular stress, tissue damage, pathogens and their environment. Nonetheless, our understanding of how immune responses originate during human development is just starting to emerge. In particular, studies to unveil how environmental and other non-heritable factors shape the immune system at the beginning of life offer great promise to yield important knowledge about determinants of normal inter-individual immune variation and to prevent and treat many human diseases. In this review, we summarize our current understanding of some of the mechanisms determining early life antibody production as a model of an immune process with sequential molecular checkpoints susceptible to influence by non-heritable factors. We discuss the potential of epigenomics as a valuable approach that may reveal not only relevant gene-environment interactions but important clues about immune developmental processes and homeostasis in early life. We then highlight the novel paradigm of human immunology as a complex field that nowadays requires a longitudinal systems-biology approach to understand normal variation and developmental changes during the first few years of life.

Keywords: antibodies; early life; epigenomics; infancy; systems immunology.

Figure 1

TNF superfamily signaling and transcriptional changes regulate terminal B-cell maturation and antibody production. Activated B-cells undergo apoptosis as default fate unless survival signals are delivered by the TNF superfamily cytokines BAFF (B-cell activation factor, TNFSF13B) and APRIL (a proliferation inducing ligand, TNFSF13) through their receptors TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor, TNFRSF13B) and BAFF-R (B-cell activating receptor, TNFRSF13C) on the surface of B-cells and BCMA (B-cell maturation antigen, TNFRSF17) on the surface of antibody secreting cells and some memory B-cells. Antibodies are exclusively secreted by ASC that arise from B-cells after profound changes in their transcriptional program (colored boxes). The generation of ASC requires that PAX5 and the transcriptional program that maintains B-cell identity (e.g., IRF8, PU.1, BACH2) are silenced and BLIMP-1, the master regulator of ASC differentiation and associated factors (e.g., XBP1, IRF4) are expressed.

Figure 2

Complex gene, environment and epigenetic interactions shape the human immune system during early life. Systems immunology in longitudinal human-based studies is needed to uncover the “master plan” of human immune development and their relationship with immune diseases. DNAm = DNA methylation, ncRNA = non-coding RNAs, TCR = T-cell receptor, BCR = B-cell receptor.