Systems Biology of Mature Human B cells in Health and Illness

Abstract

B cells play a crucial role in adaptive immunity. They perform a multitude of functions including antibody and cytokine production and antigen presentation. The human adaptive immune response would not function effectively without B cells. The genome of a B cell undergoes profound changes during maturation and differentiation. This genome manipulation is a double-edged sword that provides both adaptive immunity to a wide array of pathogens and risks creating genomic changes associated with cancer, autoimmunity, or allergic disease. Studying B cells from a healthy immune system is important for understanding natural disease course, vaccine development, and the manufacture of antibodies for research and medicine. Here, I apply a systems biology approach to understanding B cells in health and disease with the use of mass cytometry and computational tools. The goals were to 1) Characterize B cells in follicular lymphoma (FL), 2) Characterize germinal center (GC) B cell signaling in response to reactive oxygen species (ROS), and 3) Integrate and optimize computational tools such as viSNE to capture the biology of B cells. This systems biology approach produced numerous findings. The GC B cell compartment was diminished in FL tumors compared to tonsil. FL malignant B cells displayed both intra- and inter-tumoral heterogeneity in phenotype. This heterogeneity within the malignant cells was driven by cell to cell variation in expression levels of human leukocyte antigen D related antigen (HLA-DR). FL malignant B cells, which are thought to arise from a GC B cell, were phenotypically distinct from GC B cells. GC B cells were found to be more sensitive to ROS than other B cell types found in tonsil. viSNE served as a useful tool in the visualization and characterization of malignant and non-malignant cells. The systems biology approach using mass cytometry enabled simultaneous identification and characterization of B cells in health and disease settings.