Deconstructing B cell responses: Lessons learned from development, drugs and deficiencies

The human immune system is protecting us from a wide variety of potentially disease-causing pathogens, already starting directly after birth. Inborn errors of immunity or primary immunodeficiency disorders (PIDs) are a group of diseases where any or multiple of these protective components of the immune system fail. There is a close relationship between how the immune system functions in PIDs and how the immune system works in healthy individuals. The B cells of patients with defects in specific components, i.e. proteins, show how important they really are in humans. By studying the effects of the absence, reduction or modification of these key proteins we could ‘deconstruct’ healthy B cell responses. Here we add pieces of missing information to how B cell differentiation and antibody responses may work, by investigating monogenic PIDs. We did not focus on these human knock-outs only. We used different approaches and looked at healthy human B cells from different age-ranges in several experimental conditions in order to compare normal and abnormal B cell development and differentiation. A high-throughput compound screen showed us distinct mechanisms to modulate B cell responses and offered new therapeutic targets for diseases with B cell dysregulation (such as antibody-dependent autoimmune diseases). This thesis reveals important roles for both the canonical and non-canonical NF-κB pathway and the PI3K-AKT-mTOR pathway in the differentiation of naïve B cells to antibody producing plasmablasts and plasma cells