Interrogating Darwinian Selection in The Antibody Response
Name of applicant
Søren E. Degn
Institution
Aarhus University
Amount
DKK 1,414,600
Year
2018
Type of grant
Semper Ardens: Accelerate
What?
When we are exposed to an infectious microorganism, specialised immune cells termed B cells respond by producing defence molecules called antibodies. The antibodies are tailor-made to recognise the characteristic features, or 'antigens', of the microorganism which elicited the response. This tailoring occurs in so-called germinal centres in our lymph nodes and spleen, through a cyclic process: first, the B cells which can recognise antigen divide, then each B cell makes subtle changes in the antibody it produces, and finally the B cells that are best at recognising antigen are selected. This process is repeated over and over, refining the repertoire of B cells producing antibodies specific for the microorganism. The present project investigates the basic mechanisms governing this process.
Why?
From a basic science perspective, the project will shed light on the inner workings of a biological process of directed evolution, which in many respects parallels that governing the evolution of species, but unfolds on much shorter time scales. Studying this 'Darwinian microcosm' may provide fundamental insights into evolutionary processes. The ability to produce highly specific antibodies is crucial to render us immune to repeated infections with the same microorganism. However, the germinal centre reaction can also produce antibodies with untoward reactivity towards our own body, driving autoimmune disease. Therefore, from a translational perspective, a deeper understanding of germinal centre function may enable development of strategies to improve vaccines or curb autoimmune diseases.
How?
We take an interdisciplinary approach, which spans biochemistry, Nano engineering, advanced transgenic models and immunology. In collaboration with Professors Gregers R. Andersen (MBG, AU) and Jørgen Kjems (iNANO, AU), we have developed a novel 'clickable' nanoparticle vaccine, enabling on-demand mix-and-match combinatorial assembly of model antigens to desired specifications. This tool allows targeted delivery of antigen to lymph nodes and control over which cell populations are stimulated to respond. We can then interrogate the process of evolution in response to antigen in the germinal centres using microscopy in advanced transgenic reporters. The immune functions are additionally characterised in collaboration with Professor P.J. Utz at Stanford and Dr. Burcu Ayoglu at KTH/Stockholm.