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Interrogating Darwinian Selection in The Antibody Response

The Carlsberg Foundation Distinguished Fellowships

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.

SSR

Infectious diseases remain a global health challenge, particularly in the third world. Recent years have seen an increase in multiply antibiotic resistant bacterial strains and outbreaks of novel viruses. At the same time, the incidence of autoimmune disease has risen rapidly, particularly in Western societies. Today, autoimmune disease ranks third on the list of most prevalent causes of morbidity and mortality in the Western world. The present project entails basic investigations of a fundamental mechanism that contributes to balance the ability of our immune system to respond to and resist infections, while preventing autoimmune reactions towards our own tissues. In a longer perspective, the project may therefore have widespread implications for addressing these emerging challenges.