Interview anlässlich der Nature-Publikation:  Tim Rollenske, Sophie Burkhalter, Lukas Muerner, Stephan von Gunten, Jolanta Lukasiewicz, Hedda Wardemann and Andrew J. Macpherson: Parallelism of intestinal secretory IgA shapes functional microbial fitness, Nature, 13 October 2021

Prof. Macpherson your research is outstanding in multiple aspects and again you communicate about an exciting project in Nature this week. In your project, you found a multi-level control function of IgA antibodies on microbiome bacteria.

Most of the antibody produced in the body is IgA (in humans about 3 g per day), and most of this is secreted into the intestine. Yet until now, we have only had glimpses into what the IgA is actually doing there. In other words, we hardly know what the main antibody in the body does.

How did you approach this?

The problem is twofold: On one side, IgA is made up of many different components, but it has been extremely hard to pick these apart. It might be likened to trying to understand what jobs people are doing in a hospital, knowing that the workers go into the building at the beginning of the day and out at the end, also knowing that our patients mostly get better, but with no idea what individual doctors, nurses and colleagues do to achieve this. The change here is that the IgA response has been split up into its individual components using genetical technology so that each has been studied individually.

On the other hand it has been possible to detect binding of IgA to purified bacterial proteins, carbohydrates and lipids, but because one can see binding in a plastic dish, it does not tell us what the antibody is doing to bacteria in the intestine. What has happened here is that we have worked out a way to put each of the individual component antibodies back into the intestine on its own to see how it changes the functioning of the bacteria that normally live in the intestine.

This is thrilling. So you were able to identify the contribution of each element?

To explain parallelism, I shall go back to my hospital analogy, it is like following each doctor, nurse and support staff into the operating theatre, into the wards, through the corridors to see exactly what every individual does. Just as each member of staff does something different to the patient (operates, cares on the ward, brings the meals) so there is parallelism in the IgA response – each component does something different to the microbe. Just as there is more than one nurse on the ward looking after the patient, some antibodies are generic (they are different antibodies but do much the same job). At times a staff member does more than one job (I see patients in the outpatient clinic, do endoscopies and administer gastroenterology) – similarly parallelism means that one antibody can do more than one thing on the outer surface of the bacterium. As you can see, without analyzing each component separately, we would never understand how IgA works.

You worked toward a global understanding of the interactions. How could this benefit the patient?

Our immune systems are being constantly challenged by pathogens and responding to the microbes that normally live in the intestine. Each time the repertoire of the antibodies and the other white cells is changed a little. As we grow older we carry this immune history with us – this can be beneficial (as in immunization) or detrimental (as in autoimmunity or inflammatory bowel disease). The wider perspective is that as one breaks the immune responses down into their individual components it opens the possibility to ensure that immune development is beneficial rather than triggering disease.

Your research started out in the laboratory originally. Now you invest great energy into achieving better results for patients and the clinician.  Can you explain the clinical bearing of your findings?

The research published in this paper with Dr. Tim Rollenske as first author has lightened the path of important interactions of IgA. It focused on preclinical settings, knowing that understanding the mechanisms of the interaction, we will be able to produce clinically oriented output. As we e.g. published how the microbiota may trigger Crohn’s disease and limit the effectiveness of therapies in patients (Nature Medicine 2019, 25, 323-336). This is the other side of the problem and building up a mechanistic understanding of how the system works or fails means that one needs to use all the different tools that are available.

 The exciting thing is that with this technology now validated preclinically we can also look at the way in which different components of the immune system (antibodies, intestinal T cells) are responding to the changes in the microbiota in health, and how this may cause disease.

What would be these ways of response?

We can say that the immune system in the intestine is much narrower in capacity than immunity in the rest of the body. This means that intestinal immune responses are likely to be recycled over time – an antibody that has response to one microbe may be modified (the genes are slightly mutated in the white cell producing the antibody) so that the new antibody is produced to act on another microbe. I shall deal with the consequences for vaccination below. The importance for disease is that an excess of IgA can also cause problems in the rest of the body (especially the kidney) and the other white blood cells (T cells) that assist in IgA production circulate around the body and potentially trigger autoimmunity. We are also looking into the T cell responses that intestinal microbes trigger with similar methodology to that which we have just published.

Currently we are thoroughly sensitized on immunology and vaccination. Your work will affect vaccination strategies as well. Can you describe briefly in what ways the parallelism is meaningful for future vaccines?

As explained above, the intestinal (mucosal) immune system is rather narrow compared with the immune system in other body tissues. In general, oral (intestinal) immunization is not a good route for systemic vaccination, because we need to be tolerant of antigens that we eat in food and there are special downregulatory mechanisms to ensure this. We do want to be able to manipulate the dangers triggered by microbes in inflammatory bowel disease. To do this we shall likely have to use parallelism and thus exploit the fact that different components of the outer surface of microbes need to be attacked by antibodies, rather than to depend on a single target as one generally does with systemic immunization against viruses.

Prof. Macpherson, thank you very much.

Interview: Bern 13. Oktober 2021Prof. Dr. med. Macpherson, Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital, Bauchzentrum Bern, Universitätsspital Bern,

Fragen: Wissenschaftskommunikation, Marcel Wyler, Inselspital Bern