Meet Dr. Jonas Kuiper: A Leading Birdshot Research Scientist

Updated: Jul 24, 2021

Birdshot Uveitis Society of North America is celebrating its first birthday this week. As part of that celebration, we are thrilled to present this interview with Dr. J.J.W. (Jonas) Kuiper, Associate Professor in Immunology of the Eye, Department of Ophthalmology, UMC Utrecht, the Netherlands. The birdshot uveitis research of Dr. Kuiper and his colleagues is making major inroads to understanding this rare disease.

Josette: Jonas, thank you for joining me on the BUSNA Blog! We "birdies", no matter where we live, truly appreciate your efforts to understand Birdshot Uveitis. Can you share your story? What, or who, led you to study this autoimmune disease?

Jonas: In 2009, I had finished my Master’s degree in Immunology when I came across a somewhat cryptic description of a 4-year PhD research project on a poorly understood and rare inflammatory eye condition. During application for the job position, I met the prof. Aniki Rothova, a world-renowned clinical expert in Birdshot. She explained several interesting features about the condition, the impact it has on those affected, and the extreme association with HLA-A29 – which for a young immunologist was highly intriguing. This also meant that we really had to start digging since we had very little to start with at the time.

I obtained my PhD in 2014 and started my own group at the University Medical Center in Utrecht, the Netherlands. I currently still work at the department of Ophthalmology as Associate Professor in Immunology of the Eye and work on the immunology of Birdshot with the hope to further elucidate its complex biology.

Josette: How would you summarize your birdshot research?

Jonas: My research has always focused on the complex mechanisms of the immune system, a topic many clinicians or fellow scientists usually don’t like too much, given the complexity of this abstract world.

Over the years, using various approaches but always using blood of Birdshot patients, we had the opportunity to measure the building blocks of the immune system and what seems to be different in those affected by Birdshot. For example, a breakthrough was the genetic identification of changes in ERAP enzymes in Birdshot. ERAP enzymes communicate with HLA (including HLA-A29) and regulate key processes of the immune system – which helped narrow down the pathways that may drive this disease.

Fast forward, we started to see molecular connections that positioned Birdshot Uveitis in a new family of conditions, recently named “MHC-I-opathies” or “inflammatory conditions with shared genetic features and a strong link to HLA” (MHC-I is another word for HLA). This family of conditions also contains rheumatic disease linked to HLA-B27, and the inflammatory skin disease psoriasis. They are autoimmune diseases that all have a link with ERAP enzymes.

Josette: Thank you, Jonas, for sharing your recent research paper!

(Here it the link, for those who might like to look it over. Frontiers | HLA-A29 and Birdshot Uveitis: Further Down the Rabbit Hole | Immunology

Regarding your research, Jonas, what is the 1000 Genomes Project? How do you use data from the project to inform your work?

Jonas: The 1000 Genomes Project was an international research effort to provide detailed genetic data from various populations across the world and make this available for researchers interest in genetics. The data from this project has really been instrumental in dissecting the genetics of Birdshot in our studies, because it helped us understand how the genetic make-up of patients was compared to many controls from various parts of the world.

Josette: What does a typical day look like for you?

Jonas: As a group leader I supervise my laboratory team of PhD trainees and research technicians. They do all the experiments in the lab and we discuss the outcomes and decide on next steps in the research. I discuss with uveitis specialists and help interpret outcomes from molecular diagnostic tests in difficult cases. For complex analyses of large amount of data from blood of patients, I regularly use data science approaches and use computer code to do so.

Half my day is meetings with students, discussions with research colleagues from around the world, management, finance, or giving courses and lectures. Our lab is part of a large immunology facility where we closely collaborate with data scientists, rheumatologists, mathematicians etc. The other half I try to analyze data, write manuscripts, write grant applications to obtain funding for research and…think a lot and discuss with myself using a white board.

I regularly do CrossFit in the evenings to clear my mind. This is really helpful, because I typically won’t stop thinking about science – it’s just too interesting!

Josette: Do you ever use a CRISPR in your research?

Jonas: Yes, we use CRISPR in the lab on a daily basis for various reasons. Typically, we use CRISPR to turn genes on and off in highly controlled conditions in the lab. In particular to engineer model cell lines (so no patient cells) so we can mimic the birdshot eye in a lab dish and do experiments. CRISPR is a great technology, but needs some expertise to use it efficiently. We had to develop various ways to use it on the complex genes involved in birdshot.

Josette: In a nutshell, you are investigating why only some HLA-A29 positive individuals develop certain autoimmune diseases such as Birdshot Uveitis. Your recent paper referred to a possible genetic anomaly of HLA-A29 positive individuals. In general terms, what does this mean?

Jonas: Genetic variation is very common in humans and most likely favors our survival and adaptability to external factors and changes. The genetic risk factors linked to birdshot are found in most populations, but together occur naturally more frequent in those populations where birdshot is also ‘endemic’.

The combination of HLA-A29 and two key variations in ERAP enzymes strongly linked to birdshot is kind of restricted to populations of Western-European descent. Still, the number of individuals who carry these risk factors very largely exceeds the number of cases in each country – so we believe there are a number of other unknown factors involved.

Obviously, birdshot may be underreported in a number of countries because of differences in healthcare infrastructure, but we noted that HLA-A29 is common in some African populations where birdshot is rarely present, if not completely absent. Here, the combination of ERAP changes found in birdshot patients is extremely rare, which for now is a argument to solve the long-standing question, why Birdshot only affects HLA-A29-positive individuals from Western-European ancestry.

Based on the data of the 1000 genomes project, the data also suggested that birdshot patients should also be reported in Puerto Rico – most likely because more than half the population is of European Ancestry. Anecdotally, a publication on a series of hispanic patients with Birdshot from Puerto Rico came out recently.

Josette: Antigens, which are found in cells of a bacteria, virus, plant pollen or toxin, often cause our immune systems to produce defensive antibodies. Failure of this safeguard system can result in an autoimmune disease. According to what you and your colleagues have learned about antigen-producing enzymes, how might this play out in Birdshot Uveitis?

Jonas: This is the million-dollar question. It’s also difficult to not get too technical, but the genetic risk factors for birdshot are all linked to communication of the immune system. In fact, HLA-A29 and the ERAPs normally closely collaborate to update the health status of cells to the immune system.

It is tempting to speculate that somewhere in this interaction between ERAPs and HLA-A29, the wrong message or a false flag is communicated, which makes T cells “believe” there is a virus infection or aberrant changes to cells that needs to be removed. In that case, T cells attack eye tissues, causing damage and vision loss. Therapy for birdshot is directed at dampening this “attack”.

Hopefully, better understanding of the messages communicated by HLA-A29 and ERAPs in birdshot will help researchers to restore healthy communication and stop autoimmune processes. We make small steps in that direction, but this is very complex research that requires highly specialized technologies and much more research. We are working very hard to solve this question.

Josette: Simply put, peptides are organic chemical molecules that our bodies produce when amino acids bond together in a certain order. You say that peptides likely drive disease mechanisms. What are the implications for BU and for other diseases?

Jonas: The terminology used can be quite confusing. I will try to explain, but again this can be a bit technical. Indeed, small protein fragments are termed peptides and are found throughout the body, in food etc. The peptides we refer to in the context of birdshot are related to the messages communicated to the immune system. Recall that ERAPs and HLA-A29 closely collaborate in providing a “status report” on the health of a cell.

This is accomplished by ERAPs that function as scissors that continuously break down a small sample of normal proteins from the inside of a cell into peptides of about 8-12 amino acids long. Small peptides. These small peptides are then transported to the cell surface by HLA-A29 and displayed to surveilling agents of the immune system (that cannot look inside a cell), to show all is well and functioning properly.

In case a virus has infected the cell, proteins from that virus, just by change, will be cut into peptides by ERAPs and shown at the outside of the cell by HLA-A29. This is the moment where those agents see something is wrong inside the cell and will proceed and destroy the cell, to minimize spread of the infection. The current view is that HLA-A29 and ERAPs during birdshot have produced peptide messages that make it look like something is very wrong inside the cell. The logical thing for T cells in that case is to destroy the cell, which we believe in this case are cells of the eye.

Josette: Another area researchers are paying attention to is the collective microbiome. If I’ve correctly interpreted your recent paper, you suggest that some cells may be primed by microbial-derived peptides, and they can possibly disturb the homeostasis or balance of our systemic immune system. Can you clarify this for us? Do you think it might relate to a fungus infection or to the absence of a particular microbe population?

Jonas: The microbiome is exceedingly recognized as an important contributor to health (and disease). I am by no means an expert in the microbiome, but groundbreaking work from uveitis research expert Rachel Caspi has shown in models of uveitis that changes in the microbiome affect the susceptibility to uveitis or the disease severity. As is usually the case in humans, possibly, a number of factors affect the health of the microbiome and most likely not a single factor or infectious cause. More studies in humans are required and I expect those will follow in coming years.

Josette: So many of us respond differently to one treatment or another. Do you have any theories as to why some people present with more benign cases of BU?

Jonas: I have no hard evidence for subgroups of patients that we can clearly identify in advance, but the disease course among cases is heterogenous and this has been documented in literature. Prof Rothova explained in my early years that some cases experience mild disease, while other require long-term use of drugs to control their birdshot.

My close collaborators from various uveitis clinics across the world also have similar observations. Our studies into the biological fingerprint of birdshot also shows that there is variation in the immune system markers of patients, some of these are also linked to disease severity. My best guess is that birdshot is caused by a number of factors, and in more severe cases, these factors cause more inflammation of activation of the immune system.

Josette: What is the next step in your BU research?

Jonas: We are currently focusing on the communication of HLA-A29 and ERAPs, which is complex immunology and requires a multi-disciplinary teams of researcher to crack this code. In parallel, we use big data analysis of the immune system (or “multi-omics”) to obtain the biological fingerprint of birdshot patients, which we hope will help to better predict the prognosis and treatment for individual patients in advance.

Josette: And finally, tell us about Utrecht, the area of Holland where you live. Which of its features might make it a destination to consider? I definitely see a trip to The Netherlands in my future.

Jonas: Utrecht is in the green center of the Netherlands and has canals, just like Amsterdam, but is smaller, cozy and quieter – car-free and easy to get around. You can visit the Dom tower, which you can see from any point in the city. If you visit Utrecht you really need to get dinner in any of the many monumental wharf cellars with terraces by the water.

Josette: I may have to add your delightful city to my itinerary!

I'm sure I speak for birdies everywhere, Jonas, when I say thank you for all you are doing to unravel the mysteries of birdshot uveitis. You and your colleagues are helping improve diagnosis and treatment of this rare disease, and that is exciting! We hope the future brings a cure for birdshot uveitis.

Thank you for meeting with me today. Your responses could not have been more clear and insightful.

We wish you well!

Birdshot Uveitis Society of North America (BUSNA) is a volunteer organization comprised of persons diagnosed with Birdshot Uveitis. It provides information and support for North American patients and it raises funds for Birdshot Uveitis research. For more information, please visit our website. Birdies, friends, family and medical professionals are invited to join our BUSNA community at Join us! | Mysite (

If you wish to contribute to BUSNA, please visit Make a Contribution | Mysite ( Photography/Illustrations of DNA, microbes and Utrecht are courtesey of

Special thanks to science writer Dr. Susan Berk Koch for welcoming our use of her insightful blog post on CRISPR technology. You can read Dr. Berk Koch's science-related blog at Blog_Sue Berk Koch ( .

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