In taking the autoimmune disease lupus as her mantle in clinical practice and at the bench, Afroditi Boulougoura, MD, is tackling one of the most complex disorders affecting one of the body’s most complex systems. By design, she has her feet in both worlds of academic medicine–patient care and laboratory science–to unravel the unknowns around systemic lupus. A key question is how the loss of immune tolerance leads to aberrant inflammation that can damage multiple organs, including the kidneys.

A clinical fellow in rheumatology, Boulougoura sees patients at Beth Israel Deaconess Medical Center, many of whom are young women who face a lifetime of uncertainty and hard choices about medications that can impair fertility. Her bench work targets select cells in the kidneys as a possible means to avert nephritis, one of lupus’ deadliest complications, in which tissues in the kidney become inflamed and no longer efficiently filter waste from the blood.

Boulougoura is a trainee (2021-2023) with Harvard Catalyst’s Clinical and Translational (C/T) Research Academy.

How did you get interested in studying lupus?

I am interested in the complexity of the disease. When I finished medical school, I knew I wanted to work in rheumatology, and I wanted to learn more about immunology. Lupus affects all parts of the immune system, so it was an interesting disease to study.

I enjoy working in the clinic and seeing patients. This group is unique. They are mostly young females in their 20s or 30s, so there are many considerations. It’s extremely difficult to realize that the rest of their life is going to be affected by this disease, and that they will need to make decisions about medications that might interfere with pregnancy down the road. I wanted to establish a relationship with each of them to ensure continuity of care and help them through this difficult path.

The translational aspect of this research allows me to explore questions based on patient needs. I don’t want my research to be so far away from its impact on the patient. If I only worked at the bench, I might lose this connection to what is really important for them.

“The beginning of a career is always difficult. Seeing other people’s paths, and how they developed their career is very, very important – even the mistakes, the good and the bad, and learning from those.”

How has the C/T Research Academy fit into your career development?

It’s a privilege to be part of a group of people who are also at the first stage of their career and who are all interested in translational research. We have the same questions around how to establish ourselves in our fields, how to negotiate our next positions, and how to obtain funding to advance our research. We can discuss these topics among ourselves and with senior physicians and investigators who, throughout their careers, have guided others at this stage.

The beginning of a career is always difficult. Seeing other people’s paths, and how they developed their career is very, very important – even the mistakes, the good and the bad, and learning from those.

I also think the limited number of people enrolled in the C/T Research Academy allows the training to be more personalized to each individual.

What is the clinical problem that you’re trying to solve?

Currently, lupus is treated with immunosuppressive and cytotoxic medications that don’t have a specific target. This is especially true of the older and most effective treatments, which kill pretty much all immune cells. That comes with a very high risk. These patients have a heightened risk of infections to begin with, so suppressing their immune system further–and blindly, just blocking immune function globally–can lead to many complications.

We think that the key may be to find the right target in the right organ in the right cell –  to be very specific in our targeting. Our approach to lupus nephritis has been to target the immune protein IL 23 in cells called podocytes, which are unique to the kidneys, and seem to have immune function as well. We’ve observed an interplay between these so-called “resident” cells and the immune cells, raising the question of how they contribute to the inflammatory process. Could they be triggering it? We don’t know yet.

“Our main focus has been to discover what is causing damage to the kidneys and from there, find a good biomarker to monitor the disease.”

We looked at whether we could target IL 23 in mice, in which we delete the IL 23 receptor from only the podocytes. We found that doing so ameliorates nephritis to a large degree. The mice have less proteinuria, one biological marker of renal damage, and much better kidney function.

The other issue is that we don’t have good markers to monitor lupus nephritis. Blood and urine studies do not necessarily reflect what is going on in the kidneys. Our main focus has been to discover what is causing damage to the kidneys and from there, find a good biomarker to monitor the disease. In the process, we hope to find pathogenic mechanisms that will inform the development of better therapeutics, which would then be selectively targeted to groups of patients.

In a commentary in Nature Reviews Rheumatology, you and a co-author questioned whether lupus drugs newly on the market and in the pipeline were likely to help many patients. Why the skepticism?

The percentages of clinical improvement seen in these trials are not satisfactory. The trend in the field has been to add new medications in addition to the standard of care, which are immunosuppressants such as steroids or mycophenolate. So they effectively add complexity without great clinical benefit. That is not something impressive, let’s say. We still are not where we should be after so many years of studies.

We have identified a small group that responds to these new medications, but more than 50% of patients do not. This underlines the point that lupus is most likely not one disease. These patients are probably not the same in terms of the pathogenesis of their disease. Different immune pathways might be involved with each person. All of this makes the disease even more complex and helps explain the limited benefits of these newer treatments.

How do you find work/life balance?

Well, I wouldn’t say I live in a balanced way because my life is definitely not balanced. Work takes most of the time. When there is some time off from work, I enjoy spending time with my husband and inviting people out for dinner. I love food.

I love cooking also – many different cuisines, but I most enjoy cooking Greek food, because I’m from Greece. My favorite thing to make is a dish called gemista, vegetables stuffed with rice and ground beef. It takes forever to prepare and cook, so I make it when I have a day off, and we’ll invite friends over.