To commemorate World Lupus Day, we spoke to Elissa Deenick, co-lead of the Precision Immunology Program at the Garvan Institute, about the current state of lupus understanding and what needs to happen to make lupus visible.

My name is Elissa Deenick, Im a lab head and co-lead of the Precision Immunology Program at the Garvan Institute of Medical Research in Sydney, Australia, and a Scientia A/Prof at UNSW Sydney. I have 20 years of experience studying the signals that control immune cells. My research asks how we can ensure these cells make a protective immune response while avoiding harmful responses such as autoimmunity (where the immune system attacks our own bodies) and allergy. I do this by studying patients with rare genetic diseases that disrupt the immune system and applying what we learn there to understand how the immune system goes wrong in other diseases like lupus.

The exact pathophysiology of lupus and what drives it is very complicated and there are likely many factors involved. We do know that in lupus, B cells, which usually make antibodies that protect us from infection, end up making antibodies against normal parts of the body like DNA. These antibodies then bind to their targets like DNA, forming what is called immune complexes. These can build up in different parts of the body like the kidney, joints or the skin where they induce inflammation and cause the damage that we know is associated with lupus.

The incidence of lupus seems to be increasing and thats true of many autoimmune diseases so lupus is part of that trend. That increase is probably, in part, an increase in awareness and diagnosis, but theres almost certainly a real increase in incidence there as well. However, it is not clear why these diseases are increasing thats something we really need more research to understand.

Weve discovered different ways in which the immune system can become dysregulated and cause inappropriate production of antibodies.

For example, poor clearance of dead or dying cells (which means there are dead bits of cells in places they shouldnt be, containing things like DNA that can activate B cells), dysregulation of B cells, and inappropriate production of cytokines such as interferons.

But despite the fact that our understanding of lupus has increased, we still dont have a cure for lupus and patients are largely dependent on immunosuppressive drugs that can put them at risk of side effects such as infections.

One of the biggest issues in lupus is that its almost certainly not one disease, but instead a cluster of diseases with similar symptoms but completely different drivers of disease in different people. And of course, if the underlying cause of disease is different from patient to patient, then the most effective treatment is also likely going to differ too. This heterogeneity amongst patients probably partly explains why many clinical trials of new drugs have failed in the past: you may have 10% of people in the lupus population who may respond well to that drug, but thats going to be obscured by the other 90% of people who respond poorly because thats the wrong drug for them. The focus for research then needs to be on ways to identify the driver of disease in each patient so we can match the drug to the disease.

One of the ways that Im approaching that question is by studying rare patients who have what are called inborn errors of immunity. These are caused by rare genetic variants in key genes that are important for the immune system. These genetic variants disrupt the function of those pathways and make the immune system go wrong. And in some cases, part of the way they make it go wrong is that B cells produce these pathogenic antibodies that cause autoimmunity and lupus. The significance of this for us is that it identifies pathways that can be drivers of disease. So what were doing is studying those pathways and then seeing if they might also be drivers in other patients with lupus (even if they dont have the genetic variant).

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Another question were interested in is the infections in lupus patients. People with lupus have a higher risk of severe infections, which can require time in hospital to get them under control. The problem is, though, that were not good at predicting which people with lupus are at the highest risk of infection. Were trying to work out ways of predicting who is at greatest risk and whether thats because of the immunosuppressive drugs theyre on or whether its something thats intrinsic to the dysregulation of their immune system.

Recent advances in single-cell sequencing techniques, such as single-cell RNA sequencing, have enabled us to analyse immune cell populations in patients at an unprecedented level of detail. These technologies are illuminating how immune responses differ between people and vary under different conditions, such as in lupus patients or in individuals with COVID-19 infections. With new insight into these granular differences, we can achieve a much deeper understanding of how the immune system functions in both health and disease. This has enabled a deeper dive into human immunology, including lupus pathology.

I think there is increasing awareness about lupus and that may be in part from celebrities coming out but also I think the COVID-19 pandemic has driven a greater understanding of the immune system in general. The general public is now much more familiar with talking about B cells and T cells and antibodies, so when people ask me about my work theres already a much greater level of understanding of these concepts. I think that helps with understanding and awareness of immune-mediated disease as well.

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Again, I think the idea that lupus is one disease with one solution is quite commonplace, unfortunately. The reality is that the experience of lupus is very different from person to person and not all lupus can be treated in the same way.

I think we need to keep hearing stories directly from the people who are affected by lupus how it affects their lives and health. Many people still have misconceptions about what lupus is and how serious and life-altering it can be, but sharing real stories is a powerful way to raise awareness and build empathy.

A/Prof Elissa Deenick is head of the Lymphocyte Signalling and Activation Lab and co-leads the Precision Immunology Program at the Garvan Institute of Medical Research. She is a Scientia A/Prof at the Faculty of Medicine and Health, UNSW Sydney.

A/Prof Deenick undertook her PhD with Dr Phil Hodgkin at the Centenary Institute/University of Sydney. Following her PhD she moved to Canada to take up a postdoctoral position in the lab of Dr Pam Ohashi at the University of Toronto, looking at the signalling pathways controlling T cell activation and tolerance.

She returned to Sydney to work at the Garvan Institute of Medical Research, where she continues to uncover the signals controlling lymphocyte activation and differentiation and how this is controlled to ensure protection against infection while avoiding harmful immune responses like allergy and autoimmunity.

Written by

Danielle graduated with a 2:1 in Biological Sciences with Professional Training Year from Cardiff University. During her Professional Training Year, Danielle worked with registered charity the Frozen Ark Project, creating and promoting various forms of content within their brand guidelines. Danielle has a great appreciation and passion for science communication and enjoys reading non-fiction and fiction in her spare time. Her other interests include doing yoga, collecting vinyl, and visiting museums.

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