At the forefront of research in lupus

An interview with Dr. Christophe Richez, Professor of Rheumatology at Hospital Pellegrin, Bordeaux, France

Systemic lupus erythematosus (SLE or lupus) is a complex autoimmune condition that affects each patient differently.1 While the causes of lupus are not fully known, research into the physiological processes of SLE is giving new insights into this condition. We caught up with Dr. Richez to share his perspective on ongoing research and how it evolves our understanding of the disease drivers of lupus. This interview has been edited for length and clarity.

What do we know about the causes of lupus?

Dr. Richez: Lupus is a condition with a combination of genetic and epigenetic (non-hereditary) factors in a patient’s DNA. Disease activation may emerge when this genetic profile is placed under stress because of a range of factors including hormonal changes, tobacco or potentially viral or bacterial infections.2

Incorrectly transcribed genes lead the body to create autoantibodies (antibodies formed in response to its own tissues) but also an incorrect number of cytokines, substances including interleukin-6, interleukin-10, Type I and Type 2 interferon, that each play a role in regulating the way immune processes function. If cytokines are deregulated, they lead to a number of dysfunctions in the operation of the immune system, and perpetuate these dysfunctions.2,3

In healthy people for example, Type I interferon supports the innate immune response against pathogens and supports the link between innate and adaptive immunity. This action is, for instance, fundamental for clearing the body of the flu virus. In patients with lupus, inappropriate high levels of cytokines such as Type I interferon may lead the immune system to begin attacking healthy cells, as they incorrectly identify the body’s own tissue as a potential pathogen.2,4

What is the current thinking on how the immune system is involved in the pathophysiology of lupus?

Dr. Richez: Research into innate immunity in the development of lupus has come to the fore. Innate immunity is a generalized immune response that the body undertakes when some “danger” signals are detected in the body, and works in accompaniment with the adaptive immunity, which directly targets specific antigens. In the case of lupus, we now know that some intra-cellular receptors, including Toll-like receptor 7 and Toll-like receptor 9 are inappropriately activated.2-4 These receptors subsequently signal the activation of immune cells, most notably B-cells and plasmacytoid dendritic cells that in turn produce Type I interferon. T cells also play an important role, since they support B cell differentiation and autoantibody production, and they can be aggressive and induce tissue lesions. 2-4

What research has informed our understanding of the connection between Type I interferon and lupus?

Dr. Richez: The first connections between Type I interferon and lupus are generally understood to have been seen in the 1970s when serum from SLE patients was shown to inhibit the death of virus-infected cells and where the strength of that effect was associated with indicators of disease activity.5

In 1999, my colleagues in Dallas described a surprising effect of lupus sera, the ability to induce the differentiation of immune cells. They tried to understand the main driver of this differentiation and focused on Type I interferon. Indeed, this cytokine was the perfect guilty party because therapies using interferon-alpha had been described as able to induce autoimmune diseases, including lupus. Thus, they blocked interferon-alpha into the sera and inhibited the differentiation of monocytes. This discovery was the first step of multiples studies, describing the numerous effects of Type I interferon on immune cells.

Controlling elevated levels of Type I interferon may provide new possibilities in treating SLE and a range of autoimmune conditions.4

What implications do these findings have for the treatment of lupus?

Dr. Richez: As we shift from treating the symptoms of lupus to addressing the condition itself, biomarker testing can be used to understand the key drivers of the condition and help identify the right treatment. Type I interferon expression is just one such pathway that leads to the development of SLE.4 By identifying lupus patients with a high level of Type I interferon gene signature, it may be possible to target treatment to those who would benefit most from Type I interferon inhibition. That isn’t to say that this is the only way to tackle this condition. Tomorrow, maybe we will define patients by Type I interferon gene signature, neutrophils signature, plasmablasts signature and other new undiscovered characteristics.

What are the implications of this research for other conditions?

Dr. Richez: Deepening our understanding of Type I interferon gene signature may have implications for a range of conditions because of its role as a driver of immune responses. Further research may help develop treatments for a range of autoimmune pathologies, such as the Gougerot-Sjögren syndrome, myositis, and systemic scleroderma.

Where do you see research in lupus progressing in the future?

Dr. Richez: Looking further ahead, it would be exciting to explore the potential of other methods of treating of lupus, perhaps exploring the role of the metabolism as a driver of autoimmune conditions. It may be that researching metabolic processes won’t yield a cure for a condition such as lupus, but it is worth exploring. For now, we are in an exciting period of discovery and as we continue to map the pathophysiology of SLE, we get ever closer to expanding the possibilities for treating patients.

 

1. Lateef A, Petri M. Unmet medical needs in systemic lupus erythematosus. Arthritis research & therapy. 2012 Dec 18;14(4):S4.

2. Choi J, Kim ST, Craft J. The pathogenesis of systemic lupus erythematosus—an update. Current opinion in immunology. 2012 Dec 31;24(6):651-7.

3. Craft JE. Dissecting the immune cell mayhem that drives lupus pathogenesis. Science translational medicine. 2011 Mar 9;3(73):73ps9.

4. Crow MK. Type I interferon in the pathogenesis of lupus. The Journal of Immunology. 2014 Jun 15;192(12):5459-68.

5. Crow MK. Interferon-alpha: a therapeutic target in systemic lupus erythematosus. Rheumatic Disease Clinics of North America. 2010 Feb 28;36(1):173-86.

Veeva ID: Z4-7852
Date of next review: October 2018