Systemic lupus erythematosus (SLE), like other rheumatic diseases, remains poorly understood. Several genetic, immunologic, environmental, and endocrine factors are thought to influence the pathogenesis of SLE.1 Its heterogeneous presentation and multisystem involvement make the condition difficult to treat. Recent treatment frameworks suggest limiting the use of glucocorticoids and adopting a treat-to-target approach for inducing and sustaining remission. However, this recommendation is not without its challenges.

For patients with SLE, prolonged medication-free remission is rare and unfeasible for the vast majority of them. One study reported that only 1.7% of patients fulfilled the criteria for prolonged remission, which was defined as a 5-year consecutive period of no disease activity without treatment.2 The likelihood of an individual achieving remission is incumbent upon early detection of SLE and lower disease activity at diagnosis.3 To this end, determining the etiologies of SLE at the genetic level could represent a pathway for the development of new treatment strategies and therapeutics.

Akiko Iwasaki, PhD, and her team have undertaken the task of unraveling the human genome in search of the underlying mechanisms of SLE. This research has, for the first time, established an association between SLE and endogenous retroviruses (ERV). 4 Dr Iwasaki is the Sterling Professor of Immunobiology at the Yale School of Medicine, where she is also professor of Dermatology, of Molecular, Cellular, and Developmental Biology, and of Epidemiology (Microbial Diseases). An investigator at the Howard Hughes Medical Institute, Dr Iwasaki was recently awarded the 2022 Lupus Insight Prize by the Lupus Research Alliance for her discovery.


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We spoke with Dr Iwasaki, who shared her perspective on what this discovery means for the future of SLE and possible new treatments.

Can you elaborate on this discovery and its impact on SLE?

Dr Iwasaki: We have been studying these genetic elements called ERVs, which are remnants of retroviruses that have integrated into our ancestral genomes over millions of years. They now occupy about 8% of our genome, and most of these elements have been mutated or truncated to not code for any proteins. However, there are a handful of these ERV sequences that are still able to code for proteins. We focused on the envelope, which is the viral protein that is used to enter whole cells, and we wanted to see if people make antibodies to these envelope proteins. We found that people in general, even healthy people, make antibodies to these ERV envelope proteins. In patients with lupus, these antibodies were found to be toxic in that when they bind to white blood cells, they stimulate the release of inflammatory factors that are implicated in lupus disease pathogenesis.

What does this discovery mean for the future of SLE with regard to pharmacogenetics and genetics?

Dr Iwasaki: What our research showed is that patients with lupus generate antibody responses against these ERV envelope proteins that can trigger inflammatory responses. For pharmacogenetics and genetics, it means that in the future, we need to account for autoreactive antibodies against the ERV envelope as part of the equation of lupus pathogenesis. If we can interfere with that process in some way, that might provide us with a path toward therapy for these patients.

As you mentioned, these findings may have the potential to spur the development of new treatment options for SLE. Theoretically, could the expression of ERVs or their ability to produce B cells be pharmacologically targeted?

Dr Iwasaki: Yes, our hope is to find inhibitors that can prevent the development of these types of autoantibodies against the envelope, or we can think about targeting such antibodies through either inhibitors or antibodies. There are many ways one can imagine tackling the toxic antibodies that are generated in these patients. We could also target the downstream effects of the antibodies, such as neutrophil activation. That may be one way in which our insights can help develop new therapeutics.

To your previous point, the autoantibody complexes stimulate the neutrophils to release neutrophil extracellular traps (NETs), which contributes to inflammation in SLE; this almost acts as a positive feedback loop. Is there a part of the loop that acts more as a main driver than the other? Which part of the loop theoretically could make more sense to target from a pharmacologic perspective, and could different parts of this loop be targeted simultaneously, thus further reducing the damage from SLE?

Dr Iwasaki: The NETs that are released from the neutrophils are quite toxic because they contain a lot of factors that can stimulate other immune cells and even cause blood clots or other issues when they are released inside blood vessels. There is a highly inflammatory cascade that can be engaged by NET release. Targeting neutrophils and preventing NET release, as well as potentially degrading the NETS once they are formed by enzymes, can destroy components of these NETs. These are some of the hypotheses that we can test in in vitro or in vivo animal models to observe whether targeting NETs can have a positive impact on the disease. However, it does not explain the entirety of lupus because lupus is a very heterogeneous disease. Some people might be experiencing antibody responses, while others might be experiencing too many interferon responses that are engaging with other pathways. We first need to identify whom among these patients with lupus might benefit the most from targeting these pathways and then test the pharmacologic agents that can target the key driver of this disease.

From a patient characteristics perspective, more than 90% of people with SLE are women, and the condition is most often diagnosed during childbearing years, typically ages 15 to 45 years. Black Americans, Hispanic individuals, Asian Americans, and Native Americans are at 2- to 3-times greater risk than White Americans of developing SLE. Was the expression of human ERVs that affect organ damage in SLE and the rate of experiencing SLE consistent across these patient populations?

Dr Iwasaki: That is an excellent question. A vast majority of our patients were also female, so it was not even possible to do a male-to-female comparison. With respect to other potential racial or ethnic differences and demographic differences, we did look at some of these issues; however, because our number was limited, we could not really observe any significant differences among people of different racial or ethnic backgrounds. That would require a much larger study.

The ERV map used in this study also led to similar discoveries in the underlying mechanisms of breast cancer.5 Do you think the ERV map has the potential to uncover the mechanisms of other rheumatic diseases?

Dr Iwasaki: We really hope so. We want people to use this ERV map. It is publicly available, and it gives us a tool to dissect the role of different ERV genes that are inside of our human genome in a variety of different settings including not only rheumatic diseases but also cancer, newer degenerative diseases, and even aging.

We are currently applying a similar type of immune profile to look at patients with long COVID-19 syndrome. As with lupus, long COVID-19 occurs more frequently in women of childbearing age. Some reports demonstrate that lupus-related autoantibodies are elevated during the acute phase of COVID-19 in people who go on to develop long COVID-19. We feel that there may be some link between lupus and long COVID-19, and we are excited to figure out whether that link may involve antibodies to ERVs.

References

1. Justiz Vaillant AA, Goyal A, Varacallo M. Systemic lupus erythematosus. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 30571026

2. Steiman AJ, Urowitz MB, Ibañez D, Papneja A, Gladman DD. Prolonged remission in systemic lupus erythematosus. J Rheumatol. 2014;41:1808-1816. doi:10.3899/jrheum.131137

3. Golder V, Tsang-A-Sjoe MWP. Treatment targets in SLE: remission and low disease activity state. Rheumatology. 2020;59(suppl 5):v19-v28. doi:10.1093/rheumatology/keaa420

4. Iwasaki A, Tokuyama M, Gunn BM, Venkataraman A, et al. Antibodies against human endogenous retrovirus K102 envelope activate neutrophils in systemic lupus erythematosus. J Exp Med. 2021;218(7):e20191766. doi:10.1084/jem.20191766

5. Tokuyama M, Kong Y, Song E, Jayewickreme T, Kang I, Iwasaki A. ERVmap analysis reveals genome-wide transcription ofhuman endogenous retroviruses. Proc Natl Acad Sci U S A. 2018;115(50):12565-12572. doi:10.1073/pnas.1814589115