By Le Xiong
With the global prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), coronavirus disease 2019 (COVID-19) has affected the lives of billions of people and caused millions of deaths worldwide [1]. How to tame COVID-19 into submission remains quite challenging. But as the old saying goes: all roads lead to Rome, different diseases could share similar pathogenic processes.
Surprisingly, immune responses during SARS-Cov-2 infection largely resemble that in Systemic Lupus Erythematosus (SLE), an autoimmune disease [2]. SLE is characterized by the production of “autoantibodies”, which are antibodies the body produces against its own antigens and the deposition of immune complexes in different tissues. The majority of SLE patients have arthritis, skin rash, and/or serositis, glomerulonephritis, among many other manifestations. As of yet, there is no cure for SLE, so patients need to take regular immunosuppressive drugs such as tacrolimus which works by inhibiting T cell activation and some are burdened with chronic organ damage. The use of immunosuppressants, tacrolimus, for example, has been shown to be associated with better survival among hospitalized COVID-19 patients [3], suggesting the beneficial effects of SLE-related treatments on COVID-19 patients. So, could there be similarities between COVID-19 and SLE, that would help researchers to look at COVID-19 treatments in another light?
SLE-like symptoms following COVID-19
The progression of SARS-CoV-2 infection and whether it is remains in the upper respiratory airway or migrates down to the lung alveoli determines the clinical manifestations or outcomes of COVID-19. Most COVID-19 patients are asymptomatic or have only mild symptoms like fever, fatigue, and dry cough. However, some patients (nearly 20%) have progressed SARS-CoV-2 infections in the alveolar epithelium, which further triggers strong immune responses, causing severe symptoms like acute respiratory distress syndrome (ARDS) and respiratory failure [4].
Interestingly, autoantibodies associated with SLE can be detected in severe COVID-19 patients. These autoantibodies could be associated with poor prognosis and/or thrombosis. In addition, some patients develop SLE-like symptoms, including a reduced number of red blood cells and platelets, as well as positive antinuclear antibodies in the blood [5]. These clinical observations suggest that it is necessary to investigate the similar immunopathogenesis in SLE and COVID-19, which could potentially help us to explore effective medications to better treat COVID-19 patients.
Convergent immunopathology
The immunopathogenic similarities between COVID-19 and SLE involve both innate and adaptive immune responses. Certain immune and non-immune cells produce cytokines, which are small proteins and work as messengers to boost or suppress relevant immune responses. COVID-19 infection is often accompanied by an aggressive inflammatory response, with the release of a large amount of pro-inflammatory cytokines in an event known as cytokine storm [6]. Interferons (IFNs) are important cytokines that help the body fight against viral infection. During SARS-CoV-2 infection, dysregulated antiviral responses of type Ⅰ interferon lead to massive infiltration of innate immune cells which, produce cytokines among which are IL-1β, IL-6, and TNF-α. These cytokines induce pro-inflammatory responses against invaded pathogens [7]. Cytokine storms can self-amplify and afterward cause damage in lung epithelial and endothelial cells. Fluids are then leaked to the lungs, leading to shortness of breath, low levels of oxygen, and ARDS [8]. Comparably, self-antigens in SLE patients also activate innate immune responses. Macrophage-associated syndrome (MAS) presents as a serious complication of lupus. Cytokine storm is a central signature of MAS. IFN-γ-activated macrophages produce inflammatory cytokines, which in turn promote cytotoxic T cells and natural killer (NK) cells to generate excessive IFN-γ and to cause tissue damage [9].
Similar adaptive immune responses are observed in both COVID-19 and SLE. B cells are famous for their role in producing antibodies. Patients with severe COVID-19 showed activation of what is known as extrafollicular (EF) B cells, which also feature B cell responses in SLE patients [11]. Expansion of this B cell population in SLE correlates with higher disease activity of SLE and poorer prognosis; this expansion in severe COVID-19 is associated with class-switched antibody-secreting cell proliferation, increased level of anti-SARS-CoV-2 antibodies, and unfavorable clinical outcomes [12].
SLE-related treatments showing success for COVID-19
Considering the overlapped immunopathogenesis, medications used in SLE would be an interesting option to treat COVID-19. Hydroxychloroquine (HCQ) is a first-line immunomodulator for SLE. Surprisingly, this drug received a lot of media attention during the early phase of the pandemic and has been identified to have anti-viral action in vitro [13]. However, retrospective studies and clinical trials about the effects of HCQ on reducing COVID-19 incidence and mortality have been disappointing [14]. Functioning as an immunosuppressive agent, however, another drug, Baricitinib, has been reported to potentially control active SLE in previous clinical trials [15]. Baricitinib is proposed to improve inflammatory conditions like cytokine storms also in COVID-19 patients by blocking cytokine signaling and therefore reducing their hospitalization rates [16]. Tocilizumab, which targets receptors of IL-6, an important cytokine during cytokine storm, and has been reported to improve clinical parameters among SLE patients, is now used to treat certain hospitalized COVID-19 patients [17, 18]. However, considering the strong immunosuppressive effects of these drugs, when and how we can use these SLE-related medications to treat COVID-19 patients in a safe and effective way, will continue to need further clinical validations.
In summary
COVID-19 pandemic has become a public healthcare issue worldwide and attention on its impact on patients with autoimmune diseases such as SLE has also been important. COVID-19 and SLE have immunopathogenic mechanisms in common, including autoantibody generation, activated extrafollicular B cell responses, and cytokine storms. Based on the similarities of SLE and COVID-19 in clinical manifestation and immunopathology, the existing treatment options for patients with SLE are already also providing novel insights into exploring effective strategies for COVID-19.
Sincere thanks to Prof. dr. Alexandre Voskuyl for professional instructions on this article.
About the writer
Le Xiong is a second-year Biomedical Sciences master student at VU who studies immunology and infectious diseases. Le Xiong has special interests in immunology, especially in autoimmunity.
Further reading
1. World Health Organization. Coronavirus disease (COVID‐2019) situation reports. 2021 April 10, 2021]; Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports.
2. Spihlman, A.P., et al., COVID-19 and Systemic Lupus Erythematosus: Focus on Immune Response and Therapeutics. 2020. 11(2861).
3. Belli, L.S., et al., Protective Role of Tacrolimus, Deleterious Role of Age and Comorbidities in Liver Transplant Recipients With Covid-19: Results From the ELITA/ELTR Multi-center European Study. Gastroenterology, 2021. 160(4): p. 1151-1163.e3.
4. Hu, B., et al., Characteristics of SARS-CoV-2 and COVID-19. Nature Reviews Microbiology, 2021. 19(3): p. 141-154.
5. Zamani, B., S.-M. Moeini Taba, and M. Shayestehpour, Systemic lupus erythematosus manifestation following COVID-19: a case report. Journal of Medical Case Reports, 2021. 15(1): p. 29.
6. Ragab, D., et al., The COVID-19 Cytokine Storm; What We Know So Far. 2020. 11(1446).
7. Tang, Y., et al., Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies. Frontiers in Immunology, 2020. 11: p. 1708.
8. Channappanavar, R. and S. Perlman, Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Seminars in Immunopathology, 2017. 39(5): p. 529-539.
9. Schulert, G.S. and A.A. Grom, Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies. Annual review of medicine, 2015. 66: p. 145-159.
10. Castelli, V., A. Cimini, and C. Ferri, Cytokine Storm in COVID-19: “When You Come Out of the Storm, You Won’t Be the Same Person Who Walked in”. 2020. 11(2132).
11. Jenks, S.A., et al., Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus. Immunity, 2018. 49(4): p. 725-739.e6.
12. Woodruff, M.C., et al., Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Nature Immunology, 2020. 21(12): p. 1506-1516.
13. Fantini, J., et al., Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents, 2020. 55(5): p. 105960.
14. Spihlman, A.P., et al., COVID-19 and Systemic Lupus Erythematosus: Focus on Immune Response and Therapeutics. Front Immunol, 2020. 11: p. 589474.
15. Wallace, D.J., et al., Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet, 2018. 392(10143): p. 222-231.
16. Haberman, R., et al., Covid-19 in Immune-Mediated Inflammatory Diseases – Case Series from New York. N Engl J Med, 2020. 383(1): p. 85-88.
17. Illei, G.G., et al., Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum, 2010. 62(2): p. 542-52.
18. Angriman, F., et al., Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into context. Lancet Respir Med, 2021. 9(6): p. 655-664.