|Year : 2022 | Volume
| Issue : 1 | Page : 1-3
Which came first in lupus: The interferon or the infection?
TG Sundaram1, Sakir Ahmed2
1 Department of Clinical Immunology and Rheumatology, King George Medical University, Lucknow, Uttar Pradesh, India
2 Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India
|Date of Submission||01-Mar-2022|
|Date of Acceptance||09-Mar-2022|
|Date of Web Publication||14-Mar-2022|
Dr. Sakir Ahmed
Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar - 751 024, Odisha
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Sundaram T G, Ahmed S. Which came first in lupus: The interferon or the infection?. Indian J Rheumatol 2022;17:1-3
Infections are a leading cause of morbidity and mortality in systemic lupus erythematosus (SLE). It was shown in a Hungarian lupus cohort that the excess mortality due to lupus could be attributable to infections. This issue covers a lupus cohort from Mumbai that looked at the spectrum of infection and their predisposing factors. In the 100 patients, there were 54 infections: 35.2% were bacterial infections, 20.4% were viral, 16.7% fungal, and 11.1% were mycobacterial. Although this cohort has a relatively lesser number of patients with viral infections, the proportion of mycobacterial infections is higher. This is relevant since susceptibility to both viral as well as mycobacterial infections have some common factors such as the JAK‒STAT-interferon (IFN) pathways and the interleukin (IL)-12/23 pathways.
In this cohort, the use of immunosuppression, particularly moderate to high-dose prednisolone and cyclophosphamide was significantly associated with infections. Here, again disease activity is a confounding factor although SLEDAI (SLE Disease Activity Index) did not show significant correlations with infections. This may be since diagnosis and time on medications were not analyzed using survival analysis such as Cox regression modeling. Higher doses of steroids, cyclophosphamide, and rituximab use are associated with a higher risk for infections in lupus.
Lupus per se also is a risk factor for infections, independent of immunosuppression. Again, there is evidence that lupus might be precipitated or even flared by viral illnesses including Epstein‒Barr virus, cytomegalovirus (CMV), and even the novel coronavirus 2019 (SARS-CoV-2). The role of endogenous retroviruses in the pathogenesis of lupus has been debated over the past three decades. Rarely, SLE can be associated with infections, which mimic a disease flare, such as CMV, tuberculosis, and histoplasmosis. Understanding the nitty-gritty of the complex relationship between lupus and infection can help us manage this enigmatic disease better.
Lupus is associated with varied aberrations in innate and adaptive immunity that may predispose to infections. These include defects of both innate and acquired immunity. The most well-characterized are deficiencies in the early components of the complement pathways, namely C1q, C1r, C1s, C4, C2, and C3. Complement deficiencies lead to defective opsonization and removal of apoptotic debris and immune complexes, which are key mechanisms for the generation of autoantibodies and Type 1 IFNs. They also predispose to Gram-negative infections. Second, lupus patients have been shown to have impaired phagocytic activity of polymorphonuclear cells independent of immunosuppressant use. Third natural killer cells have impaired functioning in lupus, including a reduced response to IL-2.
In the acquired immunity arm, the role of IFN in lupus is well known. Higher concentration of Type 1 IFN can lead to IL-10 production and block B-cell responses to bacteria. Furthermore, Type 1 IFN responses can be detrimental for intracellular bacteria like mycobacteria and Listeria spp. Even for viral infections, both Type I and Type II IFN responses have been shown to have antiviral as well as antagonistic immunoregulatory functions during infection.
There are new causes of monogenic SLE which are being recently recognized like protein kinase C-δ deficiency that can cause B-cell deficiency and autoimmunity like lupus. In addition, many SLE susceptibility genes such as TYK2, TNFAIP3, and IRAK1 have been implicated in primary immunodeficiencies as well. Even though they are not yet proven to cause overt immunodeficiency with SLE, they might confer an increased risk of infections. Some studies have shown lymphopenia, which is an integral part of SLE, to be an independent risk factor for infections, whereas others have not. SLE has also been shown to cause reduced production of IL-2 from CD4+ T cells, which apart from inhibiting the development of regulatory T cells, but also that of cytotoxic T cells. Often lupus is not the effect of monogenic defect but an amalgamation of tiny aberrations spread over a number of genes that are activated by various environmental triggers. It is likely that all these defects also have a synergistic effect on susceptibility to infections [Figure 1].
|Figure 1: Proposed mechanisms of inherent infection susceptibility in systemic lupus erythematosus|
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Thus, infections in lupus may provide a unique perspective to study the myriad immunological pathways in this perplexing disease. This can help specialized targeted therapies in future. Combining multiomics approaches such as viromics and metagenomics with genomics and transcriptomics has the potential to unravel this intricate tapestry.
| References|| |
Kedves M, Kósa F, Kunovszki P, Takács P, Szabó MZ, Karyekar C, et al.
Large-scale mortality gap between SLE and control population is associated with increased infection-related mortality in lupus. Rheumatology (Oxford) 2020;59:3443-51.
Danza A, Ruiz-Irastorza G. Infection risk in systemic lupus erythematosus patients: Susceptibility factors and preventive strategies. Lupus 2013;22:1286-94.
Barber MR, Clarke AE. Systemic lupus erythematosus and risk of infection. Expert Rev Clin Immunol 2020;16:527-38.
Doaty S, Agrawal H, Bauer E, Furst DE. Infection and lupus: Which causes which? Curr Rheumatol Rep 2016;18:13.
Bonometti R, Sacchi MC, Stobbione P, Lauritano EC, Tamiazzo S, Marchegiani A, et al.
The first case of Systemic Lupus Erythematosus (SLE) triggered by COVID-19 infection. Eur Rev Med Pharmacol Sci 2020;24:9695-7.
Shukla A. Infections mimicking difficult-to-treat systemic lupus erythematosus. Indian J Rheumatol 2021;16:93. [Full text]
Truedsson L, Bengtsson AA, Sturfelt G. Complement deficiencies and systemic lupus erythematosus. Autoimmunity 2007;40:560-6.
Wu SA, Yeh KW, Lee WI, Yao TC, Kuo ML, Huang B, et al.
Impaired phagocytosis and susceptibility to infection in pediatric-onset systemic lupus erythematosus. Lupus 2013;22:279-88.
Spada R, Rojas JM, Barber DF. Recent findings on the role of natural killer cells in the pathogenesis of systemic lupus erythematosus. J Leukoc Biol 2015;98:479-87.
McNab F, Mayer-Barber K, Sher A, Wack A, O'Garra A. Type I interferons in infectious disease. Nat Rev Immunol 2015;15:87-103.
Lee AJ, Ashkar AA. The dual nature of type I and type II interferons. Front Immunol 2018;9:2061.
Alperin JM, Ortiz-Fernández L, Sawalha AH. Monogenic lupus: A developing paradigm of disease. Front Immunol 2018;9:2496.
Salzer E, Santos-Valente E, Klaver S, Ban SA, Emminger W, Prengemann NK, et al.
B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ. Blood 2013;121:3112-6.
Sawada T, Fujimori D, Yamamoto Y. Systemic lupus erythematosus and immunodeficiency. Immunol Med 2019;42:1-9.
Ng WL, Chu CM, Wu AK, Cheng VC, Yuen KY. Lymphopenia at presentation is associated with increased risk of infections in patients with systemic lupus erythematosus. QJM 2006;99:37-47.
Comte D, Karampetsou MP, Kis-Toth K, Yoshida N, Bradley SJ, Kyttaris VC, et al.
Brief report: CD4+ T Cells from patients with systemic lupus erythematosus respond poorly to exogenous interleukin-2. Arthritis Rheumatol 2017;69:808-13.
Ahmed S. A hypothetical future in rheumatology: Will we miss steroids in a steroid free-world? Rheumatol Int 2021;41:1369-70.