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Download PDF Download PDF Review Article Open access Published: 17 March 2025 Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics Xiaofeng Dai, Yuting Fan & Xing Zhao Signal Transduction and Targeted Therapy volume 10, Article number: 102 (2025) Cite this article

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Abstract Systemic lupus erythematosus (SLE) is a chronic inflammatory illness with heterogeneous clinical manifestations covering multiple organs.Stimulated Th cells activate B cells and contribute to their differentiation through clusters of differentiation 40 ligand (CD40L)/CD40 interactions.32 Activated B cells move to germinal centers (GCs) with the help of Tfh cells and follicular dendritic cells (DCs), where B cells generating antibodies with high antigen affinity are expanded and differentiate into the memory B cells (MBC) and antibody-producing PCs.33

Over-production of immunoactivating materials Interferons (IFNs) are cytokines with pleiotropic roles in immune regulation that can be categorized into type I, II, and III based on sequence homology.34 Type I IFNs represent the largest IFN family comprised of IFN?, IFN?, IFN?, IFN?, and IFN?; the type II family includes solely IFN?; and the type III family contains IFN?1, IFN?2, IFN?3, and IFN?4.35 Out of the three families of IFNs, type I IFNs play an immunomodulatory role that bridges the gap between the innate and adaptive immune systems.35 That is, the expression of type I IFNs is activated on the trigger of nucleic acids via intracellular pathways such as Toll-like receptor (TLR)-mediated signaling; the binding of type I IFNs to their receptors activates the intracellular signaling cascade involving the Janus kinase-signal transducer and activator of transcription (JAK/STAT) axis that leads to stimulated effectors of the innate and adaptive systems.35,36,37

There has been a well-established positive association between type I IFNs and SLE.Specifically, the blood levels of type I IFNs were documented to be elevated in approximately 50% of SLE patients.38 An even greater percentage of SLE patients were estimated to carry over-represented expression of genes involved in type I IFN-mediated signaling in their peripheral blood cells.39,40

Type I IFNs are generated in response to, primarily, the activation of nucleic acid-binding pattern recognition receptors such as the endosomal TLR3/4/7/9, the cytosolic sensor cyclic guanosine monophosphate-adenosine monophosphate (cGMP-AMP) synthase (cGAS), and the ribonucleic acid (RNA)-sensor retinoic acid-inducible gene (RIG) I like receptors (RLRs)-mitochondreal antiviral signaling protein (MAVS).41 These nucleic-acid sensing pathways are chronically over-activated in many SLE patients, with the pathogenesis roles of TLR7 in SLE being well-established.42 For instance, over-activation of the cGAS-stimulator of IFN genes (STING) pathway has been shown to be crucial in autoimmunity and SLE pathogenesis.40,43

In addition, events altering nucleic acid metabolism may also trigger type I IFNs production, where the essential roles of cytosolic nucleic acid sensors played in SLE have been well characterized.44,45 For instance, ultraviolet (UV) light exposure has been shown capable of enhancing type I IFNs response both locally and systemically, with the evidence being obtained from both the animal model and from the clinics46 (Fig.Asian have a lower regional risk of developing SLE than people from the United States,21,22 but the prevalence of SLE among people carrying the Chinese background has been reported to be increasing.23 Such ethnic differences among SLE patients may be explained by their different socioeconomic backgrounds, distinct perceptions on the condition, varied risks of getting infection or developing comorbidities especially cerebrovascular diseases, imbalanced availability of the medical resources, and non-uniform adherence to the therapeutics.3,16,17,24

SLE pathogenesis by mechanisms-of-action SLE is characteristic of increased presentation of autoantibodies such as ANA, anti-Sm, anti-double-stranded DNA (anti-dsDNA) antibody, antiphospholipid (aPL) antibodies, and anti-?2-glycoprotein (a?2GPI) antibodies,1 which even occur years prior to the clinical onset of SLE.25 Being the primary effectors of SLE inflammation and associated damage,26 autoantibodies form immune complexes (ICs) and deposit on multiple organs such as kidney, skin and central nervous system to induce local inflammation.26,27 Antibodies are produced by plasma cells (PCs) and plasmablasts, the terminally differentiated B cells.28 As the precursors of PCs and important antigen-presenting cells (APCs),29,30 B cells loose tolerance to autoantigens31 and may present them to T cells in SLE patients followed by the activation of Th cells.Adaptive immunity Rheumatic diseases Autoimmune Mechanisms in Systemic Lupus Erythematosus Introduction Systemic lupus erythematosus (SLE), canonically defined as an auto-immune disorder, can be considered as a chronic inflammatory illness with clinical manifestations encompassing various organs such as the blood vessels, brain, lungs, skin, kidneys and joints due to polymorphic biological alterations.1 It affects approximately 3.4 million people worldwide, with 400,000 individuals being newly diagnosed each year.2,3 It most commonly occurs among women between puberty and menopause,4 and individuals of the African origin have a higher risk of developing SLE.5,6,7 According to a 2023 global epidemiology study of SLE, Poland, the United States, Barbados, and China showed the highest SLE incidence.2 Though still with an unclear disease of origin, the chance of developing SLE is believed to be associated with genetic factors, epigenetic factors, environmental triggers, and hormonal factors.8

SLE can be diagnosed from the perspectives of disease onset and disease activity.The neoclassical period is characterized by 'SLE manifestions, therapeutics, and identification of the inductive role of some medications on SLE', with representative events being 'documentation of SLE with illustrations as a butterfly rash by Ferdinand Hebra', 'identification of the photosensitive nature of SLE by Jonathon Hutchison', 'definition of the two forms of SLE, i.e., discoid and disseminated SLE by Mariz Kaposi', 'use of quinine b Payne and use of adrenocorticotropic hormone (ACTH) and cortisone by Philip S. Hency', 'use of hydrocortisone by Sulzberger and Witten', and 'identificaton of the inductive role of sulfonamides on SLE'.Following the introduction of some basic knowledge of SLE including the history and epidemiology, this review characterized three key determinants of SLE pathogenesis by their mechanisms-of-action, i.e., over-activated immune response, skewed cytokine microenvironment homeostasis, impaired debris clearance machinery; summarized current understandings on SLE diagnosis by disease onset, activity and comorbidity; introduced risk factors predisposing SLE at the genetic, epigenetic, hormonal and entrinsic levels; and classified current SLE preventive strategies and therapeutics by the identified working mechanisms.In summary, we proposed three mechanisms with determinant roles on SLE initiation and progression, i.e., attenuating the immune system, restoring the cytokine microenvironment homeostasis, and rescuing the impaired debris clearance machinery; and provided updated insights on current understandings of SLE regarding its pathogenesis, diagnosis, prevention and therapeutics, which may open an innovative avenue in the fields of SLE management.Complexities regarding SLE therapeutics render it essential and urgent to identify the mechanisms-of-action and pivotal signaling axis driving SLE pathogenesis, and to establish innovative SLE-targeting approaches with desirable therapeutic outcome and safety.Fig.1 Fig. 1). 1).1).

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Review Article
Open access
Published: 17 March 2025
Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics
Xiaofeng Dai, Yuting Fan & Xing Zhao
Signal Transduction and Targeted Therapy volume 10, Article number: 102 (2025) Cite this article

Save article
View saved research
195k Accesses

268 Citations

91 Altmetric

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Abstract
Systemic lupus erythematosus (SLE) is a chronic inflammatory illness with heterogeneous clinical manifestations covering multiple organs. Diversified types of medications have been shown effective for alleviating SLE syndromes, ranging from cytokines, antibodies, hormones, molecular inhibitors or antagonists, to cell transfusion. Drugs developed for treating other diseases may benefit SLE patients, and agents established as SLE therapeutics may be SLE-inductive. Complexities regarding SLE therapeutics render it essential and urgent to identify the mechanisms-of-action and pivotal signaling axis driving SLE pathogenesis, and to establish innovative SLE-targeting approaches with desirable therapeutic outcome and safety. After introducing the research history of SLE and its epidemiology, we categorized primary determinants driving SLE pathogenesis by their mechanisms; combed through current knowledge on SLE diagnosis and grouped them by disease onset, activity and comorbidity; introduced the genetic, epigenetic, hormonal and environmental factors predisposing SLE; and comprehensively categorized preventive strategies and available SLE therapeutics according to their functioning mechanisms. In summary, we proposed three mechanisms with determinant roles on SLE initiation and progression, i.e., attenuating the immune system, restoring the cytokine microenvironment homeostasis, and rescuing the impaired debris clearance machinery; and provided updated insights on current understandings of SLE regarding its pathogenesis, diagnosis, prevention and therapeutics, which may open an innovative avenue in the fields of SLE management.

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Adaptive immunity
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Autoimmune Mechanisms in Systemic Lupus Erythematosus
Introduction
Systemic lupus erythematosus (SLE), canonically defined as an auto-immune disorder, can be considered as a chronic inflammatory illness with clinical manifestations encompassing various organs such as the blood vessels, brain, lungs, skin, kidneys and joints due to polymorphic biological alterations.1 It affects approximately 3.4 million people worldwide, with 400,000 individuals being newly diagnosed each year.2,3 It most commonly occurs among women between puberty and menopause,4 and individuals of the African origin have a higher risk of developing SLE.5,6,7 According to a 2023 global epidemiology study of SLE, Poland, the United States, Barbados, and China showed the highest SLE incidence.2 Though still with an unclear disease of origin, the chance of developing SLE is believed to be associated with genetic factors, epigenetic factors, environmental triggers, and hormonal factors.8

SLE can be diagnosed from the perspectives of disease onset and disease activity. These can be assessed using varied types of evaluation metrics such as the American College of Rheumatology (ACR) criteria and the SLE Disease Activity Index (SLEDAI). Besides, SLE is typically accompanied with increased risks of developing multiple types of comorbidities, with cancer screening being recommended by the European League Against Rheumatism (EULAR)9 and cerebrovascular disease being alarmed among female SLE patients by the American Heart Association.10

SLE is caused by an autoimmune reaction involving both the innate and adaptive immune systems, where an abnormal immune response is directed to nucleic acid-containing cellular particles. The over production of antibodies targeting these nucleic acids, known as antinuclear antibodies (ANAs), is characteristic of SLE.8 Besides, the anti-Smith (anti-Sm) antibody, which is an auto-antibody directed against a component of the spliceosome, is highly specific to SLE, with 20-40% SLE patients versus approximately 1% healthy individuals carrying them.11

Various types of agents have been used for SLE therapeutics, ranging from cytokines, antibodies, hormones, inhibitors, antagonists, to the transfusion of fresh plasma and stem cells. Importantly, while several drugs initially designed for treating other pathological conditions have been shown effective in treating SLE such as the use of the anti-malaria agent hydroxychloroquine as a SLE therapeutic, a plethora of medications have been reported capable of inducing SLE. Examples of this kind include anti-arrhythmic agents such as procainamide, broadspectrum antibiotics such as minocycline, vasodilators such as hydralazine and methyldopa, and antipsychotics such as chlorpromazine. These have unanimously complicated our understandings on the appropriate therapeutics of SLE, rendering it necessary and urgent to delve into the molecular mechanisms driving SLE pathogenesis and classify current therapeutics accordingly by their mechanisms-of-action. This may guide us towards effective management of SLE and, hopefully, help us identify the pivotal signaling axis for the establishment of innovative targeting strategies.

Following the introduction of some basic knowledge of SLE including the history and epidemiology, this review characterized three key determinants of SLE pathogenesis by their mechanisms-of-action, i.e., over-activated immune response, skewed cytokine microenvironment homeostasis, impaired debris clearance machinery; summarized current understandings on SLE diagnosis by disease onset, activity and comorbidity; introduced risk factors predisposing SLE at the genetic, epigenetic, hormonal and entrinsic levels; and classified current SLE preventive strategies and therapeutics by the identified working mechanisms. Our review not only provides comprehensive information on SLE so far available, but also proposes fresh insights on our current understandings of SLE, with a focus on its prevention and therapeutics.

Basics of SLE
Research history of SLE
The history of SLE can be dated back to 400 Before Christ (BC) and divided into three periods, i.e., the classical period, the neoclassical period, and the modern period. The classical period, cornerstoned by Hipocrates who firstly described the possible ulcers of SLE as herpes esthiomenos, identified and documented SLE as a cutaneous disorder.12 The neoclassical period witnessed the manifestations and therapeutics of SLE. During this period, Ferdinand Hebra reported the facial rash associated with SLE as a butterfly rash with illustrations; and Jonathon Hutchison noted the photosensitive nature of SLE, among other milestones. Regarding SLE therapeutics, quinine was firstly used by the Physician Payne, followed by the use of adrenocorticotropic hormone and cortisone by the physician Philip S Hency, and later hydrocortisone by Sulzberger and Witten. In addition, the inductive role of medications such as sulfonamides on SLE was found during this period.12 The modern era was heralded by the discovery of the lupus erythematosus (LE) cell (a bone marrow phenomenon involving the phagocytosis of nuclear material by polymorphonuclear leukocytes) and characterized by rapid scientific advances over the past 60 years. Before the discovery of LE cell by Hargraves in 1948, the Wasserman test for syphilis was used for SLE diagnosis. The use of immunofluorescence for ANA detection followed. The establishment of the murine models has substantially advanced the scientific field related to SLE, leading to the discovery of the genetic predisposition of SLE by Leonhardt and the familial association of SLE by Arnett and Shulman of Johns Hopkins.12 Thanks to the contributions of these scientists made along the history of SLE researches, the lifespan of SLE patients has now been extensively extended from no longer than 5 years after the initial diagnosis to living with illness12 (Fig. 1).

Fig. 1
Fig. 1
Full size image
History and etiological features of SLE. The history of SLE studies is divided into three periods, i.e., classical period, neoclassical period, modern period. The classical period is characterized by ‘SLE description’, with critical events being ‘description of SLE as herpes esthiomenos by Hipocrates’, ‘description of SLE as noli me tangere by Rogerius Grugardi & Rolando of Parma’, ‘confusion of SLE with tuberculosis by Erasmus Wilson’, ‘description of SLE as skin disorders by Robert Willan’, and ‘differentiation of SLE from other diseases by Willan’. The neoclassical period is characterized by ‘SLE manifestions, therapeutics, and identification of the inductive role of some medications on SLE’, with representative events being ‘documentation of SLE with illustrations as a butterfly rash by Ferdinand Hebra’, ‘identification of the photosensitive nature of SLE by Jonathon Hutchison’, ‘definition of the two forms of SLE, i.e., discoid and disseminated SLE by Mariz Kaposi’, ‘use of quinine b Payne and use of adrenocorticotropic hormone (ACTH) and cortisone by Philip S. Hency’, ‘use of hydrocortisone by Sulzberger and Witten’, and ‘identificaton of the inductive role of sulfonamides on SLE’. The modern period is characterized by ‘SLE diagnosis and establishment of murine model’, with milestone events being ‘discovery of lupus erythematosus (LE) cell by Hargraves’, ‘use of immunofluorescence for antinuclear antibody (ANA) detection’, ‘use of immunofluorescent microscopy for diagnosis’, and ‘establishment of murine model’, where following murine model establishment, the genetic predisposition and familial occurrence of SLE were consecutively recognized

Epidemiology of SLE
SLE is a heterogeneous disease occurring frequently among women and least common among children.8 SLE most commonly afflicts women between puberty and menopause,13 where the female/male ratio shifts from 3/1 in children to about 9/1 or even 15/1 among adults between puberty and menopause14,15 (Fig. 1).

SLE is associated with an increased risk of premature mortality that has improved over the past 30 years,16 and the risk conveys an ethnic-dependent difference.15,17 The development of lupus nephritis (LN), a SLE-associated renal complication, is considered a strong predictor of an increased mortality risk. SLE patients of African, Chinese and Hispanic origins have shown an increased risk of developing LN18,19 and thus enhanced mortality.18,19,20 Besides mortality, the disease incidence, prevalence, age-of-onset, and morbidity of SLE also vary greatly among regions.17 For instance, the annual incidence and prevalence rates of SLE in the United States each varies from 2 to 7.6 and from 19 to 159 per 100 000 individuals, respectively, for people of different racial backgrounds.5,6 In particular, individuals of the African origin, particularly those who have migrated to America or Europe, exhibit a higher incidence and prevalence, earlier age at the disease-of-onset as compared with those of the north European origin5,6,7 (Fig. 1). Asian have a lower regional risk of developing SLE than people from the United States,21,22 but the prevalence of SLE among people carrying the Chinese background has been reported to be increasing.23 Such ethnic differences among SLE patients may be explained by their different socioeconomic backgrounds, distinct perceptions on the condition, varied risks of getting infection or developing comorbidities especially cerebrovascular diseases, imbalanced availability of the medical resources, and non-uniform adherence to the therapeutics.3,16,17,24

SLE pathogenesis by mechanisms-of-action
SLE is characteristic of increased presentation of autoantibodies such as ANA, anti-Sm, anti-double-stranded DNA (anti-dsDNA) antibody, antiphospholipid (aPL) antibodies, and anti-β2-glycoprotein (aβ2GPI) antibodies,1 which even occur years prior to the clinical onset of SLE.25 Being the primary effectors of SLE inflammation and associated damage,26 autoantibodies form immune complexes (ICs) and deposit on multiple organs such as kidney, skin and central nervous system to induce local inflammation.26,27 Antibodies are produced by plasma cells (PCs) and plasmablasts, the terminally differentiated B cells.28 As the precursors of PCs and important antigen-presenting cells (APCs),29,30 B cells loose tolerance to autoantigens31 and may present them to T cells in SLE patients followed by the activation of Th cells. Stimulated Th cells activate B cells and contribute to their differentiation through clusters of differentiation 40 ligand (CD40L)/CD40 interactions.32 Activated B cells move to germinal centers (GCs) with the help of Tfh cells and follicular dendritic cells (DCs), where B cells generating antibodies with high antigen affinity are expanded and differentiate into the memory B cells (MBC) and antibody-producing PCs.33

Over-production of immunoactivating materials
Interferons (IFNs) are cytokines with pleiotropic roles in immune regulation that can be categorized into type I, II, and III based on sequence homology.34 Type I IFNs represent the largest IFN family comprised of IFNα, IFNβ, IFNω, IFNκ, and IFNε; the type II family includes solely IFNγ; and the type III family contains IFNλ1, IFNλ2, IFNλ3, and IFNλ4.35 Out of the three families of IFNs, type I IFNs play an immunomodulatory role that bridges the gap between the innate and adaptive immune systems.35 That is, the expression of type I IFNs is activated on the trigger of nucleic acids via intracellular pathways such as Toll-like receptor (TLR)-mediated signaling; the binding of type I IFNs to their receptors activates the intracellular signaling cascade involving the Janus kinase-signal transducer and activator of transcription (JAK/STAT) axis that leads to stimulated effectors of the innate and adaptive systems.35,36,37

There has been a well-established positive association between type I IFNs and SLE. Specifically, the blood levels of type I IFNs were documented to be elevated in approximately 50% of SLE patients.38 An even greater percentage of SLE patients were estimated to carry over-represented expression of genes involved in type I IFN-mediated signaling in their peripheral blood cells.39,40

Type I IFNs are generated in response to, primarily, the activation of nucleic acid-binding pattern recognition receptors such as the endosomal TLR3/4/7/9, the cytosolic sensor cyclic guanosine monophosphate-adenosine monophosphate (cGMP-AMP) synthase (cGAS), and the ribonucleic acid (RNA)-sensor retinoic acid-inducible gene (RIG) I like receptors (RLRs)-mitochondreal antiviral signaling protein (MAVS).41 These nucleic-acid sensing pathways are chronically over-activated in many SLE patients, with the pathogenesis roles of TLR7 in SLE being well-established.42 For instance, over-activation of the cGAS-stimulator of IFN genes (STING) pathway has been shown to be crucial in autoimmunity and SLE pathogenesis.40,43

In addition, events altering nucleic acid metabolism may also trigger type I IFNs production, where the essential roles of cytosolic nucleic acid sensors played in SLE have been well characterized.44,45 For instance, ultraviolet (UV) light exposure has been shown capable of enhancing type I IFNs response both locally and systemically, with the evidence being obtained from both the animal model and from the clinics46 (Fig.