Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs, impacting approximately 3.41 million people worldwide1. SLE is characterized by autoantibody production and immune complex deposition, which may result in dysfunction or destruction of organs such as the joints, kidneys, lungs and heart2. Although the exact etiology of SLE is unclear, genetic predisposition and environmental factors are recognized as key contributors to its pathogenesis2. Cardiovascular involvement is one of the most common complications of SLE, being a major cause of morbidity and mortality3. In particular, lupus myocarditis is a severe manifestation, with a mortality rate of up to 23%4. Moreover, subclinical myocarditis has been identified in 30–60% of patients with SLE through autopsy studies, highlighting the significant risk of fatal cardiac events over their lifetime5. Despite its clinical importance, the underlying mechanisms driving lupus myocarditis remain poorly understood.

Autoantibodies are thought to play a significant role in lupus myocarditis, similar to their contribution to tissue damage in other organs, including the joints and kidneys, in SLE6. However, hallmark SLE autoantibodies primarily target nuclear antigens such as double-stranded DNA (dsDNA), Sjögren’s syndrome A (SSA), Sjögren’s Syndrome B (SSB), ribonucleoprotein (RNP) and Smith (Sm), which are ubiquitously expressed across all organs and cells rather than being specific to the heart7. T cells may also contribute to adaptive immunity underlying lupus myocarditis, as shown in endomyocardial biopsies (EMBs) from affected patients8,9. However, autoreactive T cells identified in patients with SLE so far, like autoantibodies, predominantly target nuclear proteins and lack tissue specificity10,11,12. This raises the question of whether non-tissue-specific autoantibodies or autoreactive T cells alone are sufficient to drive myocarditis development in SLE or whether other immunological factors are required.

In innate immunity, type I interferons (IFN-I) are well-established cytokines involved in SLE pathogenesis. It is known that nucleic-acid-containing immune complexes bind to endosomal Toll-like receptors (TLRs), followed by the activation of downstream signaling pathways and the production of IFN-É‘, a subtype of IFN-I, in both plasmacytoid dendritic cells and non-hematopoietic cells in patients with SLE13. IFN-I is believed to contribute to further inflammation and tissue damage13. In addition, the deficiency of complement proteins, another component of innate immunity, is associated with increased susceptibility to SLE, as impaired clearance of apoptotic cells and autoantigens promotes autoantibody production and immune complex formation14. Even in patients with SLE without complement deficiencies, low levels of complement C3 or C4 are often observed due to their consumption during active inflammation requiring immune complex formation14. However, no studies so far have demonstrated lupus myocarditis specifically associated with IFN-I or complement in SLE.

The cardiac myosin heavy chain (MyHC), encoded by the MYH6 gene, is a well-known heart-specific antigen and can be targeted by both autoreactive T cells and autoantibodies in various forms of myocarditis15,16. Recent studies have revealed that hyperactivation of MyHC-specific T cells, caused by blocking the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway, contributes to the onset and progression of immune checkpoint inhibitor (ICI)-associated myocarditis in both patients and murine models17,18. In addition to MyHC, several other heart-specific proteins such as adenine nucleotide translocator 1 (ANT1), β1-adrenergic receptor (β1AR), cardiac troponin I (cTnI), muscarinic M2 receptor (M2R) and sarcoplasmic/endoplasmic reticulum Ca2+ adenosine triphosphatase 2a (SERCA2a) have been proposed as autoantigens that can activate cellular and humoral immunity, leading to myocarditis development19,20. Interestingly, some SLE mouse models that developed myocarditis exhibited elevated anti-MyHC antibody titers21,22,23,24. This may suggest a potential role of autoimmunity against heart-specific antigens in lupus myocarditis, although there are limited studies.

In this Review, we highlight key drivers in the pathogenesis of lupus myocarditis, with a focus on the adaptive immune system. We provide the latest insights into autoantibodies and autoreactive T cells associated with primary SLE and autoimmune myocarditis across clinical and preclinical studies. Furthermore, we propose a potential mechanism underlying lupus myocarditis and discuss antigen-specific regulatory T (Treg) cells as a potential targeted therapeutic strategy.

Challenges in the diagnosis of lupus myocarditis

The clinical manifestations of lupus myocarditis often overlap with those of viral myocarditis, with common symptoms including chest pain, arrhythmia and palpitations, complicating differential diagnosis25. Although EMB is the diagnostic gold standard, its invasive nature and associated procedural risks limit its use in routine clinical practice26. To address this, noninvasive diagnostic approaches, such as cardiac imaging, serologic immune markers and circulating biomarkers, are currently used, clinically tested or under development5.

Echocardiography can detect structural and functional abnormalities, including arrhythmias, myocardial infarction and conduction disturbances27,28. However, its findings are generally nonspecific and insufficient for a definitive diagnosis of lupus myocarditis without supportive evidence29,30. Advanced approaches such as cardiac magnetic resonance imaging (CMRI) and positron emission tomography provide more sensitive and detailed assessments, yet their application in lupus myocarditis remains constrained29,30. Many patients suspected of lupus myocarditis also present with concomitant lupus nephritis, where renal impairment precludes the safe use of contrast agents31,32. Furthermore, patients with severe cardiac dysfunction may be unable to perform the breath-holding maneuvers required for CMRI scanning33.

Serologic immune markers may provide complementary diagnostic support in lupus myocarditis. Notably, it has been reported that anti-SSA antibodies are detected at a higher prevalence in patients with lupus myocarditis than in those with SLE without cardiac involvement34. Similarly, cardiac injury biomarkers such as troponin and creatine kinase may be elevated during lupus myocarditis, although both markers lack specificity and must be cautiously interpreted in conjunction with other clinical and imaging findings31,32,33,34. Thus, these challenges highlight the need to better understand the cellular and molecular mechanisms underlying lupus myocarditis to facilitate the development of safer, more reliable and clinically convenient diagnostic strategies, as well as targeted therapeutic and preventive approaches.

Contribution of autoantibodies to lupus myocarditis pathogenesis

Hallmark SLE autoantibodies targeting nuclear antigens

Autoantibodies against nuclear antigens such as dsDNA, SSA, SSB, RNP and Sm are commonly detected in patients with SLE, although disease manifestation, severity and progression are widely heterogeneous7 (Fig. 1). In lupus myocarditis cases, clinical studies have shown that anti-dsDNA antibodies are present in over 70% of patients, while the positivity for anti-SSA, anti-RNP and anti-Sm antibodies widely varies between 20% and 70%35,36,37,38. By contrast, anti-SSB antibodies tested positive in relatively fewer patients (less than 23%) compared with other antibodies35,36,37,38. Among these autoantibodies, the cardiotoxicity of anti-SSA autoantibodies has been recognized. The titer of anti-SSA antibodies in patients with lupus myocarditis was a significant predictor for fibrosis and necrosis in the heart, confirmed by late gadolinium enhancement on CMRI, with high sensitivity and specificity38. Patients who tested positive for anti-SSA antibodies exhibited a significantly higher prevalence of myocarditis and conduction defects than those who tested negative34. Beyond myocarditis, a large population-based study showed that anti-SSA and anti-SSB seropositivity is associated with an increased risk of ischemic heart disease, particularly in patients under 40 years39. In addition, the occurrence of arrhythmia was strictly associated with anti-SSA autoantibody levels in adult patients with connective tissue disease (CTD)40. In neonatal cases, multiple studies have reported that anti-SSA autoantibodies can be passively transferred from pregnant mothers to fetuses, accumulate in fetal cardiac tissue and cause lethal congenital heart block41,42.

Fig. 1: Key players in the pathogenesis of lupus myocarditis.
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The activation of antibodies (Abs) and T cells targeting nuclear antigens such as double-stranded DNA (dsDNA), Sjögren’s syndrome A (SSA), Sjögren’s syndrome B (SSB), ribonucleoprotein (RNP) and Smith (Sm) is initiated by apoptotic cells, contributing to the development of lupus myocarditis. In addition, cardiac antigen-specific autoantibodies and autoreactive T cells, targeting cardiac MyHC, cardiac troponin I (cTnI) and β1-adrenergic receptor (β1AR), play a pathogenic role by damaging cardiomyocytes. MyHC-specific T cells can further differentiate into tissue-resident memory T (TRM cells in the heart. Some anti-nuclear antigen antibodies may recognize cardiomyocytes as an antigen through cross-reactivity to calcium (Ca) channels. The development of autoreactive T cells is associated with the expression of susceptible human leukocyte antigen (HLA) alleles and the presentation of neoself-antigens due to loss or decrease of invariant chain (Ii) expression. Furthermore, antiphospholipid antibodies bind directly to cardiolipin and β2 glycoprotein I (β2GPI) on endothelial cells and platelets, driving cardiovascular inflammation.

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As a potential mechanism, anti-SSA antibodies are known to recognize the Ro52 protein on the surface of apoptotic cells, forming immune complexes that stimulate IFN-I production43. In addition, anti-SSA and anti-SSB autoantibodies promoted the production of tumor necrosis factor (TNF) in macrophages, eliciting inflammation44. However, because nuclear antigens are ubiquitously expressed across all organs, it is still unclear how autoantibodies against them can contribute to specifically myocarditis and other cardiac complications in patients with SLE. As a clue, it has been reported that anti-SSA and anti-SSB autoantibodies can cross-react with cardiac L-type and T-type calcium channels, inhibiting calcium current and disrupting calcium homeostasis in the heart41,45 (Fig. 1). Despite the cross-reactivity, previous studies have shown that serum levels of anti-SSA and anti-SSB autoantibodies were comparable between patients with SLE with or without myocarditis36,37,38. This suggests that additional mechanisms may drive the accumulation and pathogenic activity of anti-nuclear antigen autoantibodies, warranting further investigation in future research.

Autoantibodies against phospholipid

Antiphospholipid autoantibodies are the hallmark of antiphospholipid syndrome (APS), which is an autoimmune thrombo-inflammatory disease frequently complicated in patients with SLE46. Among these antibodies, anti-cardiolipin and anti-β2 glycoprotein I (β2GPI) antibodies as well as lupus anticoagulant are known to be detected in approximately 50% or fewer patients with lupus myocarditis, suggesting their pathogenic role35,36,37,38 (Fig. 1). Some studies showed that the level of antiphospholipid autoantibodies is comparable between patients with SLE with or without myocarditis37,38. However, a study by Ramirez et al. revealed that the presence of anti-β2GPI antibodies was more frequent in patients with SLE with myocarditis compared with those without myocarditis and that anti-β2GPI positivity was significantly correlated with lupus myocarditis onset36. Interestingly, in this study, the authors speculated that the increase of anti-β2GPI antibodies in patients with lupus myocarditis is due to a history of APS, suggesting the involvement of cardiovascular complications of APS36. A preclinical study reported that B6.sle1.sle2.sle3 triple congenic mice, a well-established SLE model, develop myocarditis when treated with resiquimod, a TLR7/8 agonist47. This model also showed elevated levels of autoantibodies targeting cardiolipin and β2GPI, suggesting their roles in lupus myocarditis pathogenesis (Table 1). Beyond myocarditis, the presence of lupus anticoagulant in SLE patients was significantly associated with myocardial fibrosis, as detected by CMRI48. Another study demonstrated that increased anti-cardiolipin autoantibody level is strongly associated with other cardiac complications such as valvular lesions, pericardial involvement and myocardial dysfunction in patients with SLE49. It is also reported that the positivity of antiphospholipid antibodies in early SLE is associated with subsequent vascular events such as venous thrombosis, pulmonary embolism, coronary disease and cerebrovascular attack50.

Table 1 Murine models for studying lupus myocarditis.
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It is well known that patients with primary APS experience cardiac complications such as valvular disease and acute myocardial infarction51. Mechanistically, in patients with APS, anti-β2GPI autoantibodies create immune complexes associated with thrombotic events and also directly bind to endothelial cells and platelets, followed by the initiation of the coagulation cascade46. Furthermore, these autoantibodies can activate the innate immune system such as complement, monocytes and neutrophils, indicating their potential contribution to inflammation beyond thrombosis in the heart and vasculature46. Indeed, several case reports have shown the development of acute myocarditis in patients with APS positive for antiphospholipid antibodies, further supporting their potential pathogenic role in lupus myocarditis52,53.

Autoantibodies specific for cardiac antigens

Autoantibodies targeting heart-specific antigens such as MyHC, cTnI and β1AR have long been studied to understand the pathogenesis of autoimmune myocarditis, not limited to SLE conditions19 (Fig. 1). Anti-MyHC autoantibodies are detected in the serum of patients with various cardiac inflammatory conditions, including autoimmune myocarditis, viral myocarditis and myocardial infarction54,55,56. In addition, these antibodies are detected in 42–52% of EMB samples from patients with myocarditis, supporting their pathogenic role in the heart57. However, because anti-cardiac antigen antibodies are not routinely tested in patients with SLE, there is limited clinical evidence connecting these autoantibodies to lupus myocarditis. A case report showed that anti-MyHC antibodies were detected in patients with SLE with constrictive pericarditis, but no studies so far have shown their presence in lupus myocarditis58. Despite the lack of clinical studies, several animal models support a link between anti-MyHC autoantibodies and lupus myocarditis (Table 1). MRL and MRL.lpr mice, well-established SLE mouse models, spontaneously developed autoimmune myocarditis with a high titer of anti-MyHC antibodies when the PD-1/PD-L1 pathway was genetically blocked21,22. Similarly, Trex1-deficient mice or C57BL/6, FVB and NOD (CFN) mice (a triple cross between C57BL/6, FVB and NOD strains), both models for SLE and other autoimmune diseases, developed myocarditis along with the presence of MyHC-specific autoantibodies23,24. These findings highlight the need for further research into the role of anti-MyHC autoantibodies in lupus myocarditis pathogenesis.

A recent study using an advanced proteomics approach identified novel heart-specific antigen candidates potentially targeted by autoantibodies in lupus myocarditis: disco-interacting protein 2 homolog A (DIP2A), LIM domain 7 (LMO7), poliovirus receptor (PVR) and plasminogen activator, urokinase receptor (PLAUR)59. In this study, engineered human cardiac tissues were developed using human induced pluripotent stem cells to assess the cardiotoxicity of immunoglobulin G fractions from patients with lupus myocarditis59. The study showed direct binding of patient immunoglobulin G to stressed cardiac tissues, leading to impaired calcium handling and mitochondrial function in cardiomyocytes as well as increased proliferation of fibroblasts. These findings strongly suggest the pathogenic role of heart-specific autoantibodies in lupus myocarditis pathogenesis and highlight the potential of advanced techniques for identifying antigen targets.

Pathogenic role of T cells in lupus myocarditis

Autoreactive T cells targeting nucleoproteins

T cells play a crucial role in the pathogenesis of SLE by producing inflammatory cytokines, stimulating autoantibody secretion in B cells and contributing to autoimmune memory60. Studies have demonstrated that T cells in patients with SLE are chronically activated due to altered epigenetic regulation, oxidative stress and metabolic dysfunction61,62. Under SLE conditions, the expression of T cell receptor subunit cluster of differentiation 3ζ (CD3ζ) is downregulated, while the Fcε receptor Iγ (FcεRIγ) chain is upregulated, leading to inappropriate hyperactivation of downstream signaling pathways and aberrant T cell stimulation63. Mechanistically, DNA hypomethylation, lipid raft abnormally enriched with gangliosides, mammalian target of rapamycin (mTOR) pathway activation and elevated glycolysis are known to contribute to T cell hyperactivation in SLE64,65,66,67.

Similar to hallmark autoantibodies, U1-RNP70 and other nucleoproteins have been studied as autoantigens targeted by T cells in SLE at both clinical and preclinical levels. Clinical studies have reported that nuclear antigens such as U1-RNP70, SmD1, histones, SSA and SSB are recognized by CD4+ T cells in patients with SLE, resulting in cytokine production including interleukin (IL)-17, IL-10 and IFN-γ10,11,12 (Fig. 1). These T cells are detectable not only in peripheral blood mononuclear cells but also in urine, suggesting their potential as novel biomarkers10. The significance of autoreactive T cells specific for these nuclear proteins in SLE has been confirmed in animal studies. In murine SLE models, including NZB×NZW F1 and MRL.lpr mice, unprimed CD4+ T cells were activated in response to U1-RNP70 peptides, leading to autoantibody production in B cells against the same antigen12,68. In addition, histone proteins and SSB were recognized by autoreactive T cells in SWR×NZW F1 lupus mice and in vitro murine T cell stimulation assays, respectively69,70. Besides nuclear proteins, vimentin and annexin 2 have been identified as targets of autoreactive CD4+ T cells in patients with lupus nephritis71.

U1-RNP70 is a well-established nucleoprotein and known as a primary target of hallmark autoantibodies in mixed CTD (MCTD), a rheumatological disease that primarily affects the skin and muscles, and largely overlaps symptoms and pathophysiology with SLE72,73. Similar to SLE, autoreactive T cells targeting the U1-RNP70 antigen have been identified in patients with MCTD12,74. Notably, myocarditis has been known as one of the cardiovascular complications in MCTD, evidenced by case reports75,76. This suggests that U1-RNP70-specific autoreactive T cells may be a key driver in the onset and progression of myocarditis due to both SLE and MCTD conditions. However, U1-RNP70 is one of the ubiquitous nuclear proteins across all different tissues, and the mechanisms underlying its heart specificity remain unclear.

Cardiac antigen-specific TRM cells

MyHC represents a critical self-antigen involved in autoimmune myocarditis (Fig. 1). The MYH6 gene encoding MyHC is notably absent in medullary thymic epithelial cells, which are essential for the thymic negative selection of T cells recognizing tissue-restricted self-antigens15. Consequently, MyHC-specific T cell clones can avoid negative selection and migrate to the periphery, potentially becoming cardiac-specific autoreactive T cells15. The presence and pathogenicity of MyHC-specific autoreactive T cells have been studied in various inflammatory cardiac conditions, including viral myocarditis, autoimmune myocarditis, ICI-associated myocarditis and dilated cardiomyopathy15,17,77. Supporting these findings, extensive research in murine models has consistently confirmed autoreactive T cells targeting MyHC as critical players in autoimmune myocarditis15,17,18,78,79,80. Despite accumulating evidence emphasizing the pathogenic role of MyHC-specific autoreactive T cells, their involvement and underlying mechanisms in lupus-associated myocarditis remain largely understudied, highlighting a significant gap for future research efforts. Previous animal studies using lupus-prone mice showed that pathogenic T cells drive spontaneous myocarditis development in MRL, MRL.lpr and Trex1-deficient mice, as well as resiquimod-induced autoimmune myocarditis in CFN mice21,22,23,24. Although the antigenic target of these T cells has not been identified, humoral autoimmunity against MyHC was confirmed by antibody profiling in their studies21,22,23,24 (Table 1). These findings suggest the involvement of MyHC-targeting autoreactive T cells in lupus myocarditis pathogenesis as well as autoantibodies. Moreover, clinical and animal studies identified that ANT1, β1AR, SERCA2a and cTnI can be antigenic targets for T cells in autoimmune myocarditis19.

Tissue-resident memory T (TRM) cells are a subset of memory T cells that reside in peripheral tissues without recirculation and provide immediate immune responses upon re-exposure to antigens81. Clinical studies have revealed the significance of CD8+ or CD4+ TRM cells in various autoimmune diseases, including Crohn’s disease, rheumatoid arthritis, encephalomyelitis and cutaneous lupus erythematosus82,83,84,85. Several studies identified CD8+ TRM cells in the kidneys of patients and mice with lupus nephritis, suggesting the potential role of TRM cells in SLE pathogenesis86,87,88. Remarkably, a recent study discovered heart-resident TRM cells in the pericardial effusion of patients with ischemic or dilated cardiomyopathy, characterized by CD69, PD-1 and CXC chemokine receptor 6 (CXCR6) expression89. This study also shows through mouse experiments that a previous history of subclinical cardiac inflammation or ischemic injury can induce the recruitment and expansion of cardiac TRM cells, ultimately resulting in active myocarditis when immune tolerance was later disrupted by ICI treatment89. Furthermore, MyHC-specific autoreactive T cells were one of the subsets in these cardiac TRM cells89. These findings suggest that primary adverse cardiac events, even if mild or subclinical, can contribute to the development of pathogenic cardiac TRM cells as a risk factor and that a subsequent wave of autoimmunity or immune dysregulation can then activate these T cells, driving the progression of active myocarditis. Although the specific role of MyHC-targeting T cells or cardiac TRM cells in lupus myocarditis remains unknown, SLE conditions may contribute to either or both the initial cardiac damage that recruits TRM cells and later immune-related events that activate them. Future research should focus on elucidating the precise mechanisms by which heart-targeting TRM cells contribute to cardiac manifestations in SLE.

MHC and autoantigen presentation

The major histocompatibility complex (MHC), also known as human leukocyte antigen (HLA), is expressed on the cell surface to present self or foreign antigens to T cells. A strong association between HLA class II alleles and autoimmune disease has been extensively studied, suggesting activated autoreactive T cells and compromised Treg cells as potential mechanisms90 (Fig. 1). The HLA-DQA1*01:02, HLA-DRB1*03:01 and HLA-DRB1*15:01 alleles have been linked to an increased risk or prevalence of SLE across diverse racial groups91,92,93. In heart diseases, the HLA-DQB1*03:01 allele has been reported at a higher frequency in patients with idiopathic dilated cardiomyopathy, as evidenced by the development of spontaneous myocarditis in transgenic mice expressing this allele94,95,96. These studies identified the presence of autoantibodies and autoreactive T cells against MyHC in mice with myocarditis94,95. Interestingly, in patients with SLE, the HLA-DQB1*03:01 allele has also been associated with lupus anticoagulant positivity, a hallmark antibody of APS97. Another study reported a link between lupus anticoagulant and myocardial fibrosis, a potential consequence of myocarditis, in patients with SLE48. These findings suggest a possible pathogenic connection between specific HLA haplotypes, autoantibodies and myocarditis in patients with SLE.

A recent study by Mori et al. has proposed a novel mechanism for SLE pathogenesis, suggesting that the absence or downregulation of the invariant chain (Ii) enables MHC class II to present neoself-antigens to autoreactive T cells, contributing to disease development98 (Fig. 1). Under normal conditions, Ii prevents the binding of unwanted peptides and unfolded proteins to the groove of MHC class II molecules and drives the MHC class II into the endosomal–lysosomal pathway, where antigen peptide binding occurs99. Based on this mechanism, neoself-antigens that can activate heart-targeting autoreactive T cells in patients with SLE with impaired Ii chain may become a critical driver in the onset and progression of lupus myocarditis.

Potential mechanisms underlying lupus myocarditis

Based on current knowledge, we propose a two-stage model for the mechanisms driving lupus myocarditis (Fig. 2). In the first stage, initial heart damage arising from viral infections, autoimmunity, ischemic injuries or pre-existing cardiac conditions leads to cell death and exposure of nuclear antigens (Fig. 2a). In some patients with SLE, this damage directly activates nuclear antigen-targeting antibodies and T cells, resulting in lupus myocarditis development. Specifically in the context of autoimmunity at this stage, the cross-reactivity of anti-SSA antibodies with cardiac antigens or the binding of antiphospholipid antibodies to cardiac endothelial cells may directly induce apoptosis of heart-resident cells or cause tissue damage through immune complex formation41,45,46. It is known that primary myocarditis, typically caused by viral infections, is often subclinical and self-limiting in healthy individuals100. Similarly, some patients with SLE may not progress to active myocarditis or may experience only mild disease due to limited initial damage at the first stage. However, in these patients, autoreactive T cells specifically targeting cardiac antigens may still be recruited to the heart and persist as TRM cells89. Particularly, MyHC-specific autoreactive T cells can be developed and recruited following initial cardiac injury, as these T cells bypass the thymic negative selection15.

Fig. 2: Proposed two-stage pathogenesis model for lupus myocarditis.
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a In the initial stage, adverse events such as viral infections, autoimmunity, ischemic injuries and pre-existing cardiac conditions cause primary heart damage. This damage exposes nuclear antigens (Ag), activating lupus hallmark antibodies (Abs) and autoreactive T cells, which contribute to lupus myocarditis development. Even in individuals who do not progress to myocarditis, cardiac antigen-specific autoreactive T cells can still be recruited and expanded. Some of these cells reside in the heart as TRM cells. b In the second stage, immune dysregulation such as lupus flares, immunotherapies and genetic/epigenetic predisposition triggers cardiac TRM cell activation, further driving lupus myocarditis. Lupus hallmark autoAbs and autoreactive T cells exacerbate myocarditis.

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In the second stage, systemic immune dysregulation, triggered by lupus flares, immunotherapies and genetic/epigenetic predisposition, can hyperactivate cardiac TRM cells in patients with SLE, leading to active myocarditis (Fig. 2b). TRM cells expressing CD69 and/or CD103 have been identified in the kidneys of patients and mice with lupus nephritis, suggesting their presence and pathogenic role in the heart under SLE conditions86,87,88. The PD-1/PD-L1 pathway is a key immune tolerance mechanism to restrict cardiac TRM cell activation89. PD-1 inhibitor treatment, a cancer immunotherapy, markedly increased the frequency and severity of myocarditis in mice enriched with cardiac TRM cells compared with mice with no enrichment89. This is supported by a clinical report of myocarditis in a patient with SLE following ICI therapy101. Interestingly, genetic studies revealed that the PD1.3 polymorphism has been linked to increased SLE susceptibility, whereas PD1.6 is associated with decreased risk, indicating the contribution of PD-1 variants to loss of TRM regulation and lupus myocarditis pathogenesis102,103. In addition, abnormal activation of mTOR signaling in SLE may predispose patients to lupus myocarditis by promoting the development of cardiac antigen-specific TRM cells104. A study revealed that inhibition of mTOR signaling limits TRM cell formation by reducing effector T cell accumulation in the periphery105. Beyond cardiac TRM cells, autoantibodies and autoreactive T cells specific for nuclear antigens can further amplify inflammation in the heart through epitope spreading at the second stage (Fig. 2b). New antigens, most likely nuclear proteins, released from damaged cardiac cells at the first or second stage generate additional autoreactive B and T cell responses, exacerbating lupus myocarditis106,107.

In additoin, T cells recognizing neoself-antigens in patients with Ii chain downregulation are expected to play a critical role in lupus myocarditis development at both stages98. In the first stage, these T cells can directly damage cardiac tissue through recognizing cardiac-specific neoself-antigens, leading to the exposure of nuclear antigens. After priming, they may persist as inactive TRM cells in the heart. Upon systemic flare conditions at the second stage, they can become highly activated, contributing to lupus myocarditis pathogenesis.

Protective role of Treg cells in lupus myocarditis

Imbalance between regulatory and effector T cells

Treg cells are essential for maintaining immune homeostasis, and an imbalance between Treg cells and effector T (Teff) cells contributes to autoimmune disease pathogenesis108. In patients with SLE, reduced frequency and function of Treg cells have been observed, while pathogenic Teff cells and their cytokine production were increased109,110,111. Metabolic dysregulation is suggested as a key factor driving T cell imbalance in SLE. It is known that the mTOR signaling pathway downregulates immunosuppressive function and forkhead box P3 (FoxP3) expression in Treg cells, indicating an overactivated mTOR signaling pathway in SLE conditions as a mechanism underlying reduced Treg cell development and function112. By contrast, mTOR signaling pathway activation is strongly associated with the hyperactivation of pathogenic T cells in SLE66. A clinical study showed that IL-21 produced by activated Teff cells, specifically helper T (TH) 17 cells, further compromises Treg cell development and function in patients with SLE113.

The balance between Treg and Teff cells is also important in cardiovascular health. A clinical study showed that patients with chronic heart failure had a reduced number of Tregs that did not recover even after 6 months of cardiac resynchronization therapy114. These patients exhibited persistent inflammatory conditions characterized by increased cytotoxic T lymphocytes despite therapy114. Similarly, patients with autoimmune myocarditis and its sequela, dilated cardiomyopathy, showed reduced Treg cells, along with elevated TH1 and TH17 cell populations and their inflammatory cytokine production77,115. The imbalance between Treg and TH17 cells in both viral myocarditis and autoimmune myocarditis was further confirmed in mouse models116,117. One of these studies using single-cell ribonucleic acid (RNA) sequencing analysis revealed the predominance of TH17 cells and cytotoxic T lymphocytes in the heart with myocarditis, despite the presence of Treg cells117. Moreover, adoptive transfer of CD4+ T cell populations with Treg cell depletion induced fatal myocarditis and multiorgan autoimmune inflammation in BALB/c nude mice118. In SLE conditions, impaired Treg cell generation and immunoregulatory function, coupled with increased Th17 cell differentiation and expansion, may create a highly proinflammatory environment that promotes myocarditis development.

Therapeutic potential of Treg cells

Treg cell supplementation has been investigated as a potential cell-based immunotherapy for autoimmune diseases, which are characterized by a reduced number and impaired function of Treg cells108. The transfer of autologous polyclonal Treg cells to patients with various autoimmune conditions has shown benefits, including slowed disease progression. In the clinical trial NCT03241784, patients with amyotrophic lateral sclerosis who received autologous ex vivo expanded Treg cells exhibited reduced clinical progression with increased circulating Treg cell number and immunosuppressive function119. Similarly, after adoptive transfer of Treg cells to a patient with ulcerative colitis, the clinical activity disease score decreased from 7 to 2, along with enriched Treg cells in the gut120. Treg cell therapy has also been widely tested in preclinical animal models of both SLE and cardiovascular diseases. In lupus-prone NZB×NZW F1 mice, the adoptive transfer of ex vivo expanded Treg cells improved renal disease, proteinuria and mortality rate, possibly by restoring the balance between Treg and Teff cells121,122. Furthermore, Treg cell therapy protected mice from cardiovascular diseases such as hypertension, vascular inflammation, atherosclerosis and viral myocarditis through the reduction of heart antigen-specific autoimmunity, the resolution of inflammation involving both innate and adaptive immunity and the restoration of cardiovascular function123,124,125. These findings suggest that adoptive transfer of Treg cells may serve as a potential therapeutic strategy for lupus myocarditis by reestablishing immune balance and mitigating inflammation.

Antigen-specific Treg cells as a potential cell-based immunotherapy for lupus myocarditis

Antigen-specific Treg cells

Beyond the use of autologous Treg cells, antigen-specific Treg cell therapy has emerged as a targeted approach for autoimmune diseases. Single antigen-specific Treg cells might exhibit improved immunosuppression and tissue protection compared with polyclonal Treg cells due to precise organ targeting, increased antigen specificity and reduced off-target effects126. It is reported that more than 25 clinical trials have been conducted to explore the benefits of antigen-specific Treg cell therapy in treating various immune-related diseases such as type 1 diabetes, Crohn’s disease and graft-versus-host disease126. In the Crohn’s and Treg Cells Study (CATS1) clinical trial, researchers investigated the efficacy of ovalbumin-specific Treg cells in patients with refractory Crohn’s disease127. Six to eight weeks after transfer of antigen-specific Treg cells, 40% of patients showed clinical improvement with a reduction in inflammatory monocytes127. Notably, for lupus nephritis treatment, engineered human Treg cells that can specifically target the Sm antigen, a nucleoprotein involved in SLE, have been generated and shown enhanced antigen specificity and immunosuppressive activity compared with polyclonal Treg cells, as well as their therapeutic potential in a humanized mouse SLE model128. Although no studies have yet reported antigen-specific Treg cell therapy for heart diseases, cardiac antigen-specific Treg cells may be a promising candidate for a targeted cell-based therapeutic approach for various inflammatory cardiac conditions, including lupus myocarditis.

CAR-T cell and CAR-Treg cell therapies

Chimeric antigen receptor (CAR)-T cells are engineered T cells equipped with an antigen receptor composed of a single-chain variable fragment that efficiently recognizes a specific extracellular antigen, triggering downstream intracellular signaling pathways for further T cell activation129. CAR-T cells were originally developed to target tumor antigens for cancer treatment and approved by the Food and Drug Administration, but they are currently being adapted for autoimmune disease treatment126,130. In the context of SLE, CD19 is a promising target of CAR-T cell therapy because it is selectively expressed on B cells and plasmablasts, the primary producers of anti-nuclear antigen and anti-dsDNA autoantibodies. Preclinical studies have exhibited that anti-CD19 CAR-T cells effectively deplete B cells in lupus-prone mice, leading to improved lupus nephritis131,132 (Table 2). Clinically, anti-CD19 CAR-T cell therapy combined with lymphodepletion with fludarabine and cyclophosphamide has successfully improved clinical symptoms in patients with SLE by resetting the immune system and normalizing lupus-related parameters133. No significant adverse effects on major organs have been observed between 4 and 29 months after this therapy, although the patient sample size has been limited134. Nevertheless, the anti-CD19 CAR-T cell approach may only be effective for SLE driven primarily by B cells and plasmablasts, whereas its therapeutic benefit is limited in autoimmune conditions mediated by plasma cells or T cells, both of which lack CD19 expression. Furthermore, an increased risk of infections may be a limitation of CAR-T cell therapy.

Table 2 Comparison between different CAR-T cell therapies for lupus myocarditis treatment.
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Another promising strategy for reducing autoreactive inflammation in autoimmune diseases is CAR-Treg cells, which involves antigen-specific Treg cells designed for enhanced targeting and immunoregulatory function. In a recent study, CAR-Treg cells specific for the myelin oligodendrocyte glycoprotein peptides, a well-established antigen in multiple sclerosis, showed successful localization in the central nervous system, effective suppression of pathogenic Teff cells and delayed disease onset in mice with experimental autoimmune encephalomyelitis135. For SLE treatment, human CAR-Treg cells targeting the B cell antigen CD19 (Fox19CAR-Treg) were developed and adoptively transferred into humanized mice136 (Table 2). This CAR-Treg cell therapy effectively resolved inflammation in the lungs and kidneys through the reduction of circulating B cells and autoantibody production136. Given these findings, CAR-Treg cells targeting MyHC or other cardiac antigens could represent a promising therapeutic strategy for lupus myocarditis treatment (Table 2). The cardiac antigen-specific CAR-Treg cell approach would provide selective immunoregulation within the heart, protecting against lupus myocarditis. It can also potentially benefit other autoimmune cardiac disorders, not limited to B cell-driven pathology. However, cardiac antigen-specific CAR-Treg therapies would not address SLE symptoms in other organs and are at an early conceptual stage.

Conclusion

SLE is a heterogeneous autoimmune disease that can affect single or multiple organs simultaneously, posing significant challenges for diagnosis and treatment137. Despite extensive research identifying diverse cellular and molecular pathways contributing to SLE, tissue-specific autoantigens or disease mechanisms remain largely unknown138,139,140. The hallmark lupus autoantibodies play a critical role in SLE pathogenesis6. However, they primarily target nuclear antigens ubiquitous across organs and cells without tissue specificity, indicating the limitation in their diagnostic and therapeutic utility.

Myocarditis is one of the most severe cardiovascular complications of SLE4. Although the use of corticosteroids has significantly reduced the incidence of lupus myocarditis since 1975, the mortality rate remains remarkably high, between 10% and 23%4. Mechanistically, hallmark SLE antibodies and T cells may contribute to lupus myocarditis by recognizing nuclear antigens exposed by initial cardiac damage or cross-reactive targets in the heart. However, not all patients with lupus myocarditis test positive for these autoantibodies, and studies report no differences in their titers between patients with SLE with and without myocarditis, suggesting additional pathogenic mechanisms remain undiscovered35,36,37,38.

Autoimmunity against MyHC has long been investigated as a key mechanism driving autoimmune myocarditis19. The recent emergence of ICI-associated myocarditis has further highlighted the pathogenic role of MyHC-specific autoreactive T cells in autoimmune myocarditis across both clinical and preclinical settings17,18. However, the role of adaptive immunity targeting MyHC and other cardiac antigens in lupus myocarditis remains understudied. In this Review, we propose a two-stage model for lupus myocarditis pathogenesis: (1) an initial phase driven by anti-nucleoprotein antibodies and T cells and (2) a secondary phase involving autoimmunity against both nuclear and cardiac antigens (Fig. 2). However, evidence is currently insufficient to validate this model. To advance our understanding of lupus myocarditis, robust investigations incorporating both clinical and animal studies are required.

Identifying heart-specific antigens, along with their corresponding autoreactive T cells and autoantibodies, may provide a novel avenue for diagnosis and treatment of lupus myocarditis. MyHC or other heart antigens already identified could serve as promising therapeutic targets. Advanced molecular techniques such as single-cell RNA sequencing, spatial transcriptomics and proteomics hold promise for better elucidating the complex mechanisms underlying lupus myocarditis.