Poster Presentation 18th International Symposium on Dendritic Cells 2026

IFN-I–driven Ly6Chi myeloid cell expansion and anti-SSA/Ro autoimmunity are associated with myocardial injury in lupus (#226)

Haiting Wang 1 2 3 , Siqi Zhao 1 , Liling Zhao 1 , Jie Chen 1 , Grozdan Cvijetic 2 , Anatasia du Halgouet 2 , Harrison Wang 2 , Erfan Jabari 2 , Jordan Reaves 3 , Michael Stack 4 , Zhaoyuan Liu 5 , Florent Ginhoux 5 6 , Shuang Ye 1 , Mariana Kaplan 3 , Roxane Tussiwand 2 7
  1. Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  2. Immune Regulation Unit, National Institutes of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD, USA
  3. Systemic Autoimmunity Unit, Nataional Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD, USA
  4. Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD, USA
  5. Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  6. Gustave Roussy, Paris-Saclay University, Villejuif, France
  7. Immune Regulation, Life and Medical Sciences (LIMES) Institue, University of Bonn, Bonn, Germany

Background/Purpose

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody-mediated immune injury affecting multiple tissues. Cardiac involvement occurs in over 50% of patients, yet immune-mediated lupus myocarditis (LM) remains poorly understood despite its severe prognosis. Here, we sought to identify and stratify newly diagnosed SLE patients at high risk for cardiac involvement and define the immunopathogenic mechanisms underlying lupus-associated myocardial injury.

Methods

We analyzed a hospitalized cohort of newly diagnosed SLE patients. After excluding alternative causes of cardiac dysfunction, we compared 42 patients with reduced left ventricular ejection fraction (LVEF ≤55%) with 329 patients with preserved LVEF (>55%). We also used a TLR7 agonist–induced lupus model, genetically modified mice, lineage tracing, and single-cell analyses to investigate myocardial injury and myeloid cell responses.

Results

Patients with reduced LVEF showed markedly increased mortality (6/42 vs. 9/329, P = 0.0002) and were characterized by higher levels of circulating inflammatory markers compared with those with preserved LVEF. Notably, 24% (10/42) of patients with reduced LVEF fulfilled diagnostic criteria (HLH-2004) for macrophage activation syndrome (MAS), defining a distinct high-risk cardio-MAS phenotype associated with extremely poor outcomes (mortality 6/10 vs. 0/32, P<0.0001). Anti-SSA/Ro antibodies were significantly enriched in patients with reduced LVEF compared with patients with preserved LVEF (76% vs. 53%, P = 0.0083). Anti-SSA/Ro antibodies recognize two antigens, Ro52 (TRIM21) and Ro60. TRIM21 is an interferon-inducible E3 ubiquitin ligase involved in type I interferon (IFN-I) responses. In newly diagnosed SLE, peripheral blood mononuclear cells (PBMCs) bulk RNA-seq revealed stronger IFN-I pathway activation and higher TRIM21 expression in anti-Ro52+ patients compared with anti-Ro52- patients, implicating the anti-Ro52–IFN-I axis in disease pathogenesis.

Repeated treatment with the TLR7 agonist resiquimod (R848) induced lupus-like features, including IFN-I pathway activation, hyperinflammation, autoantibody production, and myocardial injury. High-dimensional immune profiling revealed an expansion of Ly6Chi myeloid cells (Lin- F4/80+ CD64- Ly6Chi CCR2+) in the hearts of female mice. This accumulation was absent in R848-treated IFNAR1 KO mice, indicating its dependence on IFN-I signaling. Lineage analysis identified cardiac Ly6Chimyeloid cells comprising CD319⁺Zbtb46GFP⁺ MDP–ProDCs, CD319⁺Zbtb46GFP⁻ MDP-derived monocytes, and CD177⁺Ms4a3Cre RosatdTomato⁺ GMP-derived monocytes. In vivo adoptive transfer indicated that type I IFN skewed both GMP and MDP differentiation toward monocytes. Single-cell analyses of bone marrow and heart identified MDP-derived CD319⁺ monocytes as a highly IFN-I-responsive population relative to other myeloid subsets. To investigate how anti-Ro52 autoimmunity may contribute to myocarditis, we studied a spontaneous autoimmunity model (Id3 KO) and a Ro52 immunization model. Anti-Ro52 titers positively correlated with serum cardiac troponin I (TnI), while CD319⁺ MDP-derived cells expanded in the hearts of mice in both models. These findings suggest that this IFN-I-responsive population may cooperate with anti-Ro52 antibodies to promote myocardial injury.

Conclusion

In summary, our study identifies a subset of newly diagnosed SLE patients at high risk for myocardial damage, characterized by a MAS phenotype and enrichment of anti-SSA/Ro antibodies. Experimental findings implicate IFN-I–associated cardiac myeloid cell accumulation and anti-Ro52 autoimmunity in myocardial injury, with CD319⁺ MDP-derived cells emerging as potential contributors.